Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this FOA is to acquire longitudinal data on an acutely traumatized population to identify objective markers of specific phenotypes of distress or dysfunction. An adult acute trauma population will naturally have a range of prior traumatic events that is an important consideration in developing models of trajectories. Serial longitudinal data may be used to understand the course and trajectory of posttraumatic syndromes and to optimize interventions based on the related pathophysiological changes observed. For a comprehensive understanding of the trajectory of specific phenotypes of distress and dysfunction, dimensional data are needed that represent continuous measurement on the spectrum from normal to abnormal across fundamental constructs of behavior, cognition, and emotion. Longitudinal, dimensional data are expected to enhance prediction, classification, and identification of targets for prevention based on epigenetic, imaging, cognitive, and other markers.

On any given day in the United States, 7-8 million people are thought to have posttraumatic stress disorder (PTSD). Many of these individuals are known to health care systems as they present in emergency treatment settings for acute care. Beyond typical civilian trauma exposure, current estimates suggest that PTSD, traumatic brain injury (TBI) or both will affect roughly 20% of the over two million service members who have served in Iraq and Afghanistan. A recent White House Executive Order, emphasizing support of service members, veterans, and their families as a top priority, called for an increase in Department of Health and Human Services/National Institutes of Health (DHHS/NIH), Department of Defense (DoD), and Veterans Affairs (VA) research to address the problems of PTSD, TBI, and suicide (http://www.whitehouse.gov/the-press-office/2012/08/31/executive-order-improving-access-mental-health-services-veterans-service). Research involving civilians, Military, and Veterans exposed to traumatic events is needed to improve understanding in these areas. In response to the White House's call to action, this FOA proposes the longitudinal study of adults presenting in emergency care settings to examine trajectories of response following an index trauma. This research has the potential to improve the care for individuals at high risk for post-traumatic stress conditions across civilian, Military, and Veteran populations.

Historically, the manifestation of mental health problems following traumatic stress exposure has been considered largely under the umbrella of PTSD, with acknowledgement that there is high variability in presentation and frequent comorbidity with other conditions including depression, substance abuse, and a variety of other symptoms. Despite recent advances in technology and understanding spanning biomedicine, cognitive psychology, and neuroscience, the mechanisms that underlie the heterogeneous responses to traumatic stress in humans have not been identified. Exploring these changes in real time, under naturalistic conditions in humans exposed to traumatic events may improve understanding of the mechanisms and reveal potential targets for intervention.

In response to a traumatic event, people commonly experience a range of symptoms, e.g., hyperarousal, avoidance, re-experiencing, and changes in thoughts and mood. Quickly, many individuals progressively improve and symptoms recede. Those who continue to experience distress may develop diagnosable mental health problems, including PTSD, which may become chronic. However, scientists and clinicians lack the ability to predict, at an individual level, who will suffer from mental health problems and who will recover naturally after trauma exposure. Data from neuroimaging, neurochemistry, physiological, cognitive and behavioral studies reveal significant differences within PTSD subjects as well as between PTSD and trauma exposed, but otherwise healthy, subjects. Further evidence of heterogeneity in PTSD is that response to the best evidence-based treatment is highly variable. Patients ostensibly suffering from the same disorder often respond differently to empirically supported treatments (both psychological and pharmacological). Why some but not other patients derive benefits is largely unknown.

A necessary step to understand the variable responses to traumatic stress exposure is to uncover the causes and mechanisms of changes that occur. One approach advanced by NIMH to better understand the underlying causes of psychopathology is the Research Domain Criteria Project (RDoC) (http://www.nimh.nih.gov/research-priorities/rdoc/index.shtml). To speed the translation of new knowledge that continues to emerge in genetics, neuroscience, and behavioral science to clinical applications, RDoC aims to define basic dimensions of functioning (e.g., fear, arousal, attention) at the level of genes, neural circuits, and behaviors. It is expected that this approach will improve understanding of the mechanisms responsible for discrete phenotypes of illness to inform both development of new interventions and better matching of current treatments to individual patients.

