Department of Health and Human Services
Part 1. Overview Information

 

Participating Organization(s)

National Institutes of Health (NIH)

United States Department of Agriculture (USDA)

Components of Participating Organizations

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Funding Opportunity Title

Development of Biomarkers of Dietary Intake and Exposure (U2C Clinical Trial Required)

Activity Code

U2C Resource-Related Research Multi-Component Projects and Centers Cooperative Agreements

Announcement Type

New

Related Notices
None 
Funding Opportunity Announcement (FOA) Number

RFA-DK-20-005

Companion Funding Opportunity

RFA-DK-20-007, U24 Resource-Related Research Projects – Cooperative Agreements

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

93.847; 10.310

Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement is to invite applications from multidisciplinary teams to establish Dietary Biomarkers Development Centers that explore and develop metabolomics-based dietary intake biomarkers. 

Key Dates

 

Posted Date

July 2, 2020

Open Date (Earliest Submission Date)

September 21, 2020

Letter of Intent Due Date(s)

September 21, 2020

Application Due Date(s)

October 21, 2020

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.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

February/March 2021

Advisory Council Review

May 2021

Earliest Start Date

July 2021

Expiration Date

October 22, 2020

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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


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

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



  3. Table of Contents

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

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


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

    Adoption of sustained healthy dietary habits and dietary patterns is critical for preventing and delaying the onset of a variety of chronic diseases including obesity, diabetes, cardiovascular disease and cancer. Nutritional epidemiological studies explore the role of dietary constituents in human health and disease. Dietary exposure information, which is crucial for establishing such associations, is often derived from self-reported 24-hour dietary recalls, Food Frequency Questionnaires (FFQ), food diaries and other similar dietary intake assessment instruments. However, these instruments are often subject to a variety of systematic and random measurement errors. In addition, these measurements are further limited by incomplete food composition databases that are used for converting the intake information to examine the associations. There is a critical need for objective biomarkers of dietary intake that can serve as independent markers of dietary intake and complement current dietary intake assessment methods. While nutrient biomarkers have been extensively explored, their utility in the clinical research is limited, and non-nutrient dietary constituents are not well integrated into the dietary biomarker discovery pipeline. Moreover, metabolic transformation of dietary constituents, especially the non-nutrients by host and microbial metabolism has not been efficiently harnessed into this pursuit. Unbiased metabolomics platforms especially Liquid Chromatography-Mass Spectrometry (LCMS)- based approaches present an unprecedented opportunity for measuring both nutrient and non-nutrient metabolites, based on their chemical composition, giving us larger chemical space to explore. A recent workshop convened by the NIH has explored the potential of omics approaches especially metabolomics for dietary biomarker development.  The workshop report can be found here: https://academic.oup.com/advances/article/11/2/200/5544358.  

    Research Objectives

    This FOA invites applications for establishing Dietary Biomarker Development Centers (DBDCs). These DBDCs comprised of multidisciplinary teams will have the necessary expertise and demonstrated experience in conducting dietary intervention and assessment studies, biostatistical analysis of dietary intake data, metabolomics and bioinformatics for exploring metabolomics-based dietary biomarkers of intake and exposure. Specifically the applicants will be responsible for generating an initial set of metabolite signatures for major food groups or specific food types as described by USDA https://www.choosemyplate.gov/, in response to controlled feeding to a small group of study volunteers. Biological samples such as urine and blood from these participants will be analyzed for candidate dietary biomarkers of intake and exposure, employing untargeted LCMS-based metabolomics. They will also characterize initial biomarker properties and performance such as dynamic range by analyzing the biospecimens, for example blood and urine, collected before and after intervention and/or the half-life of the dietary metabolites. In a follow-up study, these biomarkers will be evaluated for predicting recent and habitual consumption, using multiple dietary recalls and food diaries. The performance of the biomarkers will also be compared with the current benchmark predictive markers such as 24-hour urinary analysis of protein and/or sodium or energy intake. These biomarkers may also be compared in mixed meal diets or in specific dietary patterns, if appropriate. Final validation and/or ability of these biomarkers to predict both recent and habitual consumption of dietary components will be conducted preferably in independent cohorts along with 24-hour dietary recalls and food records and other benchmark biomarkers. It is anticipated that the applicants will take advantage of existing infrastructures for dietary intervention studies such as metabolic kitchens and dietary assessment expertise; have access to ongoing larger cohort studies and have the capability to collect and store biological samples from dietary intervention studies. The applicants can propose a variety of study designs including controlled feeding studies, crossover, nested case control, and randomized clinical trials as appropriate for moving the dietary biomarkers through the development process.

    Organization of the DBDCs: In order to facilitate the dietary biomarkers development, the DBDCs will have the following organizational components. Each DBDC will comprise four cores namely, an Administrative Core (AC), an Intervention Core (IC), a Metabolomics Core (MC) and a Data Analysis Core (DAC). These cores support the Biomarkers Project (BP) for developing dietary biomarkers. The DBDCs and their members must be willing to collaboratively work together and with the consortium (see below).  

    Administrative Core (AC): The Administrative Core will oversee the overall performance of the DBDC and is responsible for overall management of the DBDC. The Director of this core will serve as the contact PI and will lead the DBDC. S/he will work closely with intervention, metabolomics, and data analysis cores to lead the dietary biomarkers project and will develop necessary protocols and procedures for the center. The Director of this core is also responsible for the overall planning and coordination of the project and management of the center and working with other DBDCs, DCC, NIH and USDA (Consortium, see below).  

    Intervention Core (IC): Intervention Core (IC) will lead and be responsible for all the tasks related to the dietary intervention and clinical study components of the study. It is anticipated that this core will have the necessary expertise for designing and implementing dietary interventions, conducting controlled feeding studies, running metabolic kitchens, collecting biological specimens and other clinical data from the participants. This core is also responsible for developing and administering dietary intake assessment instruments to the participants and collecting the dietary intake data. This core will function harmoniously with the AC and support the PI of the DBDC in conducting the center goals. It is also expected that the Director and this team will work collaboratively with the consortium during the entire project. Along with other members of the consortium, the IC core will participate in the planning phase, provide leadership and expert advice in developing common strategies for the study design, making necessary collective decisions for the selection of food groups, for which dietary biomarkers will be developed and participate in developing common protocols. They will also continue to work with consortium members collaboratively in exchanging ideas, expertise, resources and data as needed, after the project commences.

