National Institutes of Health (NIH)
Rare Genetic Disorders as a Window into the Genetic Architecture of Mental Disorders (U01 Clinical Trial Not Allowed)
U01 Research Project – Cooperative Agreements
This initiative will foster collaborative and coordinated efforts to characterize the underlying genetic architecture of diverse neuropsychiatric phenotypes within and across rare genetic disorders and identify the shared genetic risk across rare and idiopathic neuropsychiatric disorders. Projects from multi-disciplinary teams will utilize genome-wide data to comprehensively assess the contribution of genetic variation to the variable expressivity and incomplete penetrance of neuropsychiatric phenotypes across rare genetic disorders. Projects are encouraged to leverage existing resources, cohorts, and collaborative networks with established infrastructure for consistent and high-quality phenotypic data collection and genomic data generation. Projects should seek to enhance the quality of the phenotypic data available for rare genetic disorders by developing or applying phenotyping methodologies that create a pipeline for standardizing assessments and that cut across rare genetic disorders and across developmental time points. Under this initiative, investigators will form a network to facilitate data sharing and harmonization of clinical and genetic data across different studies within the network, as well as accelerate characterization of genotype to phenotype relationships across rare genetic disorders. This network will also generate a resource of bio-samples, as well as phenotypic and genetic data for broader dissemination to the scientific community.
This FOA should be used for applications that are not collaborative between sites. Applications requiring two or more collaborating sites to complete the proposed research should apply as a linked set of collaborative U01 applications to the companion collaborative U01 FOA (RFA-MH-19-201).
All awards supported under this FOA and the companion collaborative U01 FOA (RFA -MH-19-201) will be governed by the Mental Health Rare Genetic Disease Network (MHRGDN).
June 7, 2018
July 9, 2018
30 days prior to the application due date
August 9, 2018, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
August 10, 2018
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.
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
The last decade has seen unprecedented progress in psychiatric genetics and large-scale team science driven efforts have begun to unravel the complex genetic architecture underlying the etiology of neuropsychiatric disorders, implicating hundreds of variants across the allelic spectrum with a broad range of effect sizes. Highly penetrant rare variants of large effect provide a unique opportunity to dissect the genetic factors influencing vulnerability and resilience to psychiatric disorders and to illuminate the underlying neurobiology of these complex disorders. For example, there are several known pathogenic variants in single genes (e.g., MECP2 and SCN2A) and pathogenic copy number variants (e.g., 3q29 Del, 16p11.2 Del/Dup, and 22q11.2 Del/Dup) that confer a substantially elevated risk for multiple clinically distinct disorders, including schizophrenia, autism spectrum disorders, anxiety, and attention deficit hyperactivity disorder. These rare genetic disorders are highly pleiotropic, with the same mutation leading to a variety of neuropsychiatric phenotypes across the life span and different mutations converging on similar phenotypic expressions. Additionally, the phenotypic presentations in these subjects often parallel those seen in idiopathic cases of mental disorders. It is posited that background common variation of small effect, as well as other rare variation and environment, shape the penetrance and expressivity of neuropsychiatric phenotypes in these rare genetic disorders.
The variable expressivity and penetrance observed for these rare genetic mutations present a unique opportunity to better understand the genetic factors underlying neuropsychiatric disorders not only in people with these rare syndromes but also in those with idiopathic psychiatric disorders more generally. Past studies in this field have been limited by small sample sizes and efforts toward meta-analyses have been hampered by a lack of field-wide standards for integration and standardization of phenotypic measures across dimensional traits, a lack of genome-wide data in general, and limited amount of data from the non-genomic factors affecting the developmental course of these phenotypes. A coordinated investigation with a detailed and comprehensive genetic and dimensional phenotypic characterization of large cohorts of individuals with rare genetic disorders is needed to amass a sufficient number of well-phenotyped patients across these rare genetic disorders to inform robust genetic analyses.
This FOA encourages collaborative research efforts to comprehensively assess the contribution of genome-wide variation to the variable expressivity and incomplete penetrance of neuropsychiatric phenotypes across rare genetic disorders using well-phenotyped clinical cohorts.
A project under this initiative MUST include both:
1) Deeper characterization of genomic-wide contributions and phenotypic dimensions across domains of psychopathology in rare genetic disorders AND
2) Study designs that consider both direct measures of psychopathology as well as broader phenotypic dimensions and seek to gain insights into variable expressivity and penetrance of these rare genetic syndromes to developing neuropsychiatric phenotypes. For example, such designs could include assessments of: a) more than one rare genetic disorder with similar phenotypic presentations (e.g., 22q11.2 del and 16p11.2 del); or b) a single genetic disorder spanning multiple diagnoses (e.g., 22q11 with autism or psychosis or ADHD). Such designs WILL include assessments of multiple phenotypic traits, combining clinical diagnostic assessments and dimensional measures.