Data collected under this FOA should be used to identify discrete phenotypes of post-traumatic stress conditions and generate reliable multi-method risk prediction algorithm(s) based on biomarkers and cognitive tests to predict these phenotypes. This work is expected to generate functional understanding of the course and trajectory of changes that occur in response to traumatic events. This understanding will in turn allow the field to stage pilot proof of concept and mechanistic studies to optimize treatments based on markers of the pathophysiological changes observed.

The proposed sample size should be adequate in light of prior work on the trajectories of recovery from traumatic stress exposure, the heterogeneity of presenting problems, and the need for subgroup analyses based on sex, history, and other factors known to influence outcomes. Studies should be adequately powered to conduct psychometric analyses with respect to reliability, sensitivity, and predictive validity of algorithms.

In the later years of the award, studies may be conducted to investigate functional biomarkers and promising intervention targets. For these studies, PDs/PIs should propose a general strategy to enhance measurement of promising markers, examine their relationship to narrow clinical features, and refine approaches to assessing sensitivity to change. Target development studies will be based on analyses of data from the initial years of investigation.

The scope of work to be accomplished with this Funding Opportunity Announcement is to:

1. Establish methodologies for the multi-site collection, quality assurance/quality control, and appropriate distribution/sharing of data at multiple levels (e.g., epidemiological, clinical, behavioral, cognitive, genomic, transcriptomic, epigenetic, proteomic, metabolomic, neuroimaging, inflammation, or neuroendocrine).

2. Collect serial data at multiple levels on acute trauma patients at risk for post-traumatic psychopathology to a) characterize pathophysiological changes, cognitive functions and clinical functions as markers of adjustment, dysfunction, and disorder over time and b) develop multi-method risk prediction algorithm(s) based on biomarkers and cognitive tests that represent distinct phenotypes.

3. Collect, process, store, and analyze serial data to reveal the longitudinal associations between risk factors, psychological variables, biological variables and post-traumatic clinical problems.

4. Develop and refine measures of molecular and clinical targets established or confirmed by data collected during the initial longitudinal assessment phase of the award. Although intervention trials will not be supported under this FOA, target development studies of biological, behavioral, and cognitive markers aimed at assessing the functional relationship between such markers and clinical phenotypes and developing reliable measures of target engagement for use in future experimental therapeutic trials are relevant. Additional guidance on this objective is provided in Section IV.2, Section V.1, and Section VI.2.

5. Promote efficient design and maximize results through flexible/adaptive designs including interim analyses that will aid in decision making or changes in assessment intervals and measures and generate leads for target development studies. Some assessments may be excluded or replaced in follow-up time points based on interim analyses.

6. Make longitudinal data available through sharing in an open fashion (both raw and constructed variables) with qualified investigators (while safeguarding the privacy of participants and protecting confidential and proprietary information). The goal of sharing beyond an immediate study team is to facilitate analyses beyond the scope of this original project but also to combine with other existing data to provide better powered and robust analyses (e.g. through the Psychiatric Genomics Consortium).

A leadership structure will be needed to delineate areas of responsibility and ensure progress of this ambitious research. A governing Leadership Committee (comprised of the PD/PI, DCC leaders, site leaders, as well as NIMH project scientist) should develop the scientific content and direction of the program, monitor progress over time, and ensure cross-site coordination and quality control.

The multi-site nature of the project, the settings in which recruitment will take place, the need for coordinated interim analyses, the inclusion of target development studies, and the need for safety monitoring and reporting will require that the research team be supported by an identified Data Coordinating Center (DCC) that has the requisite experience and knowledge in customizing and implementing robust scalable electronic data capture systems and in supporting multi-site, multi-disciplinary clinical research programs. It is expected that the DCC will provide ongoing management support and consultation in the design, execution, and analysis of the proposed studies and ensure that the proposed studies are of the highest scientific integrity. Details regarding expectations for the DCC are outlined in Section IV.2, PHS 398 Research Plan. Applicants may also anticipate tailored work groups such as a target development studies work group to faciliate aspects of the project.