    Metabolomics Core (MC): This core is responsible for analyzing the biological specimens, employing state of art LCMS- based metabolomics platforms, performing necessary quality control measures, harmonizing, curating and annotating the metabolite biomarkers. The Director of this core will have demonstrated expertise in conducting large population-based metabolomics studies and overseeing the data analysis and coordination with the DCC. The Director of this core and the team will work with the PI of the DBDC in developing manual of operations and other standard operating procedures for the DBDC. This core will also work with the consortia members in providing leadership for developing optimal biological specimen collection strategies for metabolomics assays, devising plans for the analysis of specimens, procedures for data quality control measures, curating and annotating the metabolomics data.

    Data Analysis Core (DAC): This core is responsible for providing statistical expertise and for evaluating the performance of the biomarkers developed in the pipeline. The Director of this core will participate in the consortium-wide planning activities and provide necessary advice in developing common strategies and protocols for the dietary intervention. This core will work with the other DBDCs and DCC in determining the final statistical analytical strategies for the biomarker analysis and performance. This core will provide statistical expertise for determining the sample size with appropriate power analysis for each phase of dietary biomarker development project and devise necessary recruitment and retention strategies. Once the project commences, this core will be responsible for managing the data entry, cleaning and analyzing the data generated by the respective DBDC. This core will also devise an initial data analysis strategy for comparing the dietary biomarker performance as opposed to the dietary intake assessment data and against benchmark biomarker data. During the project implementation, this core will continue to provide statistical expertise to evaluate the biomarker performance.  

    Biomarkers Project (BP): It is anticipated that the Biomarkers Project will follow three phases. An initial set of metabolite signatures for each of major food groups as described by USDA https://www.usda.gov/media/blog/2017/09/26/back-basics-all-about-myplate-food-groups will be generated in a controlled feeding study of recruited volunteers. The properties such as half-life of the metabolite or pharmacokinetics and initial performance of the biomarkers will also be analyzed in this phase.  In the second phase, the performance of these biomarkers for dietary components - either as  single dietary intervention or as part of larger dietary patterns - will be evaluated and compared with dietary intake assessments, such as multiple 24-hour dietary recalls and food diaries, along with other benchmark predictive markers, such as 24-h urinary analysis of protein and sodium or energy intake. Final validation and/or ability of these biomarkers to predict habitual consumption will be conducted preferably in independent cohorts along with 24-hour dietary recalls and food records and other benchmark biomarkers. The DBDC investigators are expected to provide a detailed state of art dietary biomarkers development plan, which is supported by robust preliminary data, sound scientific basis, expertise and available resources.

    It is anticipated that the proposed projects will be mostly conducted as single site studies. However, the DBDCs will follow similar dietary intervention protocols, common analysis strategies, milestones and timelines developed by the consortium as described below.

    Consortium activities: In order to strategically plan and execute the dietary biomarkers project across the funded DBDCs, there is a critical need for collaborative effort among the DBDCs. In order to facilitate these collaborative activities, a Data Coordinating Center (DCC) will be funded separately with a companion FOA (RFA-DK-20-007). DBDCs along with the DCC and NIH and USDA staff will comprise the ‘Dietary Biomarkers Development Centers consortium’s' Steering Committee (SC). The DCC will be responsible for the overall coordination of the consortium and support the development of study design and protocol development, protocol implementation, and data analysis. The Steering Committee will work together to facilitate the planning process and to conduct the study implementation support.

    It is anticipated that the awardees will participate in a planning phase during the first six months of the award. In this phase, the awarded teams will work collaboratively with each other, with the DCC and with the staff of NIDDK and USDA-NIFA, for developing common dietary intervention strategies based on the collective methods proposed by the DBDCs. While, each DBDC will be responsible for carrying out the proposed Biomarkers Project, they will also be guided by common strategies developed across the consortium. The information provided by the awardee in the applications will serve as the initial basis for these discussions in the planning phase. The consortium will develop common strategies, milestones and timelines for the dietary biomarkers project. In order to accomplish this, the consortium will develop common intervention strategies and study designs across the centers to interrogate metabolite markers in different food types. They will develop common analytical strategies for performing metabolomics assays and data analysis and strategies for determining the candidate biomarkers. They will also develop the strategies for comparing the performance of biomarkers with appropriate dietary assessment instruments and other gold standard biomarkers. Plans for data harmonization and curation will be developed during the planning phase. Regarding dietary components and food groups, it is anticipated that it is almost impractical to develop biomarkers for all the food groups by a single Center. A divide and conquer strategy will be employed by dividing up the food groups/food types between the funded sites to cover a broad range of food groups. The DBDCs will be responsible for generating the metabolite data, initial analysis and deposition in the DCC along with the metadata and raw data such as relevant spectral libraries.  Once the candidate dietary biomarkers have been identified, the teams will decide on appropriate strategies for further exploring the performance of biomarkers for individual dietary components or as part of specific dietary patterns. It is expected that DBDCs will deliberate and decide on common strategies employed for biomarker discovery, evaluation, validation and analysis methods. Some of the biomarker development strategies are expected to be site-specific, particularly some of the dietary interventions.

    The DCC will coordinate both the planning and implementation phases and lead the discussions on study design, protocol development, implementation, and data analysis. The DCC will be responsible for creating a dietary biomarkers database along with the metadata. The DCC will work with the DBDCs to ensure seamless data deposition, data quality and completeness. It will also conduct independent analysis of the data. It is expected that all the data generated by the consortium will be made publicly available as per NIH and NIDDK data sharing policies, by conforming to best practices for data safety and accessibility.

