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

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

This FOA is designed to enable development and pilot testing of assays that will facilitate the wider use of genome integrity investigation into epidemiological and population studies. Epidemiological, clinical, or population investigations involving human subjects focused on associations between environmental stressors and the risk of environmentally influenced disorders should be integrated with supporting studies of assay development.

Genome integrity research is a cornerstone of environmental health. More intimate knowledge of the variation among people in the cellular pathways that maintain genomic stability against a constant barrage of chemical and lifestyle stressors is needed to fulfill the promise of Precision Medicine to better predict individual disease and to direct effective treatment. Significant mechanistic advances have been achieved in the laboratory and a variety of diseases have been linked to insufficiencies of known genome integrity pathways. For example, Xeroderma pigmentosum, a hypersensitive skin condition that is among the most studied environmental diseases, results from a defect in one of seven nucleotide excision repair genes or in the gene coding for polymerase eta. Recent clinical and population studies suggest that insights on genome integrity pathways can inform measures of disease risk as well as treatment protocols.

The knowledge of individual repair capacity is beginning to be applied, as in predicting which patients will respond positively to chemotherapeutic drugs, such as temozolomide, and further research holds great promise to reveal intimate details about disease risk. However, while investigation in the area is leading to important and clinically useful steps, the translation of knowledge from the laboratory to prevention strategies and the clinic has not been fully realized. Presenting a roadblock to translation is the dearth of epidemiology studies that explore the functional variation among individuals or populations in responding to DNA damage, in removing DNA adducts or accumulating mutations or chromosomal damage that influence disease risk, or undergoing mutagenesis and sequence rearrangements that influence disease risk. Furthermore, only a handful of reports include functional analyses, the most accurate indication of an exposure - induced response. In addition, many studies are limited in scope, for example, to determination of genetic polymorphisms associated with genome integrity and/or disease. Admittedly, the labor-intensive and costly methods to monitor genome integrity currently available likely contribute to the apparent absence of population studies. However, the resultant lack of population studies integrating these potentially informative measures with other factors limits our understanding of the fundamental cellular response to environmental exposures.

Through earlier initiatives, NIEHS has taken steps to bridge the gap from laboratory advances to population studies which have assisted in establishing several promising methods of determining genome integrity capacity. These include the Comet-Chip (J. Ge, et al. J. Vis. Exp. 2014. 18;92), DNA Repair Beacons (D. Svilar, et al. J Vis Exp. 2012. 6;66.), and the Multiplex Flow-Cytometric Host Cell Reactivation Assay (Z.D. Nagel, et al. Proc. Natl. Acad. Sci. USA. 2014. 111:E1823.). The Comet-Chip is commercially available and field testing in human populations is a critical next step.

Based on the compelling needs to advance this area, NIEHS convened a Workshop on New Approaches for Detecting Environmentally-induced DNA Damage & Mutations in Population Studies (June 11 - 12, 2015) to guide translational genome integrity research. The Workshop included experts in environmental health, epidemiological approaches, and basic scientists who have been pioneering genome integrity assays. This current FOA is based on the findings of that panel, the overriding recommendation of which was to promote development of functional genome integrity capacity assays leading to new insights into individual and population susceptibilities. A commentary based on the discussions is available (Nagel, et al. Mutat. Res. 2017. 800-802:14-28).

This FOA is technological in nature and supports a framework for basic scientists and epidemiologists to work together to improve on existing and/or new genome integrity tools to meet the needs of epidemiological studies. For the purpose of this FOA, genome integrity refers to DNA repair (BER, NER, DR, DDR, etc.), genome instability (as indicated by, e.g., micronuclei formation), and mutagenesis linked to exposures and variations in DNA repair capacity. Relevant assays include measures of overall DNA repair capacity or of individual repair pathways; mutagenesis; genome instability; as well as innovative measures of repair at the chromosomal level provided that the endpoint reflects individual capacity to prevent or respond to damage. Adduct formation as an endpoint in and of itself, primarily as a measure of exposure to endogenous or exogenous chemicals rather than a measure of response will not be considered responsive to this announcement. However, applications that consider upstream toxicological pathways that regulate relative capacity of individuals to resist or are permissive for adducts may be permitted if well justified. High priority will be given to development of functional assays that can be performed directly on tissues of interest for a disease entity or that aim to demonstrate strong correlations of activities in the target tissue with that of accessible biosamples (blood, skin, buccal tissue, etc.). Methods that require small amounts of tissue, as well as single cell technologies, are strongly encouraged. The relevance of proposed assay results to genome integrity in tissues of interest and for environmental health and disorders should be considered.