In order to meet the scientific objectives of this FOA, applicants will need to involve multidisciplinary teams (e.g., psychopathology, pathophysiology, cognitive science, imaging, clinimetrics, omics, clinical epidemiology, longitudinal research, data base management, patient tracking expertise, etc.).

Additionally, because trauma care settings are complex and challenging environments in which to conduct research, a range of trauma care staff (e.g., nurses, emergency medicine physicians, emergency medical technicians, social workers, psychologists, and psychiatrists) may be considered for inclusion in the research team to aid in recruitment and design.

It is expected that the research team will include a Safety Monitor, whose responsibility will be the tracking and reporting of any adverse events and serious adverse events, and following-up on any individual subject safety concerns.

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

Higher Education Institutions

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

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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.

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

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

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

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

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

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

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the 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:

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

The letter of intent should be sent to:

Farris Tuma, Sc.D
Telephone: 301-443-3648
Fax: 301-443-4611
Email: ftuma@nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• For this specific FOA, the Research Strategy section is limited to 30 pages. Applicants are encouraged to allocate the following space in the 30 page research strategy limit:
  • Background and overview: 6 pages
  • Innovation and approach: 16 pages
  • Study leadership, management, and operations 8 pages

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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, with the following additional instructions:

Specific Aims: Describe plans to explore the pathogenesis of syndromal brain disorders post trauma, develop predictive algorithms, and conduct target development studies to develop and refine measures of targets/engagement.

Research Strategy: Organize the Research Strategy in the specified order and using the additional instructions provided. Start each section with the appropriate section heading.

Background and Overview: This section should include a general introduction to the study topic area, including relevant literature reviews to support the subsequent design strategies. Additionally, this section should be used to describe:

• Overall study design, including how the proposed design will enable the research team to perform interim analyses to guide decisions about changes in assessment intervals and measures.
• Site selection, including a brief summary of general medical ED/ER and other settings to be included and their rationale (i.e., a description of the patient populations and prior history of successful research conducted in such settings).

Innovation: This section should describe how bringing together the multidisciplinary team of investigators and proposed data collection and analyses will help to achieve the overall aims of the project and advance understanding the pathogenesis of phenotypes of traumatic stress reactions using an RDoC framework.

Approach: This section should describe metrics of screening, risk algorithm development, and capacity to develop/refine measures of promising putative targets and mechanisms through target development studies. This section should also include plans to classify psychopathology on dimensions of observable behavior and neurobiological measures across multiple units of analysis (e.g., from genes to neural circuits to behaviors) cutting across disorders as traditionally defined.

This section should be used to describe:

• The major goals and objectives of the project and their relationship to the overall effort of the study.
• Include a discussion of the targeted dimensions of risk markers, timeliness, and justification of measures as well as a plan for determining the optimal risk algorithm.
• Methods for coordination and collection, quality assurance/quality control, and appropriate distribution/sharing of multi-site data at multiple levels as well as the timelines and milestones to conduct serial assessments.
• Applicants' ability to integrate the proposed research into trauma care settings to facilitate adequate patient flow and success of the overall research effort.
• When possible, the use of existing research networks and infrastructure to identify, enroll, and track patients and support multi-site investigations. For example, some existing networks include the Clinical and Translational Science Awards (CTSA https://www.ctsacentral.org), the Mental Health Research Network (MHRN http://www.healthpartners.com/hprf/research/research-areas/mental-health/mhrn/index.html) and Emergency Medicine Network (EMNet http://www.emnet-usa.org/aboutpage.htm).
• Collection, processing, storage, and data analysis.
• Plans to recruit an adequate sample (with attention to attrition) for analyses on a variety of trajectories with attention to specific phenotypes and subgroup analyses. Samples are expected to be at least several hundred adult participants.
• Plans to develop risk algorithms for distinct phenotypes and examine markers of function as mechanisms of pathophysiology.
• Identification of settings in which research is not only feasible but also viable for efficient recruitment of traumatic stress populations that would be eligible for inclusion in this protocol. This should include description of the number of sites, patients, design strategy, and power analyses. Plans should also integrate research staff with traditional patient providers in the acute stage post-trauma.
• A plan for the longitudinal serial follow-up of enrolled participants and the metrics to be included at the various time points.
• A plan for interim analyses that will guide subsequent assessment strategies and to validate potential targets for further exploration. Interim analyses may be used to eliminate or replace some measures in the assessment battery.
• A plan for establishment or adoption of standardized imaging and other biomarker protocols across sites with appropriate quality control procedures.
• A summary of key outcome variables and the rationale for their selection.
• Target development studies (approximate range of 8-30 subjects per study) to refine protocols to assess biological, cognitive, behavioral function; clarify how putative markers relate to narrow clinical features and refine measurement protocols for establishing sensitivity to change
• Focus follow-up assessments in subgroups to clarify (i.e., do they continue to separate/remain predictive)
• Although it is the primary aim of this FOA to uncover brain-behavior relationships of posttraumatic stress syndrome responses, investigators should describe plans to pursue target development studies in the later years of the project period to be informed by data gathered in the first years of the study. While NIMH does not anticipate that any clinical trials will be performed in the context of this award, these target development studies should be conceptualized within an experimental medicine paradigm (http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml) so the data from these target development studies may inform future clinical trial applications. Target development studies should be budgeted for starting in year 3. This section should discuss plans to involve necessary expertise including, but not limited to, external experts, IRBs, and NIMH staff in finalizing designs and studies. It is likely that plans developed in this application will be further refined in consultation with the NIMH per the terms and conditions of an award.

Study Leadership, Management, and Operations While this may be a multi-site project, it is not a collaborative U01. As a result, there will be one grant awarded, with the expectation of multi-subcontracts to study sites. This may either be a single or multiple PD/PI project. With regard to Study Leadership and Management, this section should include:

• A description of the research team and a plan to assure the maintenance of close collaboration and effective communication among members of the research team.
• The overall study leadership structure, and reference the submission of letters of commitment to this plan by all key personnel (letters should be attached in Letters of Support).
• A description of a Leadership Committee comprised of the PD/PI, DCC leaders, site leaders, as well as NIMH project scientist.
• A description of focused working groups (e.g. target development studies working group) to include the PD(s)/PI(s) and NIH Project Scientist as well as additional members from the PD/PI’s group, consultants and NIH staff. Description should include how the working groups will set strategic direction and guide the work flow on an ongoing basis, frequency of meetings to review results of interim analyses and study designs, and the plan for producing progress reports to meet study milestones.
• The capacity for target development studies. Applicants responding to this FOA should 1) Identify one or more study sites that will conduct target development studies of biomarker, cognitive, and behavioral changes. 2) Indicate prior experience performing work similar to the proposed studies. ?3) Have experience performing multi-site (if applicable) studies including provision of scientific oversight, facilitating collaboration among the investigators, integrating complex protocol management, acquiring data, and analyzing bio-statistical data.
• It is expected that interim data analysis from the longitudinal probe of trajectories and mechanisms of posttraumatic phenotypes of distress or dysfunction (e.g. establishing novel viable targets) will inform the design of target development studies. Therefore, the applicants should describe the process to conduct interim analyses once sufficient primary data are gathered within the longitudinal cohort (i.e., target development studies are not expected before year 3). Where such interim data are proposed, investigators, with collaboration from the NIMH Project Scientist, must also indicate a willingness to prepare, through the target development studies workgroup, a report of milestones and initial data to be submitted to the NIMH for review prior to initiating target development studies.
• A target development studies workgroup may be planned (comprised of PD(s)/PI(s), NIMH Project Scientist, as well as additional outside scientific consultants including additional NIMH staff) to propose plans for approval by the NIMH Project Officer.
• Inclusion of plans for frequency of scheduled meetings, proposed rosters of group members (including NIMH Science and Program Officers), and documenting and disseminating group meeting proceedings should be described.
• Describe the steps that will be taken to ensure successful completion of the research proposed should a key member leave the project.
• Describe the role of all key personnel in the overall study design and implementation.

