Department of Health
and Human Services (HHS)
and Human Services (HHS)
National Institutes of Health (NIH)
R01 Research Project Grant
New
None
None
93.113
The purpose of this funding opportunity is to solicit applications that fully integrate recent innovative advances of in vitro functional genomics tools/technologies and approaches for environmental health and toxicology research. The overall goal of this NIEHS led initiative is to generate proof-of-principle studies incorporating these new in vitro approaches, together with well characterized exposures, to further our understanding of gene-environment (G x E) interactions in complex human disorders.
January 2, 2021
February 1, 2021
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Not Applicable
June 2021
October 2021
December 2021
Not Applicable
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
Background:
Many complex human diseases are known to involve multiple, potentially interacting genetic and environmental factors. Gene-environment (G x E) interaction or interplay is interchangeably used for the purposes of this FOA. G x E is defined broadly as a varying effect of an environmental exposure(s) depending on genetic background (susceptibility) of an individual or the stimulation of a gene variant(s) to cause disease phenotype or dysfunction only under certain environmental conditions.
Human epidemiology studies that aim to identify any interplay between genetics and environmental factors face many challenges. Foremost is the need for large sample sizes to detect an exclusive G x E association, relative to main effects, and the need for the study population to exhibit a range of both genetic and environmental variation. Consortium approaches to increase power can face difficulties in the harmonization of exposure measures and unevenness in quality of exposure assessments across different study populations. Addressing the temporality of exposures and compound mixtures brings additional complexities. Patterns of linkage disequilibrium and genetic and phenotypic heterogeneity can also reduce power to identify potential causal variants. Finally, the location of most GWAS hits in non-coding regions hinders mechanistic interpretation, and this is even more true for G x E findings with non-coding variants.
Despite these challenges, epidemiology studies supported by NIEHS and other NIH Institutes have revealed a few intriguing G x E interactions associated with several complex diseases. These potential G x E interactions were often identified through unique human population studies (with specific exposures, ethnic backgrounds, or rare disease phenotypes), making it extremely difficult to replicate or validate many of these limited G x E findings in other appropriate human populations. New approaches to therefore both identify and validate gene-environment (G x E) paradigms relevant to human disease are sorelyneeded.
Recent advances in a variety of in vitro functional genomics approaches can provide additional avenues to experimentally characterize and further interpret both newly identified as well as existing G x E findings. In vitro functional studies can further dissect susceptibility loci in physiologically relevant cells to elucidate underlying G x E mechanisms/AOPs (Adverse Outcome Pathways) driving complex diseases. These approaches can lead to a better understanding of specific response pathways that elicit or drive cellular/tissue dysfunction following environmental insults. The following in vitro functional genomics approaches, tools, and technologies may be particularly pertinent examples for dissecting G x E interactions:
Single Cell Analyses and Innovative Culture Systems:
A variety of new single cell analyses allow greater insights into cell-type specific responses to exposures, particularly in heterogeneous tissues. These single-cell studies are further advancing the understanding of somatic mutagenesis and molecular signatures generated from environmental exposures. Organoid culture models (OCMs), tissue-chip platforms, and other innovative culture systems and microfluidics have also allowed more accurate in vitro human models of many human diseases, particularly in brain and other solid organs (such as heart, liver, and lungs) from which human tissue is not readily accessible or surrogate tissue is not informative. These models may allow new paradigm shifts in the understanding of windows of susceptibility (WOS) and the role of external insults on later-in-life disease manifestations among susceptible individuals.
Population-based Models:
More sophisticated diversity cell panels from population-based model organisms (including the Collaborative Cross (CC) and Diversity Outbred (DO)) allow population-level studies to be performed in vitro. These resources have proven to be powerful tools for identifying individual quantitative trait loci (QTL) and candidate genes related to G x E interplay in complex human diseases. These cell populations are also useful for high throughput in vitro assays, toxicity screens, and functional validation experiments. In addition, populations of more mature patient-derived induced pluripotent stem cell (iPSC) models from relevant cell types could generate more detailed phenotypic endpoints to be tested. This can lead to better recapitulation of specific functions of in vivo cells (including a more thorough understanding of epigenetic reprogramming, mitochondrial functions, and xenobiotic metabolism).