    Steering Committee:                                                                                                          

    The Steering Committee (SC) is comprised of investigators of the DBDCs, DCC, and the program staff from NIH and USDA-NIFA and serves as the main governing body for the study. The SC is primarily responsible for the general planning, developing study protocols, metabolomics analysis and data analysis plans and other study related procedures and manual of operations. Investigators of the individual DBDCs, the DCC, the project scientists from NIDDK and the USDA will hold one vote each for any action item that requires voting. The SC will initiate appropriate working groups for efficient management of the consortium. In addition, the SC will develop various policies for the consortium for the implementation strategies. These may include procedures for modification of study design, analysis of study samples and data, publication and presentation of study findings, monitoring study progress, determining completeness and quality of data collection, and other performance measures. The SC will conduct regular phone calls for accomplishing consortia tasks and meeting the milestones. It is expected that the Steering Committee will meet a minimum of two times in person, in Bethesda, MD region during the planning phase, one time soon after the award of the grants and another time at the end of first six months for finalizing the dietary intervention strategies. The SC will also meet once annually during the implementation of the project. They will also engage in regular teleconferences and other interactive discussions driven by science and consensus of the consortium. It is anticipated the PD/PIs of the DBDCs and DCCs are actively engaged in all the consortia related activities during the entire duration of the study.

    In accordance with NIDDK data sharing policies, all dietary biomarker data produced by the consortium will be made publicly available, following current best practices regarding data safety and privacy policies. It is also expected that data will be stored in standardized formats in appropriate data repositories.

    While eligible applicant institutions may apply for both the DBDCs and DCC components of this program, the PD/PI cannot be the same individual(s).

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

    Section II. Award Information

     

    Funding Instrument

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

    Application Types Allowed

    New

    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.

    Clinical Trial?

    Required: Only accepting applications that propose clinical trial(s)

    Need help determining whether you are doing a clinical trial?

    Funds Available and Anticipated Number of Awards

    NIDDK intends to commit $1,800,000 for fiscal year 2021 to fund one award.

    USDA-NIFA intends to commit $2,000,000 for fiscal year 2021 to fund one to two awards.

    Award Budget

    Application budgets are limited to one million in direct costs per year.

    Award Project Period

    The maximum project period may not exceed 5 years.

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

    Section III. Eligibility Information
    1. Eligible Applicants
    Eligible Organizations

    Higher Education Institutions

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

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

    o   Hispanic-serving Institutions

    o   Historically Black Colleges and Universities (HBCUs)

    o   Tribally Controlled Colleges and Universities (TCCUs)

    o   Alaska Native and Native Hawaiian Serving Institutions

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

    Nonprofits Other Than Institutions of Higher Education

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

    For-Profit Organizations

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

    Governments

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

    Other

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

    Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
    Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

    Required Registrations

    Applicant Organizations

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

    • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
    • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • o   NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. 
    • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
    • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

    Program Directors/Principal Investigators (PD(s)/PI(s))

    All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

    Eligible Individuals (Program Director/Principal Investigator)

    Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

    For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

    2. Cost Sharing

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

    3. Additional Information on Eligibility
    Number of Applications

    Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

    The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

    • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
    • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
    • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).
    Section IV. Application and Submission Information
    1. Requesting an Application Package

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

    2. Content and Form of Application Submission

    It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

    Letter of Intent

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

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

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

    The letter of intent should be sent to:

    John F. Connaughton, Ph.D.
    Chief, Scientific Review Branch
    National Institute of Diabetes and Digestive and Kidney Diseases
    Telephone: 301-594-7797
    Email: NIDDKletterofintent@mail.nih.gov

    Page Limitations

    Available Component Types

    Research Strategy/Program Plan Page Limits

    Overall

    12 pages

    Administrative Core (AC)

    6 Pages

    Intervention Core (IC)

    6 Pages

    Metabolomics Core (MC)

    6 Pages

    Data Analysis Core (DAC)

    6 Pages

    Biomarker Project (BP)

    6 Pages

    Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed

    Instructions for the Submission of Multi-Component Applications

    The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

    The application should consist of the following components:

    • Overall: Required, (Minimum: 1 Maximum of 1)
    • Administrative Core (AC): Required, (Minimum: 1 Maximum of 1)
    • Intervention Core (IC): Required, (Minimum: 1 Maximum of 1)
    • Metabolomics Core (MC): Required, (Minimum: 1 Maximum of 1)
    • Data Analysis Core (DAC): Required, (Minimum: 1 Maximum of 1)
    • Biomarkers Project (BP): Required, (Minimum: 1 Maximum of 1)
    Overall Component

    When preparing your application, use Component Type ‘Overall’.

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

    SF424 (R&R) Cover (Overall)

    Complete entire form.

    PHS 398 Cover Page Supplement  (Overall)

    Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

    Research & Related Other Project Information (Overall)

    Follow standard instructions.

    Other Attachments: The following items should be included as attachments under 'Other Attachments'.

    Milestone Plan: The filename "Milestone Plan.pdf" should be used.

    Applicants are required to provide detailed interim performance measures and timelines for completing key objectives and administrative functions for the proposed planning phase (first six months of the first year) and the dietary biomarker project, as applicable. The Milestone plan is separate and distinct from the Study Timeline, which should be included in the Research Strategy.  Milestones should be easily measurable and realistic.

    Milestones may include, as applicable, but are not limited to:

    • ·    Finalization of the protocol, recruitment plan and consent forms;
    • ·    Finalization of a manual of operations;
    • ·    Preparation of data forms and database for clinical data;
    • ·    Standardization of outcome measures to be shared by all clinical sites;
    • ·    Approval of study documents by a DSMB and IRB;
    • ·    Execution of contracts/third party agreements;
    • ·    Plan for training of study staff.