Study Operations, including Safety Monitoring: In addition to the oversight provided by the study PD/PI(s), it is expected that the study will have an identified Data Coordinating Center (DCC). It is expected the DCC will include a multi-disciplinary staff, consisting of appropriate statistical leadership and data management expertise. The DCC will work with the Leadership Committee and serve as a technical support organization to the investigative team by implementing the decisions of the Leadership Committee regarding protocol development, protocol execution including quality control, data processing, and analysis. Prior to the initiation of a study, it is expected that the DCC will collaborate with the study investigators in the development of the data collection forms and will take the lead on the development of detailed manual of operation and training manuals.

• Describe the role of the DCC in the design and implementation of sampling procedures, specification of the performance monitoring procedures, and training of the study personnel in the data acquisition, processing and quality control procedures.
• Describe the role of the DCC in the design and conduct of the proposed protocol, including development of electronic data capture systems, integration of multiple data streams, development and implementation of quality control and routine site auditing procedures and clinical site monitoring plans, development of reports for safety and adverse events, analysis of data, reporting of results, and the development of a shared and or limited public access de-identified dataset at the completion of the study.
• Describe systems for data collection, analysis, coordination, and quality assurance.
• Applicants should provide a description of their experience in designing these different types of projects with special emphasis on the epidemiological, biomarker, and statistical expertise required, as well as examples of past or current projects requiring this expertise.

Adverse Event/Safety Monitoring: Careful attention should be paid to how Safety Monitoring will occur in a timely and efficient matter. It is expected that the aforementioned DCC will take primary responsibility for the timely reporting of AEs/SAEs.

• Describe procedures for monitoring and tracking adverse events.
• Describe the role of the Safety Monitor, including a plan for how the Safety Monitor will gather, summarize, and report AEs and SAEs to the project PD/PI, Leadership Committee and NIMH.
• Propose a strategy for characterizing, tracking and addressing worsening of symptoms over time.

Letters of Support: Letters of support from key personnel as well as the Emergency Department personnel who will support the use of facilities for initial recruitment of participants should be provided in the application.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Consistent with NIH efforts to establish and promote the use of common standardized measures and methods, the harmonization of data across sites, and the sharing of data with the wider research community, applications are expected to include a Data Sharing Plan that addresses as appropriate:

• Plans for dissemination of raw and constructed variable data
• Plans for data dictionary preparation and careful documentation of data collected
• List of key elements for data sharing
• Data sharing schedule/timeline (i.e., release of data)
• Plan for post-award disposition of data
• Included in the plan if biosamples are to be collected is the ability to share raw and analyzed samples for the duration of the project and ability to maintain or transfer ownership if the samples are to be stored beyond the funding period.
• Plans to share or transfer ownership of master control file for the purpose of further recontact of study participants for additional research protocols.

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

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

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

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.

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 by the Center for Scientific Review, NIH and responsiveness by NIMH. Applications that are incomplete and/or nonresponsive will not be reviewed.

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

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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? Does the design of the project have the capacity to provide prediction to discrete phenotypes seen in the wake of exposure to traumatic events? Is the proposed exploration of phenotypes likely to implicate important therapeutic targets and inform how to direct existing therapies to those who will most benefit?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the application describe how bringing together the multidisciplinary team and the proposed data collection and analyses will help to achieve the overall aims of the project and advance understanding the pathogenesis of phenotypes of traumatic stress reactions?