CRISPR/Cas9 and Other Genome Editing Tools:
The use of CRISPR/Cas9 and other genome editing tools have the potential to generate robust high-content genome-wide screens in combination with environmental exposures of interest for probing relevant/predictable genetic variants that drive susceptibility to environmental exposures. The National Academies of Sciences 2018 workshop entitled: “The Promise of Genome Editing Tools to Advance Environmental Health Research” recommended more proof of concept and pilot studies using next gen gene-editing tools in studies with well-characterized chemical exposures to advance environmental health and toxicology research. Specific recommendations from this workshop included: the further development of in vitro assays and technologies that facilitate expanding functional endpoints beyond cell viability, the application of the next-gen gene editing tools to readily identify candidate variants that predispose differential response to the environment, and the creation of new synthetic genomes to enable novel genome-wide mechanistic research in vivo and in vitro relevant to environmental health. Workshop participants commented that although massively parallel functional assays have been utilized to understand genomic coding regions and regulatory elements, these and other higher-content assays (including CRISPR-induced saturation mutagenesis) have not broadly been combined with exposures to help characterize G x E interactions.
Integration with Omics Data:
Experimental in vitro data generated with many of these functional genomics tools and technologies can now be integrated with a variety of omics data (including transcriptomics, metabolomics, proteomics, etc.) with various annotation information (including DNAse I hypersensitive sites, ENCODE, Roadmap Epigenomics, and GTEx data, etc.). Integration of epigenomic data may be particularly valuable given that many G x E interactions are known to be mediated by environmental exposure effects on epigenetic processes. Additionally, omics data relevant to molecular phenotypes may potentially boost power for detecting G x E interactions because intermediate molecular endpoints are more tightly associated with exposure.
Integration/Application of Computational Approaches:
Integration of in vitro functional data with novel computational approaches incorporating existing biological knowledge of biochemical networks can also be extremely useful for making predictions related to G x E function. The application of rapid exciting advances in computational approaches (such as machine-learning, quantitative structure activity relationships (QSAR), and artificial intelligence/deep neural networks, etc.) to experimental data could further advance the understanding of the underlying molecular effects of G x E interactions on biological pathways implicated in environmentally-relevant disease pathogenesis. Combining in vitro data with in silico approaches can also help to prioritize variants most likely to be differentially expressed or responsive to environmental exposures.
Research Objectives/Scope:
The overall objective of this initiative is to generate proof-of-principle studies relevant to the environmental health and toxicology communities by utilizing novel high-throughput or high-content in vitro functional genomics approaches in studies with well-characterized exposures to discover or validate/refine G x E findings. A variety of in vitro approaches, resources, and strategies, such as those listed in the Background section above, could be exploited to better identify and interpret variants/pathway effects for environmentally-relevant disease outcomes.
NIEHS Environmental Exposures of Interest:
Applications are required to include an environmental chemical or toxicant having a clear link to a human disease outcome (animal or human studies) with physiologically appropriate doses/exposures considered for the species under consideration. Environmental agents which are considered of primary interest for NIEHS include: industrial chemicals or manufacturing byproducts, metals, pesticides, herbicides, air pollutants and other inhaled toxicants and particulates, as well as biologically derived toxins. The following factors should not be used as the sole environmental risk factor proposed for a study but can be used in combination with other relevant environmental chemical exposures or toxins/toxicants:
NCI Environmental Exposures of Interest:
Exposures relevant to NCI could include but are not limited to: endocrine disrupting chemicals (e.g., BPA, phthalates), per- and polyfluoroalkyl substances, and polyaromatic hydrocarbons, as well as lifestyle and behavioral exposures.
Applications responding to this FOA may focus exclusively on validation of existing G X E or on discovery of new G X E. Applications that combine discovery and validation are also appropriate.
Expectations for G x E Validation Applications:
Applications aimed at validation or further characterization of existing G X E findings must also include:
*Preliminary data or substantial cited published literature demonstrating an existing G x E “hit” and its relevance to a human disease outcome
*Studies using at least two independent in vitro functional genomics tools or technologies (examples included in Background above)
*Use of multiple independent validations (in different species/strains/animal or cellular systems) and/or multiple cellular/molecular readouts (gene expression or miRNA changes, proteomic, metabolomic, epigenomic analyses, etc. ) to ensure robust validation of the G x E findings
*Consideration of cellular or tissue-specificity context, which could include traditional reporter assays, CRISPR-based editing, or various cellular or organelle-specific phenotype assessment
Validation applications are strongly encouraged to include:
*Some in vivo validation of in vitro findings (with appropriate animal model, human population, etc.)