    Statement of Willingness: Please title this attachment "Willingness to Participate". A statement of willingness may be provided to:

    • ·    Participate collaboratively in the DBDC consortium
    • ·    Work collaboratively with the NIDDK and USDA-NIFA staff, the DCC to participate in the initial and annual meetings thereafter during the grant award;
    • ·    Cooperatively interact with the NIDDK and USDA-NIFA staff, the DCC and other DBDCs and provide expert opinions during the planning phase for developing best strategies for the project and collectively come up with common strategies to be implemented across the consortium;
    • ·    Efficiently carry out the project during the implementation phase to produce quality data on dietary biomarkers, share and work with other DBDCs to analyze the data and identify candidate dietary biomarkers, and evaluate dietary biomarker performance;
    • ·    Deposit well curated data in a timely fashion to the DCC project activities related to dietary biomarkers development;
    • ·    Work collaboratively and collegially with the DCCs to deposit well curated data and associated metadata in a timely fashion for creating a dietary biomarkers database;
    • ·    Actively interact with DCC and provide guidance on the needs of the dietary biomarkers project that may arise during the performance of the project; and
    • ·    Participate in regular conference calls and other meetings organized by the DCC, attend planning and annual meetings.
    Project/Performance Site Location(s) (Overall)

    Enter primary site only.

    A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

    Research & Related Senior/Key Person Profile (Overall)

    Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

    A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

    Budget (Overall)

    The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.  

    A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

    PHS 398 Research Plan (Overall)

    Specific Aims:  Describe the overall focus and goals of the proposed DBDC, its organizational structure and functions along with the proposed biomarker project. 

    Research Strategy:

    The applicants should present a detailed organizational structure along with required components namely an Administrative Core (AC), an Intervention Core (IC), a Metabolomics Core (MC), and a Data Analysis Core (DAC). The applicants should also present a Biomarkers Project (BP) with a clear strategy for the development of biomarkers of dietary intake and exposure, along with the available resources and infrastructure employing untargeted LCMS-based metabolomics. The applicant should clearly articulate the significance of the proposed study and provide preliminary data to support dietary biomarker development strategy and indicate feasibility where appropriate. It is also important to describe any prior relevant experience related to dietary biomarkers exploration. It is expected that awardees will participate in a planning phase for the first six months of the project to plan and decide on the common strategies for the study designs, biospecimen analysis and data analysis that can be employed across the DBDCs for the Biomarkers Project. These decisions are largely driven by the expertise and experience of the consortia members and the resources and infrastructure available to them.  

    Activities in the planning phase include, but are not limited to:

    • Establishment and participation in a Steering Committee made of the key personnel from DBDCs and DCC and NIH ad USDA staff, and any needed subcommittees to work together as a consortium;
    • Agreement on necessary consortium policies, such as data sharing and safety or publication of data from shared study elements;
    • Finalization of the common elements of the study protocol(s), including biospecimen processing, analysis and data analysis protocols as necessary;
    • Development of consent form(s);
    • Development of manuals of operations which would include, but is not limited to, procedures, validation, and quality control for any clinical or laboratory/mechanistic testing which will be performed;
    • Development of a Data and Safety Monitoring Plan (DSMP). NIDDK will appoint a Data and Safety Monitoring Board (DSMB) to conduct oversight of the clinical trials. The DBDCs will implement similar but distinct protocols. It is expected that they will propose single site clinical studies and obtain local IRB approvals from their parent institutions;
    • Development of training materials and training/certification plans for study staff, if appropriate;
    • Other elements as necessary.

    Letters of Support:

    Letters of support from all the key collaborators should be included.

    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

    Generally, Resource Sharing Plans are expected, but they are not applicable for this component.

    Appendix:

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

    PHS Human Subjects and Clinical Trials Information (Overall)

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

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

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

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

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

    PHS Assignment Request Form (Overall)

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

    Administrative Core

    When preparing your application, use Component Type ‘Administrative Core.’

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

    SF424 (R&R) Cover (Administrative Core)

    Complete only the following fields:

    • ·    Applicant Information
    • ·    Type of Applicant (optional)
    • ·    Descriptive Title of Applicant’s Project
    • ·    Proposed Project Start/Ending Dates
    PHS 398 Cover Page Supplement (Administrative Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Administrative Core)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Administrative Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Administrative Core)
    • ·    In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘DBDC Director' and provide a valid eRA Commons ID in the Credential field.
    • ·    In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • ·    Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • ·    If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   
    Budget (Administrative Core)

    Budget forms appropriate for the specific component will be included in the application package.

    The minimum level of effort expected for the PI is 1.2 person months (10% effort). A program coordinator may support the PI, but the total, combined effort may not exceed 2.4 person months. No requests for the purchase of major equipment costing more than $5,000 will be supported. Travel costs for the entire DBDC include budget for two face to face meetings in the first year and one annual consortium meeting thereafter. Include travel costs for the DBDC Director and others as appropriate (i.e. co-Director, core Directors) to attend the annual SC meeting.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Administrative Core)

    Specific Aims: List the broad, long-range objectives of the proposed Core.   

    Research Strategy:

    This core is led by the PD/PI of the DBDC and is responsible for the overall planning and management of the site, coordination of the project across various components of the DBDC, and for the coordination with other DBDCs, DCC, NIH and USDA (Consortium). The PI is responsible for assembling highly talented multidisciplinary teams with appropriate and demonstrated expertise for the project. The PI also ensures that all the components work seamlessly and harmoniously across the center. This core will set the overall budgets for all the functioning cores and the dietary biomarker development project including the travel budget for the entire center.  The PI and the AC are expected to work with the Intervention Core for developing the study design, obtaining necessary approvals for the project, overseeing the implementation of dietary intervention studies, management of recruitment of the participants, collection of data and biospecimens, working with the Metabolomics Core for analyzing analysis of biospecimens, facilitating data analysis by the Data Analysis Core and ensuring the data deposition into the DCC database. 

    The PI is instrumental for assembling highly talented multidisciplinary teams with appropriate and demonstrated expertise for the project. The PI should present a clear plan for the Biomarkers Project and specific milestones for the DBDC. Applicants need to present a detailed strategy on how these functions will be planned, executed and managed. They will also present a timeline for the implementation of the entire project with appropriate milestones. It is anticipated that the awardees will be willing to participate in a consortium along with other DBDCs, DCC and NIH and USDA staff to develop dietary biomarkers, work collaboratively on common goals and develop common protocols and share the data within the consortium and with the public. The applicants are expected to present appropriate proof of their past collaborative experience and participation in large consortia.

    Letters of Support: Letters of support from all the key collaborators specific only for this core should be included.