Does the application describe a Leadership Committee comprised of the Program Director/Principal Investigator (PD/PI) of the cooperative agreement, the leaders of the DCC, leadership from each of the sites, and the NIMH Project Scientist for general project coordination?

Does the application describe plans for oversight and reviewing target development study plans?

Does the application describe a Data Coordinating Center (DCC) involving multi-disciplinary staff and plans for coordinating protocol development, protocol execution including quality control, data processing, and analysis?

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 research proposed classify psychopathology on dimensions of observable behavior and neurobiological measures across multiple units of analysis (e.g., from genes to neural circuits to behaviors) cutting across disorders as traditionally defined? Will this research, if successful yield more accurate, specific, and acute prediction of trajectory following trauma exposure? Does the application discuss a flexible design that will enable the research team to perform interim analyses to guide decisions about changes in assessment intervals and measures and to conduct target development studies in later years of the project based on interim analyses?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? Are clear milestones for recruitment at each site (if applicable) established? Is there a plan to conduct serial assessments, develop risk algorithms, probe potential mechanisms of pathophysiology?

Are the targeted risk factors and measures justified?

Are there adequate plans for establishment or adoption of standardized imaging and other biomarker protocols across sites with appropriate quality control procedures?

Is there evidence of the capability for target development studies and are plans scientifically rigorous?

Is there an adequate process described for initiating initial target development study designs? For example, is the plan for a target development study working group to report on interim analyses and to utilize relevant expertise to receive NIH approval for proceeding with target development studies in years 3-5 adequate?

Does the application acknowledge that some of the details for later stage target development studies may be revisited as data are analyzed? Where decisions about viable markers are contingent on interim data analyses, does the applicant describe clear plans to involve the appropriate expertise including but not limited to external experts, IRBs, and NIMH staff in finalizing designs?

Does the application describe the systems for data collection, analysis, coordination, and quality assurance?

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? Does the application describe a strategy for characterizing, tracking and addressing adverse events or worsening of symptoms over time?

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? Do the acute care settings selected have a history of supporting active research with successful recruitment of participants in a timely manner? Does the applicant take advantage of existing research networks and infrastructure to identify, enroll, and track patients and support multi-site investigations? For example, some existing networks include the Clinical and Translational Science Awards (CTSA https://www.ctsacentral.org), the Mental Health Research Network (MHRN http://www.healthpartners.com/hprf/research/research-areas/mental-health/mhrn/index.html) and Emergency Medicine Network (EMNet http://www.emnet-usa.org/aboutpage.htm).

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 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.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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) Genome Wide Association Studies (GWAS).

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 the 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:

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

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

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

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

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.

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 the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• The project effort as a whole, including the research design and the actual performance of the Longitudinal Assessment of Posttraumatic Syndromes (LAPS) effort.
• The PD(s)/PI(s) will attend all project Leadership Committee meetings, will annually document progress in written reports to the NIMH Program Officer, and will provide periodic supplementary reports upon request.
• Awardees will have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. A data sharing plan is expected for this FOA, and is expected to specifically state as appropriate:
• when and how the longitudinal databases (raw and constructed variables) will be placed in the public domain,
• how the data will be made available to qualified investigators while safeguarding the privacy of participants and protecting confidential and proprietary information,
• the plans for data dictionary preparation and careful documentation of data collected,
• what key elements will be included for data sharing
• the data sharing schedule/timeline (i.e., release of data),
• the plan for post-award disposition of data,
• the ability to share raw and analyzed samples for the duration of the project and ability to maintain or transfer ownership if the samples are to be stored beyond the funding period,
• Timely publication of major findings by the Group members is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIMH support, including the assigned cooperative agreement award number. The Leadership Committee will establish procedures and criteria for presentation and publication of data developed in LAPS effort so these criteria are consistent throughout the project.
• The awardees will have primary authority and responsibility to define objectives and approaches and to plan and conduct the proposed research. She/he will assume responsibility and accountability to the applicant organization and to the NIMH for performance and proper conduct of all research supported in the study The PD(s)/PI(s) will be a member(s) of the Leadership Committee, described further below.