Projects must be supported by clear evidence of the pathogenicity of the genetic variants chosen (e.g., criteria published by the American College of Medical Genetics and Genomics or/and the Association for Molecular Pathology in 2015 - PMID: 25741868, 21681106) and of the relevance of these variants to the neuropsychiatric phenotypes under investigation. Successful applicants are expected to synergize activities across disorders so that the thematic focus and rationale for including the disorders and the choice of phenotypic measures are both clear and compelling (e.g., overlapping phenotypes). Use of dimensional and quantitative phenotypes in the spirit of Research Domain Criteria (RDoC) is encouraged.
While applications submitted in response to this FOA may propose any research design that fits within the limitations described above, there are also specific areas of interest to the NIH components that are participating in this FOA. Specifically:
NIMH is particularly interested in projects seeking to explore variants which have a substantial neuropsychiatric outcome and will not consider projects exploring variants that lack primary neuropsychiatric outcomes and/or primarily result in intellectual disability.
NICHD is particularly interested in genetic and genomic variants that are associated with intellectual disability, including Down syndrome and the subset of those with Down syndrome who have co-occurring mental health conditions.
Due to the multi-disciplinary nature of the projects and the focus on collaboration, this FOA requires applicants to assemble a synergistic team of investigators (KEY PERSONNEL) with demonstrated track records (e.g., publications, education, etc.) in computational, statistical and clinical genetics, genomics, psychiatry, and other specialties as appropriate (e.g., neurology, developmental disabilities, and rare disorders).
Investigators under this initiative will form a network with a primary focus of facilitating data sharing and harmonization of clinical and genetic data across different studies in the network, as well as accelerating characterization of genotype to phenotype relationships across rare genetic disorders.
Network members that will be recruiting are strongly encouraged to generate a resource of bio-samples (e.g., DNA, blood, fibroblasts and induced pluripotent stem cells), as well as phenotypic and genetic data for broader dissemination to the scientific community through NIH designated repositories (e.g., dbGaP, ClinGen/ClinVar, NIMH Data Archives, and NIMH Repository and Genomics Resource) to the extent possible. Projects are expected to incorporate state-of-the-art integrative computational and statistical genomics methods.
Specifically, this initiative seeks collaborative and coordinated research efforts that will both:
Projects under this FOA are strongly encouraged to: 1) Incorporate broad measures of psychopathology (e.g., Social Responsiveness Scale (SRS), Personality Diagnostic Questionnaire (PDQ), and Child Behavioral Checklist (CBC)) to aid cross-network harmonization and comparisons; 2) utilize measures that may be applied across a broad range of developmental stages or to modify/tailor existing measures so that they can meaningfully translate across age groups; 3) utilize interoperable data platforms, such as common APIs, webtools, workflows, storage infrastructure, standardized data formats and meta-data standards, and standard vocabularies/ontologies to facilitate data access and integration efforts within projects and across the network, as well as with other consortia focused on rare genetic diseases, where possible. 4) utilize or adapt existing and/or develop new common vocabularies, ontologies, and Common Data Elements (CDEs) applicable across a broad array of disorders, where appropriate, (e.g., Human Phenotype Ontology [HPO], PhenX Toolkit, Neuro-QoL, NIH CDE Repository, NBSTRN CDEs, and RD-Connect CDEs); 5) leverage relevant instruments, tools, registries, and other resources developed by related NIH-sponsored programs (see list in Organization and Management section below) and collaborate with such programs, as appropriate; 6) utilize broadly consented patient registries and work with relevant patient advocacy groups (e.g., Unique and advocacy groups within other NIH programs or those aligned with the neuropsychiatric disorders of interest) for recruitment and other study goals; 7) leverage existing collaborative networks, as well as national and international collaborations, especially those that have infrastructure for consistent and high-quality sample collection and data generation and cohorts that could be re-contacted; 8) apply innovative solutions for consistent, high quality, and cost-effective phenotyping and genotyping across large cohorts of subjects (e.g., digital phenotyping, leveraging of EMR systems, leveraging mobile and web-based platforms, and partnering with consumer genomics groups); 9) make use of cost-effective recruitment strategies to ensure consistent assessments and use of standardized measures across sites.
Applicants are strongly encouraged to discuss their plans with the scientific contact designated for this FOA prior to applying.