    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

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

    Appendix:

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

     
    PHS Human Subjects and Clinical Trials Information (Administrative Core)

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

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

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

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

    Intervention Core

    When preparing your application, use Component Type ‘Intervention Core.’

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

    SF424 (R&R) Cover (Intervention Core)

    Complete only the following fields:

    • ·    Applicant Information
    • ·    Type of Applicant (optional)
    • ·    Descriptive Title of Applicant’s Project
    • ·    Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Intervention Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Intervention Core)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Intervention Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Intervention Core)

    • ·    In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
    • ·    In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • ·    Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • ·    If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

    Budget (Intervention Core)

    Budget forms appropriate for the specific component will be included in the application package.

    The Core Director must devote a minimum of 0.6 person months to the Core to ensure adequate oversight. No requests for the purchase of equipment more than $5,000 may be allowed. Clinical research and dietary intervention costs are allowed expenses.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Intervention Core)

    Specific Aims: List the broad, long-range objectives of the proposed Core.

    Research Strategy:

    This core is responsible for all the tasks related to the dietary intervention and clinical study components of the study. The Director of this core and the team will be responsible for developing the appropriate study designs, obtaining necessary approvals, recruitment subjects, implementation of the dietary intervention regimen, collection of participant baseline clinical data, dietary intake assessment information, collection of biological specimens and storage. The Director will allocate reasonable time necessary for managing this core. It is anticipated that this core will have necessary expertise and experience for designing and implementing dietary interventions, conducting controlled feeding studies, running metabolic kitchens, administering dietary intake assessment instruments and collecting data from the participants. This core will also have the necessary infrastructure for collection and storage of biological specimens, biorepositories for long-term storage and collecting other clinical data from the participants.

    Applicants are expected to present evidence for their expertise, experience in conducting dietary intervention studies, along with other relevant experience. A detailed description of the available resources should be provided for conducting dietary intervention studies, conducting controlled feeding studies, such as metabolic kitchens, dietary intake available resources for assessment instruments to the participants and collecting data.  They will also discuss the choice of dietary components that will be explored for biomarker development along with appropriate preliminary data. No budget requests for infrastructure are allowed. A detailed plan of the proposed dietary biomarker development project describing the study design, projected number of subjects to be recruited for each phase, the subject recruitment and retention strategies, data collection and biospecimen collection plans, storage of biospecimens and necessary Data Safety and Monitoring Plans (DSMP). However, the applicants should avoid duplication of information that will otherwise be submitted under the Clinical Trial Info Forms section https://grants.nih.gov/policy/clinical-trials/new-human-subject-clinical-trial-info-form.htm.

    Letters of Support: Letters of support from all the key collaborators specific only to this core should be included.

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

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

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

    PHS Human Subjects and Clinical Trials Information (Intervention Core)

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

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

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

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

    Metabolomics Core

    When preparing your application, use Component Type ‘Metabolomics Core.’

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

    SF424 (R&R) Cover (Metabolomics Core)

    Complete only the following fields:

    • ·    Applicant Information
    • ·    Type of Applicant (optional)
    • ·    Descriptive Title of Applicant’s Project
    • ·    Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Metabolomics Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Metabolomics Core)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s)(Metabolomics Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Metabolomics Core)

    • ·    In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
    • ·    In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • ·    Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • ·    If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.    

    Budget (Metabolomics Core)

    Budget forms appropriate for the specific component will be included in the application package.

    The Core Director must devote a minimum of 0.6 person months to the Core to ensure adequate oversight. No requests for the purchase of equipment more than $5,000 may be allowed.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Metabolomics Core)

    Specific Aims: List the broad, long-range objectives of the proposed Core.

    Research Strategy:

    This core is responsible for analyzing the biological specimens employing state of art LCMS- based metabolomics platforms, performing necessary quality control measures, harmonizing, curating and annotating the metabolite biomarkers. Applicants are expected to present evidence for their expertise, experience in conducting large metabolomics studies, and handling of large number of biological specimens especially from dietary intervention studies, if appropriate. The Director will allocate reasonable time necessary for managing this core. A detailed description of the available instrumentation and bioinformatics resources for data analysis should be provided. Detailed description on the metabolomics platforms that will be employed to capture the entire chemical space of dietary metabolites, quality control measures, data curation steps, harmonization and annotation methodologies and data analysis pipelines should also be provided. Prior experience of working with depositing data into larger databases and the ability to conform to variety of data deposition templates should also be presented, if applicable.  No equipment requests or other requests for instrumentation are allowed.    

    Letters of Support: Letters of support from all the key collaborators specific for this core should be included.

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

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

    Appendix:

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

    PHS Human Subjects and Clinical Trials Information (Metabolomics Core)

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

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

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

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

    Data Analysis Core

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

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

    SF424 (R&R) Cover (Data Analysis Core)

    Complete only the following fields:

    • ·    Applicant Information
    • ·    Type of Applicant (optional)
    • ·    Descriptive Title of Applicant’s Project
    • ·    Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Data Analysis Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Data Analysis Core)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Locations(s)(Data Analysis Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Data Analysis Core)

    • ·    In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
    • ·    In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • ·    Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • ·    If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

    Budget (Data Analysis Core)

    Budget forms appropriate for the specific component will be included in the application package.

    This category should include salary support for key personnel, including statistical support, database managers, and other staff necessary for the functioning of the Biomarker Project. No equipment more than $5,000 may be allowed. The Core Director must devote a minimum of 0.6 person months to the Core to ensure adequate oversight.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Data Analysis Core)

    Specific Aims: List the broad, long-range objectives of the proposed Core.     

    Research Strategy:

    This core will provide statistical expertise for determining the sample size with appropriate power analysis for each phase of dietary biomarker development and devise necessary recruitment and retention strategies. This core will also devise an initial data analysis strategy for comparing the dietary biomarker performance as opposed to the dietary intake assessment data and against benchmark biomarker data. During the project implementation, they continue to provide statistical expertise to evaluate the biomarker performance. It is also expected that this core will assist Administrative Core in facilitating the data transfer and data analysis to the DCC. Accordingly, it is expected that they will establish seamless working relations with the DCC.