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

• An NIMH Program Official will be responsible for the normal scientific and programmatic stewardship of the award, including programmatic monitoring and assistance in the coordination of the overall project and implementation of the data and research resource sharing plans and will be named in the award notice.
• In addition to the Program Official, during performance of the award, an NIMH Project Scientist will be named to the study team. The role of the NIMH Project Scientist is one of substantial involvement above and beyond the normal program stewardship role of a Program Official. The Project Scientist will be an active member of the Leadership Committee and will have voting rights as a committee member. The Project Scientist will serve as scientific liaison among the awardee, other NIH program staff and consultants who may be asked to provide advice and guidance around target development studies. The participation of the NIMH staff Project Scientist is intended to assist the project Leadership Committee in efforts to ensure that the broad scientific goals of NIMH are reflected in the final design, implementation, and reporting of results from the study. The NIMH Project Scientist will participate in decisions about the study design, instrumentation, clinical assessment, and target development studies. The NIMH Project Scientist will participate in all major project meetings and may cooperate with the awardee as author or co-author of resulting publications in accordance with publication policies developed by the Leadership Committee of the awarded project. Publications involving NIMH staff must follow NIH and NIMH publication policies.

Areas of Joint Responsibility include:

A governing Leadership Committee composed of the PD(s)/PI(s), leaders of the DCC, each of the site PD(s)/PI(s) and NIMH Project Scientist will be established to assist in developing the scientific content and direction of the program, and to monitor progress over time, including the critical role of interim analyses that are expected to inform adjustments in assessments and assessment intervals as well as target development studies. The Leadership Committee will review progress of any work groups and will review evidence to assess whether interim analyses support proceeding with proposed/modified target development studies in years 3-5. The Leadership Committee members will meet periodically to review study progress, plan and design research activities, and establish priorities, policies and procedures. Adoption of study policies and procedures will require a majority vote. Each member will have one vote in any decision to be made by the Leadership Committee with respect to study policies and procedures. The NIMH Project Scientist will be a voting member of the Leadership Committee but may not serve as the Chair of the Leadership Committee. The frequency of meetings, not fewer than two per year (it is expected these will be much more frequent in the startup phase of the project), will be determined by the PD(s)/PI(s) who will be responsible for scheduling the time and place and for preparing concise proceedings or minutes (two or three pages), which will be delivered to the NIMH Project Officer within 7 days of the meeting.

Work groups: If the PD/PI determines workgroups are needed to oversee specific aspects of the project (e.g., target development studies workgroup), all workgroups will be co-chaired by the PD/PI and an NIMH-Project Scientist and will include additional members from the scientific team of the grant, consultants and NIH staff as needed to ensure project success. Work groups will meet as needed and will produce progress reports for evaluation by the Leadership Committee.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. The three members are: a designee of the Leadership 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 designees; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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. During the first few months of the project, the PD/PI and NIMH will review proposed milestones for recruitment of subjects into the longitudinal study and an interim analysis plan to ensure data gathered will support a decision for target development studies. Specific milestones and advancement criteria will be submitted to the NIMH Project Officer for review. The NGA starting in year 3 will be amended to include approved study-specific milestones and advancement criteria. For each subsequent year of the project, the milestones and advancement criteria will be updated in a similar process and incorporated into NGAs. Continuation of U01 funding for the target development studies will depend on achievement of the target development study-specific milestones and approval by the NIMH Project Officer. The NIMH will evaluate requests based on scientific merit, portfolio balance, and budget considerations.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Farris Tuma, Sc.D
National Institute of Mental Health (NIMH)
Telephone: 301-443-3648
Email: ftuma@nih.gov

David Armstrong, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3534
Email: armstrda@mail.nih.gov

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: siscor@mail.nih.gov

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.