*The use of novel functional genomics approaches and the development of new assays, technologies, or methods that further facilitate the expansion of in vitro functional endpoints and readouts (beyond cell viability and other crude measurements) relevant to disease phenotypes
*The inclusion of a human component (human cells, biospecimens, biomarkers in human samples, etc.) for human disease model translation
Expectations for G x E Discovery-Based Applications:
Applications aimed at discovery of a G x E interaction must also include:
*Biological plausibility for the association of gene pathways/exposures with human disease outcomes supported through preliminary experimental animal or human data and/or appropriate relevant literature citations
*At least two independent in vitro functional genomics tools or technologies (examples included in Background above)
Discovery-based applications are strongly encouraged to include:
*The utilization of novel functional genomics approaches and the development of new assays, technologies, or methods that further facilitate the expansion of in vitro functional endpoints and readouts (beyond cell viability and other crude measurements) relevant to disease phenotypes
Expectations for Combined G x E Discovery and Validation Applications:
Applications that include both discovery and validation of G x E must meet the expectation criteria, described above, for both discovery and validation.
Additional Considerations:
Novel computational approaches to use the biological knowledge gained in the application to ultimately inform or better predict G x E function and/or integration of experimental data with prior knowledge of biological networks/systems computationally is encouraged as appropriate. However, applications that are solely focused on in silico analyses, modeling, statistical methods, or computational approaches alone without in vitro experimental data will not be considered responsive to this FOA. In addition, tissue-chip platforms, tissue models, OCMs, or multi-tissue iPSCs platforms should already be established/validated as an appropriate model; the application should not be primarily focused on development of a new tissue or organotypic culture model. Multiple PD/PI projects are encouraged to promote a multidisciplinary or transdisciplinary approach, particularly with respect to combining environmental health expertise with other disciplines. Applications should also incorporate a strong data management plan and sharing expectations so that these studies could be made readily available to the scientific community in a timely fashion. Additionally, NCI specifically encourages applications focused on research that incorporates biological and genetic information from population-based studies to provide insights into the interplay of germline genetic variation and exposures and how these contribute to cancer risk and outcomes; projects with potential for human disease translation are strongly encouraged.
Specific Areas of Research Interest:
Examples of in vitro functional studies responsive to this FOA include but are not limited to those listed below:
See Section VIII. Other Information for award authorities and regulations.
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
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.
Need help determining whether you are doing a clinical trial?
NIEHS intends to commit $4 million in FY 2022 to fund approximately 6 awards.
NHGRI intends to commit $.5 million in FY 2022 to potentially co-fund approximately 2 awards.
NCI intends to commit $1 million in FY 2022 to fund one award and potentially co-fund one additional award.
Application budgets are limited to $499,999.00 Direct Costs per year.
The maximum project period is 5 years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
For-Profit Organizations
Local Governments
Federal Governments
Other
Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
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:
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
Leroy Worth Jr., Ph.D.
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 984-287-3340
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.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Research Strategy:
Investigators proposing both discovery and/or validation studies should clearly identify and justify the functional genomics tools utilized. Validation studies should also describe how independent validations will be conducted and how cell and tissue context will be considered. Investigators should include appropriate rationale for how the studies will ultimately inform human population studies and human disease/disorder relevance. If validation with other model organisms is proposed (particularly lower model organisms such as C. elegans, fish, Drosophila, etc.), strong rationale for the choice for any model organism system(s) should be clearly articulated, and justification for how any lower model organisms and orthologous gene pathways are known to be involved in human disease must be provided. The choice and rationale for the exposure(s) utilized and study design(s) incorporated should also be justified (with appropriate support for biological relevance of the dose(s) of the exposure chosen as well). The applicant should describe controls, plans to reduce bias (blinding, randomization, inclusion and exclusion criteria, etc.), power analyses, and statistical methods as appropriate. The applicant should justify animal numbers, including reference to appropriate statistical methods for power and sample size calculations. Appropriate justification should be given if only one sex is considered in the study design, including details regarding given exposures (dose range) for the single sex that is being interrogated.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
The following modifications also apply:
Investigators are expected to include data management and sharing plans to ensure that the datasets generated are made readily available to the scientific community in a timely fashion. Submission of data to relevant publicly accessible databases (for example, FlyBase, JAX Mouse Phenome database, etc.) is highly encouraged, and plans should describe how data can be adapted broadly for use by the environmental science community. Plans for data management and sharing will be discussed during the initial scientific merit review. Other biological resources (tissues, samples, etc.) as well as unique protocols and study designs should also be shared when feasible to the broader scientific community.