    The applicant must describe various statistical methods to be employed, including detailed statistical plans for the sample size projections and power calculations, and for comparing biomarker performance with dietary intake assessment methods. The sample size and statistical power calculations should contain enough detail, including a discussion of assumptions made, so that a reviewer can readily duplicate the sample size projection. The power analysis should include a discussion of the anticipated rates of follow-up (i.e., drop out/lost to follow up) during key outcome collection contacts. A discussion of how missing data will be handled should be included. Any planned interim analyses should also be described. An explanation should be provided on how candidate biomarkers will be prioritized from the untargeted metabolomics analysis and how the biomarker performance will be evaluated. They will also provide various scenarios for determining the performance of dietary biomarkers and alternative strategies for combining biomarkers to enhance their performance either independently or in combination with dietary intake data. The Director will allocate reasonable time necessary for managing this core. 

    A clear description of how this component will work with the DCC for uploading the data and analysis.

    Letters of Support: Letters of support from the key collaborators specific only to this core should be included.

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

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

    Appendix:

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

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

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

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

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

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

    Biomarkers Project

    When preparing your application, use Component Type ‘Biomarkers Project.’

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

    SF424 (R&R) Cover (Biomarkers Project)

    Complete only the following fields:

    • ·    Applicant Information
    • ·    Type of Applicant (optional)
    • ·    Descriptive Title of Applicant’s Project
    • ·    Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Biomarkers Project)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Biomarkers Project)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Locations(s) (Biomarkers Project)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Biomarkers Project)

    • ·    In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
    • ·    In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • ·    Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • ·    If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   

    Budget (Biomarkers Project)

    Budget forms appropriate for the specific component will be included in the application package.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Biomarkers Project)

    Specific Aims: List the broad, long-range objectives of the proposed Core. 

    Research Strategy:  

    The Biomarkers Project is part of the Research Strategy and should include a clear and systematic rationale approach for the development of biomarkers of dietary intake and exposure, employing untargeted LCMS- based metabolomics. It is expected that the USDA https://www.usda.gov/media/blog/2017/09/26/back-basics-all-about-myplate-food-groups will be used as a starting point for selecting major food groups. A clear description on the choice of dietary components/food groups that will be explored for biomarker development along with appropriate preliminary data should be included. A detailed description on the study design with sample size calculations including power calculations for dietary interventions studies needs to be included for all the phases. Dietary biomarker validation strategies and biomarker performance analysis plans should be well articulated. Metabolomics analytical pipelines and data analysis strategies should also be clearly described. In addition, clear plans on how the DBDC will work collaboratively with other centers and consortium components should be described.  

    Letters of Support: Include Letters of Support only relevant to the project.

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

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

    Appendix:

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

    PHS Human Subjects and Clinical Trials Information (Biomarkers Project)

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

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

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

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

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

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

    4. Submission Dates and Times

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

    Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

    5. Intergovernmental Review (E.O. 12372)

    This initiative is not subject to intergovernmental review.

    6. Funding Restrictions

    All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

    Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

    7. Other Submission Requirements and Information

    Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

    For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

    Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

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

    Important reminders:

    All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

    See more tips for avoiding common errors.

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

    Use of Common Data Elements in NIH-funded Research

    Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies.  CDEs are data elements that have been identified and defined for use in multiple data sets across different studies.  Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records.  NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository).  NIH has established a “Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection.  The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.  Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

    Post Submission Materials

    Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

    Section V. Application Review Information
    1. Criteria

    Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

    A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

    For this Funding Opportunity Announcement, note the following:

    Reviewers will be asked to evaluate the overall Dietary Biomarkers Development Centers program (DBDC), individual cores and the Biomarkers Project (BP), emphasizing the following criteria. The overall impact score is not the average for these components.

    • Overall research strategy including the focus on dietary biomarkers development project, expertise of the entire research team, quality of research, collaborations among members, relevance to the DBDC's proposed research focus, and proposed implementation of the scientific program. 
    • Individual cores namely, Intervention Core, Metabolomics Core and Data Analysis Core, as stand-alone components of the DBDC, in addition to how well they are integrated to establish the DBDC and to carry out the Biomarkers Project, prior experience of the team in the dietary biomarker’s development.
    • The Administrative Core evaluation will include committee structure, DBDC management plans, and lines of communication. The qualifications and experience of the Investigator will also be part of this evaluation.
    • Biomarkers Project (BP) evaluation will include the study design, recruitment strategies, choice of proposed dietary interventions and scientific rigor with which the clinical studies will be conducted.
    • DBDC Director (PD/PI) evaluation will include past leadership experience and commitment to the stated goals and objectives of the DBDC.
    Overall Impact - Overall

    Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the DBDC 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 DBDC proposed).

    Scored Review Criteria - Overall

    Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a DBDC that by its nature is not innovative may be essential to advance a field.

    Significance

    Does the proposed DBDC address the needs of the Biomarkers Project that it will serve? Are the cores and the scope of their activities proposed for the DBDC appropriate for its needs? Will successful completion of the aims bring unique advantages or capabilities to the DBDC? Does the proposed DBDC address the needs of the field? Does the DBDC propose biomarker development strategies based on sound preliminary data?

    Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy?  For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

    Investigator(s)

    Are the PD(s)/PI(s) and other personnel well suited to their roles in the DBDC? Do they have appropriate experience, training, and demonstrated experience and an ongoing record of accomplishments in managing dietary biomarkers research? Do the investigators and key personnel of the cores have necessary expertise and are they well suited for the proposed Biomarkers Project? With regard to the proposed leadership for the DBDC, do the PD/PI(s) and other key personnel have the expertise, experience, and ability to organize, manage and implement the proposed dietary biomarker trial and meet milestones and timelines? Does the DBDC PI have experience overseeing selection and management of subawards, if needed? If the DBDC is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach, governance, plans for conflict resolution, and organizational structure appropriate for the DBDC? Is there evidence for the cores to collaborate for developing strategies for dietary biomarker development and sharing the data publicly?

    With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics?