Applications should aim to expand understanding of environmental diseases or exposure effects with the additional knowledge that genome integrity assays will bring. Transdisciplinary research should focus on a common research theme related to the role of environmental exposures. NCI is interested in applications focused on DNA repair assays that relate to cancer risk and outcomes. As appropriate, the project should also facilitate integration of laboratory and human research to collectively increase understanding of the contribution of genome integrity variation and environmental factors to understand risk, pathogenesis, prevention, or resistance to disease. Utilization of laboratory models for testing and data interpretation may be included, for example for proof of concept and clarification of data interpretation. Gene engineered or intentionally bred animals as well as appropriate isolated cell and tissue models may be employed for this purpose. Use of the model(s) and their generalizability for environmental health issues should be considered

Applicants to this announcement must propose human studies (defined as research that directly involves individuals or groups of individuals or that uses data from humans) or clinical research (performing research on human tissue) that utilizes established or prototypic assays of genome integrity. The focus should be on evaluating and optimizing tools to determine indicators and biomarkers of altered genome integrity and the interpretation of results. Population or clinical studies on existing cohorts or new pilot studies of a small number of subjects or patients are acceptable as are limited recruitment to reinforce existing cohorts for reasons of power, etc. Sub-studies to existing cohort studies and the use of stored tissue or biosamples are acceptable. While health outcomes do not necessarily need to be the goal of the application, a minimum of phenotypic data on the subject population should be included, including age, gender, and ethnicity. The use of Common Data Elements is encouraged (see Part 2, Section IV and http://cde.nih.gov/). New recruitment of large cohorts and clinical trials will be not supported under this FOA and requests to establish new cohorts will be considered not responsive. Applicants should justify the target cohorts, subjects, and /or patient sets; including e.g. size and proposed use of cohorts, sets of human subjects, exposure, or medical treatment information, etc.

Multiple PD/PI projects are encouraged to promote a multidisciplinary or transdisciplinary approach. The program will foster collaborations among basic biologists, clinical researchers, and/or epidemiologists with the technical skills and insights to produce and validate assays, methods, and protocols to obtain measures and clarify the interpretation of genome integrity capacity. The aims of the collaborations should be to field test promising assays and, through parallel bench studies, to clarify the interpretation of the measures for physiology and disease susceptibility and pathogenesis. The results of such measures are expected to lead to improved understanding of individual and population susceptibility, a central concept for Precision Medicine, as well as to expedite discovery of early disease biomarkers. The assays are also expected to be useful in guiding patient treatment protocols based on individual resistance or predilection for therapeutic drugs.

Successful applications will address most or all the following goals:

• Formation of coordinated partnerships among basic scientists and epidemiologists to seek to improve measures of DNA repair capacity for individuals and population studies.
• Successful design or modification of DNA repair or mutagenesis assays and pilot implementation in designated cohorts.
• Validation of assay results against currently accepted biomarkers and physiological parameters to advance studies of risk assessment in populations
• Further development of functional assays to improve on currently accepted biomarkers in terms of precision, tissue specificity, throughput, labor demand, cost, etc.
• Strengthening of interpretations of assay results in parallel studies on human tissue, human-derived stem cells, or well established mammalian animal models versus levels of established biomarkers.
• Discovery and characterization of biomarkers in accessible samples, such as blood or tissue scrapings, and determination of their reflection of DNA repair capacity or mutagenesis in target tissues of interest.
• NCI is particularly interested in studies that include data with cancer related phenotypes and tools that facilitate such investigation.

This program will be organized as a consortium and NIH staff will work closely with the supported projects to ensure increased cooperation and sharing of advances. NIH Staff will continuously assess progress, evaluate the need to bring additional resources to the projects, ensure sharing of emerging data among the participants, and provide guidance on research directions, consistent with achieving the goals of the program.

For more information, please see Section VI. Award Administration Information; 2. Administrative and National Policy Requirements; Cooperative Agreement Terms and Conditions of Award

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

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

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)
• U.S. Territory or Possession

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

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

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).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

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

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

Leroy Worth, PhD
NIEHS Scientific Review Branch
Division of Extramural Research and Training
NIEHS, Mail Drop K3-03
Research Triangle Park, NC 27709
Telephone: 919-541-0670
Fax: 301-480-3722
Email: worth@niehs.nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

All instructions in the SF424 (R&R) Application Guide must be followed. The overall aim of the project should be in concert with implementing effective assays into epidemiological or clinical research in order to provide insights into genome integrity capacities and environmental health of the general population and/or those with disease conditions. The aims and supporting data need to describe plans to improve on existing or new genome integrity tools that can be applied rapidly and efficiently in the field. Extensive planning and pilot testing is acceptable prior to testing on subject or patient populations. Methods that require small amounts of tissue, including single cell technologies, are strongly encouraged. Mechanistic studies performed prior to or alongside human subject studies are encouraged in order to clarify physiological interpretation of results.

All instructions in the SF424 (R&R) Application Guide must be followed. Applications should describe the teams designed to tailor assays to ongoing epidemiology studies or for small subject or patient groups on which to pilot test the proposed approaches. Mechanistic biologists and epidemiologists/clinical scientists are expected to be essential collaborators in the project. Omission of individuals without expertise in such areas needs to be clearly justified. Inclusion of appropriate personnel or collaborations with statisticians is essential and should be described.

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

Applicants should budget for the lead investigators and key team members to travel to a minimum of one consortium meeting per year at a site local to one of the participating teams.