All applications, regardless of the amount of direct costs requested for any one year, should include a detailed Data Management and Sharing Plan, addressing the following elements:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:
If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
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 non-responsive will not be reviewed.
In order to expedite review, applicants are requested to notify NIEHS by email at worth@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.
Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Will relevant/important insights underlying the mechanisms of a new or existing G x E finding likely be accomplished at the conclusion of the project? How relevant will the findings be to a human disease outcome(s)?
Investigator(s)
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?
To what extent do the PD(s)/PI(s) and other key personnel have adequate expertise in genetics, genomics, computational and bioinformatics methodologies, molecular biology, biochemistry, cell physiology, analysis of genome-wide data, high-throughput experimental protocols, toxicology, environmental exposure assessment, environmental epidemiology, animal models, and/or other fields relevant to the project, as well as expertise in and understanding of the mechanistic complexity of the environmentally-relevant disease of interest? Do the investigators have complementary and integrated expertise and skills? How facile are the PD(s)/PI(s) in curation of large data sets, including multiple layers of complex genomic data relevant to genetic analysis? How facile are the PD(s)/PI(s) in the understanding and management of functional genomics and environmental measure outcomes?
Innovation
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Does the application propose novel or unique in vitro genomic functional approaches to characterize the biochemical, physiologic, and regulatory roles of functional genomic elements with an appropriate environmental exposure? Are the proposed concepts, approaches, methodologies, instrumentation, or interventions in the application new to the field of environmental health research? Does the application utilize and/or develop new or improved robust and/or high-throughput genetic and epigenetic screening techniques, methods, or assays? Are any approaches proposed that improve on functional endpoints and readouts for in vitro studies? Are the uses of model organisms, culture models, or tissue-chip platforms in the application allowing new paradigm shifts in the current understanding of the impact of environmental exposures in complex disease development?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
How effectively will the project use novel in vitro functional genomics approaches to expand our mechanistic understanding of G x E interactions relevant to a disease or organ/tissue dysfunction outcome? Is there sufficient biological plausibility or evidence (for validation applications) of a proposed G x E interaction between gene pathways/exposures (or AOPs) with disease outcomes or organ/tissue dysfunction? Does the application propose adequate and robust plans for experimental validation of function(s) and identification of underlying molecular mechanisms? Does the project adequately address issues of statistical power?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?
Environment
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?
Are the facilities/resources commensurate with the proposed study design along with appropriate core facility expertise/infrastructure? Are the computational informatics facilities and data management infrastructure sufficient for what is proposed?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
Protections for Human Subjects
For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
Inclusion of Women, Minorities, and Individuals Across the Lifespan
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
Not Applicable
Renewals
Not Applicable
Revisions
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.
Applications from Foreign Organizations
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
Authentication of Key Biological and/or Chemical Resources:
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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 will receive a written critique.
Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications 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:
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
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.
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.
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.
Not Applicable
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
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
Kimberly A. McAllister, PhD
National Institute of Environmental Health Sciences (NIEHS)
Telephone: 984-287-3287
Email: mcallis2@niehs.nih.gov
Stefanie Nelson, PhD
National Cancer Institute (NCI)
Telephone: 240-276-6944
Email: nelsons@mail.nih.gov
Rongling Li, MD, PhD, MPH
National Human Genome Research Institute (NHGRI)
Telephone: 301-480-2487
Email: lir2@mail.nih.gov
Leroy Worth, PhD
National Institute of Environmental Health Sciences (NIEHS)
Email: worth@niehs.nih.gov
Telephone: 984-287-3340
Jenny Greer
National Institute of Environmental Health Science (NIEHS)
Telephone: 984-287-3332
Email: jenny.greer@nih.gov
Deanna L Ingersoll
National Human Genome Research Institute (NHGRI)
Phone: 301-435-7858
Email: deanna.ingersoll@nih.gov
Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email: wolfreyc@gab.nci.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.
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