    Innovation

    Does the application propose novel organizational concepts, management strategies, or instrumentation in coordinating the Dietary Biomarkers Development Centers program (DBDC) it will serve? Are the concepts, strategies, or instrumentation proposed by the DBDC and the individual cores novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts, management strategies or instrumentation proposed?

    Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

    Approach

    Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the Dietary Biomarkers Development Centers program (DBDC) it will serve? Will the investigators and the cores promote strategies to ensure a robust and unbiased scientific approach across the DBDC, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the dietary biomarkers development program is in the early stages of operation, does the proposed strategy adequately establish feasibility and manage the risks associated with the activities of the DBDC? Has an appropriate plan for workflow and a well-established timeline proposed? Have the investigators and the cores presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

    If the DBDC 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?  

    Does the application adequately address the following, if applicable?

    Study Design:

    Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

    Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity? Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

    Data Management and Statistical Analysis:

    Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

    Environment

    Are resources available within the scientific environment to support electronic information handling? Do the PD/PI multidisciplinary teams and the cores have all the resources needed for the project? Have they assembled appropriate cores and teams for the project?

    If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

    Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

    If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

    If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate

    Additional Review Criteria - Overall

    As applicable for the DBDC 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.

    Study Timeline:

    • Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment?
    • Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
    • Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
    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 Biomarkers 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

    Not Applicable.

    Renewals

    Not Applicable.

    Revisions

    Not Applicable.

    Additional Review Considerations - Overall

    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.

    Milestone Plan:

    Is the Milestone Plan, acceptable for the proposed DBDC?

    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 .


    Authentication of Key Biological and/or Chemical Resources

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

    Budget and Period of Support

    Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

    2. Review and Selection Process

    Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by National Institute of Diabetes, and Digestives and Kidney Diseases  in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

    As part of the scientific peer review, all applications:

    • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
    • Will receive a written critique.

    Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

    Applications will be assigned  to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Diabetes and Digestive and Kidney Diseases Advisory Council . The following will be considered in making funding decisions:

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

    After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

    Section VI. Award Administration Information
    1. Award Notices

    If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

    A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

    Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

    Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

    Project investigators whose applications are selected for USDA-NIFA funding will work with the USDA-NIFA program officials and follow USDA-NIFA policies and procedures for the award and grants administration for the duration of the project.

    Individual awards are based on the application submitted to, and as approved by the NIH and are subject to the IC-specific terms and conditions identified in the NoA. 

    ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

    Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all 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. 

    Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

    Prior Approval of Pilot Projects

    Awardee-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation. 

    The awardee institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.

    The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

    2. Administrative and National Policy Requirements

    All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

    Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights 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.

    Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency.  HHS provides 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/fact-sheet-guidance/index.html and https://www.lep.gov.  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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

    Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities.  Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

    HHS funded health and education programs must be administered in an environment free of sexual harassment.  Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf.  For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

    Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws.  Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions.  Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/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.    

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

    Cooperative Agreement Terms and Conditions of Award

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

    The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH and USDA 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. USDA-NIFA's purpose is to provide a consulting and supportive role for the success of the project(s). Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

    1. Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.

    2. Establishing a Steering Committee to implement, coordinate and manage the project(s). Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.

    3. Designating Protocol Chairs. The Program Directors/Principal Investigators (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the Program Director/Principal Investigator does not assume this role) for each protocol to be carried out by the study group. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Significant modifications to approved protocols must be approved by the Steering Committee.

    4. Implementing collection of data specified by the study protocol. For a multi-center study, each awardee/site is required to ensure that data will be submitted expeditiously to the Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.

    5. Establishing procedures for data quality and completeness. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to facilitate cooperation/referral of study participants by physicians to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple sites, a plan for analysis of pooled data will be developed by the Steering Committee.

    6. Submitting interim progress reports, when requested or agreed upon by both parties, to the NIDDK and USDA-NIFA Program Officials, where indicted, including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK and USDA-NIFA Program Officials may require additional information from individual awardees/sites. Such reports are in addition to the required annual noncompeting continuation progress report.

    7. Reporting of the study findings. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, NIH and USDA policies. The awardee must also be adherent to Study Publication and Presentation Policy. The NIDDK and USDA-NIFA will have access to and may periodically review all data generated under an award. NIDDK and USDA-NIFA staff may co-author publications of findings with awardees consistent with NIH and USDA study policies.

    8. Any third-party (including industry, academia, and foundations) collaboration should be governed by a research collaboration agreement (e.g., Clinical Trial Agreement, Research Collaborative Agreement) or any third-party contract mechanism(s) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH/NIDDK policies and procedures, and with written approval from NIDDK and USDA-NIFA Program staff. Any relevant proposed third-party agreements related to the network studies between grantee and third-party will be provided to the NIDDK Program staff and NIDDK Technology Advancement Office for review, comment, and approval to assure compliance with NIH/NIDDK policies and network policies. Further, at the request of the NIDDK and USDA-NIFA Program staff, any other network-relevant third-party agreements must be shared with NIDDK. Failure to comply with this term may prompt action in accordance with NIH Grants Policy Statement, Section 8.5 titled: “Special Award Conditions and Remedies for Noncompliance (Special Award Conditions and Enforcement Actions”, and Section 8.5.2, titled: “Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding Support”, noncompliance with the terms and conditions of award will be considered by the funding IC for future funding and support decisions and may result in termination of the award.”

    9. Any involvement of a third-party (including industry, academia, and foundations) in the study and network activities that includes access to any network study data and biospecimens, or study results that are not publicly available, or using the name of the network or study or the name of the NIH or NIDDK or USDA-NIFA, is permitted only after written permission by the NIDDK or USDA-NIFA Program staff, who will consult with others at NIH and NIDDK Technology Advancement Office.

    10. Study investigators are required to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and Steering Committee policies on publications.

    11. Maintaining confidentiality of information: The awardee(s) will maintain the confidentiality of the information developed by the investigators (e,g., protocols, data analysis, conclusions) as well as proprietary information of an individual company or other entity collaborating with the study. Any exception requires written approval from NIDDK and/or USDA-NIFA Program staff.