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

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

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

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:

Applications should discuss plans for sustainable storage and maintenance of data in a curated resource such as dbGaP ( https://www.ncbi.nlm.nih.gov/gap ). The phenotypic and, if appropriate, genotypic, variables to be deposited should be detailed. The consortium Steering Committee will likely provide guidance on the issue of curated and/or publicly accessible data as the program proceeds.

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

Appendix:

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify Leroy Worth, PhD Referral Office by email at {worth@niehs.nih.gov} when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Common data elements (CDEs) are encouraged for this program. 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. PD/PIs are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

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

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

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

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? How will the described assay, protocol, or methods be applied to understanding genome integrity and/or environmental health? How generalizable is the assay to population studies, clinical, or public health applications?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the team include appropriate expertise from mechanistic biology, clinical research, and/or epidemiology, and statistical methods to perform the necessary investigation?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? Do the aims and supporting preliminary data suggest a strong feasibility of success with the chosen study populations and/or tissue? Will the expected results provide clear information that can be interpreted in light of environmental health and/or public health?

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

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

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

For research that involves human subjects but does not involve one of the six 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 six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

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.

Inclusion of Foreign Components

Reviewers will assess whether foreign components of the the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to

monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

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

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

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIEHS, 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate National Advisory Council or Board. The following will be considered in making funding decisions:

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

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.

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.

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. 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. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• This program will be organized as a consortium and awardees will be expected to contribute to the collective effort by sharing preliminary findings and resources with the other Consortium participants as appropriate and consistent with achieving the goals of the program. Considerable sharing of data and progress is expected among the projects. Applications should discuss plans for sustainable storage and maintenance of data in a publicly accessible, curated resource such as dbGaP (https://www.ncbi.nlm.nih.gov/gap ). The phenotypic and, if appropriate, genotypic, variables to be deposited should be detailed.
• Expected joint activities for the consortium include: regular conference calls and face-to-face meetings; opportunities to commonly validate assays and protocols; and sharing of ongoing
• progress, prototypes, and best practices.
• Consortium members will be encouraged to cross-test and validate prototypical assays across projects, where appropriate. Third party testing of the assays may also be made available as part of the development and validation process, if funds are available.
• Applicants should budget for the lead investigators and key team members to travel to a minimum of one consortium meeting per year at a site local to one of the participating teams.
• 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, and NIH policies.

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

One or more NIEHS or NCI Program Directors will have substantial scientific and programmatic involvement in the Genome Integrity Assays Program as NIH Project Scientists. NIH Project Scientist(s) will have the following responsibilities to all U01 awardees:

• Have substantial involvement to guide, coordinate, and participate in the conduct of the U01 activities.
• Attend and participate in all Steering Committee and subcommittee meetings.
• Coordinate and facilitate the interactions among the awardees under this cooperative agreement.
• Serve as a liaison between the Steering Committee, the NIH and other federal agencies as needed.
• Facilitate and coordinate the exchange of information and interactions between awardees to support collaborative efforts.
• Participate in organizing and coordinating Genome Integrity Assay Program scientific meetings as required.
• Advise on the design of pilot studies, sharing of resources and methods within the program, and/or management and technical performance of projects, as appropriate.
• Participate as collaborators to U01 investigators in some shared activities, as appropriate.
• Evaluate the adherence of grantees to any approved data sharing plans or intellectual property plans.

Areas of Joint Responsibility include:

A Steering Committee will serve as the governing board for the Validation Projects.

Governance of the Consortium will be through a Steering Committee composed of a representative of each cooperative agreement project and of each supporting NIH Institute. The Steering Committee will be a discussion forum charged with providing direction and guidance for the program, such as recommendations for collection of minimal phenotypic data; data analysis and standardization; recommending sharing strategies and requirement for depositing data in curated and/or publicly accessible data bases; consulting on the use of additional funds as may become available; and other issues that may become relevant.

Annual face-to-face meetings of awardees, NIH staff, and appropriate consultants will be organized jointly at a project site designated by NIH staff in consultation with the Steering Committee

The Steering Committee will be comprised of the following voting members:

• The Principal investigators from U01 program will have one vote.
• The NIEHS Program Director will have one vote.
• The NIH Project Scientist and other staff members may participate in Steering Committee meetings as non-voting members.
• A Steering Committee Chair will be elected every twelve months from amongst the Steering Committee members by the committee. An individual may continue serving as Chair for more than one year if all committee members agree. NIH staff cannot serve as Steering Committee Chair.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, 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)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

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

Les Reinlib, PhD
National Institute of Environmental Health Sciences
Telephone: 919-541-4998
Email: reinlib@mail.nih.gov

Leah Mechanic, PhD, MPH

Genomic Epidemiology Branch
National Cancer Institute (NCI)
Telephone: 240-276-6847
Email: mechanil@mail.nih.gov

Leroy Worth, PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-0670
Email: worth@niehs.nih.gov

Barbara Gittleman, MA
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 919-541-0585
Email: barbara.gittleman@nih.gov

Carol A Perry
National Cancer Institute (NCI)
Telephone: 240-276-6282
Email: perryc@mail.nih.gov

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

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