Organization and Management of the NIMH Rare Genetic Disease Network
All awards supported under this FOA and the companion FOA (RFA-MH-19-201) will be governed by the Mental Health Rare Genetic Disease Network (MHRGDN). The role of the MHRGDN will be to facilitate harmonization efforts for measures and data across members to enhance rigor and reproducibility and generate a resource for network members and the scientific community. Network members will be expected to develop and implement best practices for data integration and harmonization across and within projects. When developing these best practices, network members are strongly encouraged to utilize methods that would enable interoperability of data sets generated by this new network with those from other NIH-funded collaborative networks studying rare diseases (see list below). While the development of new resources may be necessary, NIMH expects that network members will seek to leverage CDEs, instruments, tools, registries, and other existing resources developed by other rare disease programs where possible and, to the extent permitted, make every effort to collaborate with these existing NIH-funded efforts in areas of mutual interest, including ensuring compatibility of the data collected for rare neurodevelopmental disorders across programs. Examples of such programs include, but are not limited to:
Protection of Human Subjects: Applications with data collection plans that involve multiple respondent groups (e.g., clients/patients, therapists/providers, supervisors, and administrators) should address provisions for human subjects' protections and consenting procedures for all participant groups accordingly. The NIMH has published updated policies and guidance for investigators regarding human research protections and clinical research data and safety monitoring (NOT-MH-15-025). The application's Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations. Applicants collecting data and samples from minors are strongly encouraged to consider the possible need for reconsent in the future when the participants are adults and may find it necessary to plan for the use of consent forms that explicitly state that deidentified data and samples may still be used for research if re-contact is not possible (See: https://www.genome.gov/27559024/informed-consent-special-considerations-for-genome-research/). Likewise, applicants may need to take into account special considerations for participants with reduced or questionable capacity to provide informed consent (see: https://grants.nih.gov/grants/policy/questionablecapacity.htm).
See Section VIII. Other Information for award authorities and regulations.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Not Allowed: Only accepting applications that do not propose clinical trials
NIMH and NICHD intend to commit a total of at least $4,500,000 in FY 2019 to fund a total of 3-5 applications under this FOA and the companion FOA (RFA-MH-19-201). The total amount awarded and the number of awards will depend upon the quality, duration, costs and the receipt of a sufficient number of meritorious applications.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
The project period is limited to 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:
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
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 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:
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, 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:
The letter of intent should be sent to:
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 with the following additional instructions:
Facilities and Other Resources:
Applicants should describe the facilities and resources at their institution and any sub-contracts which will facilitate the goals of the project.
Other Attachments: The following items must be included as other attachments.
1. Project Management Plan
Applications must provide a Project Management Plan submitted as a single pdf attachment with the title "Project Management Plan."
Provide a plan detailing the measures that will be taken to ensure cross-disciplinary communication and integration across the team (i.e., the collaborating laboratories) and addressing the division of labor across the team. The Project Management Plan must provide a detailed description of how different elements of the project would operate in a synergistic and integrated manner, including a data coordination plan. The following guidelines and framework must be followed in developing this plan:
2. Data and Samples Plan
Applications must provide a Data and Samples Plan with the title "Data and Samples Plan" that includes the following information:
All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions:
Personnel should document their track records in computational and statistical genetics, genomics, psychiatry, and psychology.
All instructions in the SF424 (R&R) Application Guide must be followed. Applicant should allot at least 10-15% of the proposed budget to provide funds for participation in Network activities, including, but not limited to, harmonization and integration of data with other network sites, joint analyses across network sites, as well as organization of and attendance at Network meetings (see Cooperative Agreement Terms).
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:
Applicants must describe how the project will characterize and more completely define the connection between genotype and phenotype for multiple rare genetic variants that convey risk for neuropsychiatric disease through a combination of comprehensive genome-wide analyses and deeper phenotypic characterization. Applicants should:
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:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
When involving NIH-defined human subjects research, clinical research, and/or 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
2.5 Recruitment and Retention Plan.
Document access to a substantial subject population with the rare variants that are the focus of the application. Describe resources for outreach, recruitment, and retention of these subjects.
Describe any use of existing collaborative networks, national and/or international, with infrastructure for consistent and high-quality sample collection and data generation and re-contactable cohorts.
Section 3 - Protection and Monitoring Plans
3.1 Protection of Human Subjects
Provide a detailed description of any available data and/or samples that will be leveraged for this project that are considered human subject research, including amounts, quality, type, location, procedure for acquiring, etc. This should also include a description of data and samples available at each site.
If planning any prospective recruitment, re-phenotyping, or re-sampling, justify the need (e.g., missing data, inclusion of first-degree relatives, previously collected DNA or phenotypic data that is of insufficient quality or quantity and/or rare genetic disorders for which existing samples and data are limited) and provide reasonable assurance that the patients and human specimens needed for research are readily available (e.g., re-contactable cohort).