    12. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. Prior to enrolling participants, the PI or his/her designee will coordinate with the NIDDK Central Repository to develop a Data Sharing Plan and prepare the collected data for eventual archiving and distribution. In addition, if applicable, the PI or his/her designee will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, storage, and sharing of study samples that are to be maintained in the Repository. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study’s leadership will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently, samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing (http://grants.nih.gov/grants/policy/data_sharing/ and, https://grants.nih.gov/policy/sharing.htm, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm), as well as the NIDDK policy for data sharing in multi-center and large single-center clinical studies https://www.niddk.nih.gov/research-funding/human-subjects-research/policies-clinical-researchers.

    13. Study investigators are required to comply with NIH Policy on the Dissemination of NIH Funded Clinical Trial Information as stated at https://grants.nih.gov/policy/clinical-trials/reporting/understanding/nih-policy.htm. Per policy, the awardee is responsible for meeting the expectations of this policy. Refer to additional information at https://grants.nih.gov/policy/clinical-trials/reporting/index.htm.

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

    NIDDK and USDA-NIFA Project Scientists with substantial involvement will:

    1. Serve as the contact point for all facets of the scientific interaction with the awardee(s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK/USDA-NIFA staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Project Coordinator, who will provide direct technical assistance to the awardees to optimize the conduct and/or analysis of the study, or who may assist in the coordination of activities across multiple sites.

    2. For multi-center studies, participate in the Steering Committee that oversees study conduct. The NIDDK and USDA-NIFA Project Scientist or Project Coordinator will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.

    3. Serve as a resource to study investigators with respect to other ongoing NIDDK and USDA-NIFA activities that may be relevant to the study to facilitate compatibility with the NIDDK/USDA-NIFA missions and avoid unnecessary duplication of effort.

    4. Have substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below:

    a. Assisting by providing advice in the management and technical performance of the investigations, coordinating required regulatory clearances for investigational agents used in the study, which are held by NIDDK and USDA-NIFA. The NIDDK and USDA-NIFA may reserve the right to cross file or independently file an Investigational New Drug Application or an Investigational Device Exemption form with the FDA.

    b. The NIDDK and USDA-NIFA Project Scientists or Project Coordinators may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.

    c. Reviewing procedures for assessing data quality and study performance monitoring.

    d. The NIDDK and USDA-NIFA Project Scientists or Project Coordinators may be co-authors on study publications. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results; and (d) preparation and authorship of pertinent manuscripts.

    The NIDDK and USDA-NIFA Program Officials identified in the Notice of Award will:

    Interact with the Program Director(s)/Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include regular communications with the Program Director/Principal Investigator and staff; periodic site visits; observation of field data collection and management techniques; quality control; fiscal review, and other relevant matters; as well as attendance at Steering Committee, Data Safety and Monitoring Board (DSMB), and related meetings. The NIDDK retains, as an option, periodic review of progress by researchers not involved with the study.

    Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.

    The NIDDK/USDA-NIFA Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; (f) low likelihood of showing a benefit of the intervention (futility); and (g) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure except as specifically approved by the NIDDK and USDA-NIFA.

    Make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

    Appoint an independent Data and Safety Monitoring Board (DSMB) as appropriate for Phase III clinical trials or other high-risk studies, or an Observational Study Monitoring Board (OSMB) for observational/epidemiologic studies; these Boards will review study progress, safety data, and interim results, as appropriate, and provide guidance to the NIDDK. The NIDDK Program Official or their Project Coordinator will serve as the Executive Secretary and/or NIDDK program representative on the DSMB/OSMB.


    Areas of Joint Responsibility include:

    In addition to the interactions defined above, NIDDK Project Scientist and Awardees shall share responsibility for the following activities:

    Steering Committee

    A Steering Committee organized by the study investigator(s) will be the main governing body of the study.

    The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among awardees, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK and USDA-NIFA Program Official and will provide periodic supplementary reports upon request.

    The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), (including those of data coordinating /statistical centers, if any) and co-investigators as deemed necessary, and the NIDDK and USDA-NIFA Project Scientists. The final structure of the Steering Committee and voting procedures will be established at the first meeting. The NIDDK and USDA-NIFA Project Scientists will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.

    A Chairperson of the Steering Committee, other than the NIDDK and USDA-NIFA Project Scientists, will be selected by the NIDDK, in consultation with the Steering Committee. The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings, representing the study group to the External Oversight Committee established by the NIDDK, and by interacting closely with the awardees during protocol development and implementation.

    Dispute Resolution

    Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK and USDA-NIFA may be brought to dispute resolution. A dispute resolution panel will be composed of three members: one selected by the awardee (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.

    3. Reporting

    When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

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

    Section VII. Agency Contacts

    We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

    Application Submission Contacts

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

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

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

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

    Scientific/Research Contact(s)

    Padma Maruvada, Ph.D.
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    Telephone: 301-594-8884
    Email: maruvadp@mail.nih.gov

    Helen Chipman, Ph.D.

    United States Department of Agriculture- National Institute of Food and Agriculture (USDA-NIFA)

    Telephone:202-701-3524

    Email: helen.chipman@usda.gov

    Peer Review Contact(s)

    Lan Tian, Ph.D.

    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    Telephone: 301-496-7050

    Email: tianl@nih.gov

    Financial/Grants Management Contact(s)

    Sharon Bourque
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    Telephone: 301-594-8846
    Email: bourques@mail.nih.gov

    Awards Management Division (AMD)

    United States Department of Agriculture- National Institute of Food and Agriculture (USDA-NIFA)

    Email: SM.AMDAdministrativeContacts@usda.gov

    Section VIII. Other Information

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

    Authority and Regulations

    Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.  

    All funds granted by USDA-NIFA under this FOA shall be expended solely for the purpose for which the funds are granted in accordance with the approved application and budget, the regulations, the terms and conditions of the award, the applicable Federal cost principles, the Department's assistance regulations and the NIFA General Awards Administration Provisions consistent with 7 U.S.C. 3319b and subsection (b) of section 2 of the Competitive, Special, and Facilities Research Grant Act (7 U.S.C. 3157(b)), as amended by section 7504 of the Agriculture Improvement Act of 2018 (Pub. L. 115-334).

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