Delayed Onset Study
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.
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.
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 the NIMH Referral Office by email at firstname.lastname@example.org 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. 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 well will this project characterize and more completely define the connection between genotype and phenotype for rare genetic variants that convey risk for neuropsychiatric disease?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
How well does the team assembled comprise a multi-disciplinary team of experts with demonstrated track records in computational, statistical and clinical genetics, genomics, psychiatry, and other specialties as appropriate (e.g., neurology, developmental disabilities, and rare disorders)?
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?
How well will the genomic analyses allow new insight into the genotype-phenotype relationships in rare genetic disorders? Are the plans to develop new measures, CDEs, or tools well justified? Are the plans for new recruitment, new genomic data generation, or new phenotypic data generation well justified? If applicable, how does the project apply innovative solutions for consistent, high quality, cost-effective phenotyping and genotyping across large cohorts of subjects?
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?
Is adequate justification provided for the choice of variant(s) in relation to their pathogenicity and relevance to neuropsychiatric phenotypes? How do(es) the chosen variant(s) or phenotype(s) synergize to a single thematic focus? How does the project integrate both comprehensive genome-wide analyses and deeper phenotypic characterization? Are the phenotyping methodologies well described and justified? How will the phenotyping methodologies contribute to building consistent, well-validated phenotypic data within the project, as well as allow for harmonization of data across projects and across age groups (e.g., use of broad measures of psychopathology and measures that meaningfully translate across age groups)? Are the genomic analyses well powered? How has the project included plans to incorporate the best practices of the field for their database management and data analyses (e.g., use of existing CDEs, APIs, tool, resources, and collaborative networks)? How does the project make use of existing infrastructures?
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.
Project Management Plan
Is the Project Management Plan adequate and appropriate to ensure coordination of the different elements of the project? To what extent would this plan ensure that all elements would operate in a synergistic and integrated manner? To what extent does the plan include adequate procedures to ensure reliability and quality control, comprehensive transparency of data reporting, and sharing of resources consistent with the goals of the program? To what extent does the application include adequate plans for maintenance of close collaboration and effective communication among members of the project? To what extent are the plans for data standards and data integration adequate to the need of the project? To what extent are adequate plans presented for the completion of the project following the loss of a key member of the group?
Data and Samples Plan
Are all proposed uses of existing data and samples adequately described? For prospective data collection, how have they demonstrated access to the patient populations necessary to conduct this research?
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.
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.
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.
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 NIMH, 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:
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Mental Health Council. The following will be considered in making funding decisions:
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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see 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 https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
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's 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.
All awards supported under this FOA and the companion FOA (RFA-MH-19-201) will be governed by the Mental Health Rare Genetic Disease Network (MHRGDN) Steering Committee, composed of the PDs/PIs of each project, NIMH Project Scientist(s), and the NIMH Program Officer to assist in monitoring and developing scientific content and direction of the program.
The PD(s)/PI(s) will have the primary responsibility to:
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
The NIMH Project Scientist (or designated alternate in the event that the Project Scientist is not available) will have substantial programmatic/scientific involvement to:
In addition, an NIMH Program Officer has usual stewardship responsibility for monitoring the conduct and progress of the project. The Program Officer carries primary responsibility for periodic review and approval of the study protocol in relation to stated recommendations regarding continuance of the project, receives all required reports and determines that satisfactory progress is being made, and attends the Steering Committee meetings as a non-voting participant. The Program Officer negotiates throughput, quality control, validation, and cost goals with the awardees as necessary, suggests reprogramming efforts, including options to modify projects/programs when certain objectives of this FOA are not being met, and may recommend withholding of support, suspension, or termination of a U01 award for lack of adherence to required policies and/or procedures.
Areas of Joint Responsibility include:
All awardees under this FOA will be governed by the Steering Committee composed of the PDs/PIs of each grant, NIMH Project Scientist(s), and the NIMH Program Officer to assist in monitoring and developing scientific content and direction of the program. The PD/PI and any MPI are required to serve as members of the Steering Committee. Key personnel from projects may also serve in addition to PD/PIs. Each project, project being either a single U01 supported under RFA-MH-19-200 or a collaborative U01 set supported under RFA-MH-19-201, will have one vote in Steering Committee decisions. The Steering Committee will select, by majority vote, a Chair from among the PDs/PIs for a two-year term.
The Steering Committee will:
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. Those three members include: 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.
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)
(Questions regarding application instructions and process, finding NIH grant
Email: GrantsInfo@nih.gov (preferred method of contact)
Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
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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