Purpose

This Funding Opportunity Announcement (FOA) encourages research project grant applications to leverage large-scale, real-world data from electronic health records (EHRs) from a variety of systems (e.g., the Department of Defense, Department of Veterans Affairs (VA), Centers for Medicare and Medicaid Services administrative claims as well as public or private health care systems and networks) to understand impact of treatments and services for mental and neurological disorders and to identify promising new mental health and neurological disorders research directions. There is particular interest in leveraging EHRs and administrative data to 1) understand and improve the treatment of post traumatic psychopathology including posttraumatic stress disorder, depression, traumatic brain injury (TBI), and risk for suicide and 2) characterize post trauma multi-symptom recovery trajectory patterns of TBI that may include posttraumatic stress disorder, depression, cognitive impairment, pain, substance abuse disorder, and risk for suicide.

Background
Given the prevalence of PTSD, depression, TBI, and suicidality among Service Members and Veterans, the NIMH, the NINDS and the VA Office of Research & Development (ORD) are particularly interested in health record examinations that may reveal new approaches to treatment of post-traumatic mental health and TBI sequelae. Both PTSD and TBI may be experienced by Service Members and Veterans and are prevalent in the general population as conditions that could develop after life-threatening trauma. PTSD and TBI presentations are heterogeneous and overlap with several problems associated with exposure to trauma. People exposed to trauma also may experience other severe neurological, psychological, behavioral, medical, and social dysfunction, including TBI, depression, anxiety, cognitive impairment, pain, substance abuse, and suicidality. There is also a growing awareness that post-traumatic psychopathology is linked to other serious health conditions (e.g., hypertension, smoking, heart disease).

This FOA aligns with a 2012 White House Executive Order directing the Departments of Defense (DoD), Veterans Affairs (VA), and Health and Human Services (HHS) to develop a National Research Action Plan (NRAP) on PTSD, other mental health conditions, and TBI, specifically through better use of EHRs to gain insight into the risk and mitigation of PTSD, TBI, and related injuries.

The healthcare landscape in the United States is constantly changing, creating new challenges for the delivery of high quality treatments and services to children, youth, adults, and older adults with unmet or under-met mental health needs. Epidemiological findings suggest that approximately one half of the United States population meets lifetime criteria for a mental disorder, and approximately one quarter of the population meets criteria in any given year. However, only one half of people with any mental health disorder and only two thirds of people with a serious mental health disorder received mental health services in the previous year. Of those that find their way into mental health care, many fall out of care and/or do not receive guideline concordant treatment. Disparities in population status (e.g., members of racial, ethnic, sexual, and gender minority communities), a fragmented healthcare system, provider shortages, healthcare affordability, and other factors moderate these findings. Research is needed to improve access, continuity, quality, equity, efficiency, and value of mental health services, and to bring effective strategies to scale to maximize public health impact.

In the past 40 years, major advances have been made, including the inception of the diagnosis of PTSD. There is now strong evidence to support the use of psychotherapies and the systematic rollout of Prolonged Exposure and Cognitive Processing Therapy throughout the Veterans Affairs Healthcare System has improved access for veterans receiving care within that system. Although no medications have been specifically developed for treatment of PTSD, two medications repurposed from other mental health disorders have been approved by the US Food and Drug Administration for PTSD treatment. Despite these advances, many individuals suffering from PTSD do not receive minimally adequate care. Similarly, recent evidence in TBI suggests that nearly half of patients presenting at Emergency Departments for TBI do not seek follow-up care 3 months post-injury despite recent evidence that a significant portion of mild TBI patients continue to report symptoms up to a year post-injury. Even among patients who have access to and receive the best evidence-based care for their diagnosis, far too many people will not respond adequately. Health care providers do not have guidance to suggest which patients will best respond to available treatments and often take polypharmacy approaches that include off-label approaches to try to address patients complaints.

Efforts are underway across the federal sponsors of research to improve existing evidence-based treatments and to develop new pharmacological, psychosocial and device-based interventions e.g., VA PTSD Psychopharmacology Initiative (PPI), NIMH Clinical Trials Funding Opportunity Announcements: First in Human, Exploratory Experimental Therapeutics, Confirmatory Efficacy, and Effectiveness. However, these and other initiatives will require substantial time and the yield is uncertain. The urgent clinical and public health needs associated with exposure to trauma including post-traumatic psychopathology and TBI broadly requires guidance in the short term for practicing clinicians. The use of large-scale, real-world data in EHRs may inform care in the near term.

The sponsors of this FOA recognize that while imperfect, data captured in large health care systems and information exchanges/networks which link together multiple electronic record systems have the potential for new insights. Health care systems such as the VA and DoD as well as integrated public or private health care systems and networks are believed to be valuable resources for rapidly understanding both the false positive and false negative results of failed clinical trials as many of the same medications are routinely prescribed. Health record examination may also inform which patients successfully adhere to or do not complete evidence-based treatments, highlighting the importance of complete treatment course or reasons why failures occur as pathways to promote better healthcare. Further, identifying clinical and functional impacts of current on- and off- label treatment practices is also a priority. Data from large EHR systems can also provide longitudinal health information valuable for understanding and characterizing post-traumatic disease course beyond what is currently known about the general trajectories of illness recovery (e.g., the role of pain in the development of illness). These longer-term outcomes have utility for classifying outcome trajectories based on treatment of post-trauma symptoms and clusters of symptoms. Understanding the role of care in altering post-trauma symptom trajectory as well as novel mediators and moderators can be used to develop prognostic risk models, inform treatment strategies, and be used for patient stratification in future clinical trials.

Research Objectives
Electronic Health Records queried under this FOA should be used to address urgent clinical and public health needs, especially those associated with post-traumatic psychopathology and TBI, but also for other mental disorders that could be better interrogated using EHR data. Data and measures selected are expected to reflect the care of the population and support the possibilities of hypothesized relationships between care and outcomes of interest. This work is expected to advance understanding of which patients may most benefit from available on and off-label treatments, including psychotherapies, pharmacotherapies, and devices. As this work hinges on the data available in the EHR and other records, inherent opportunities, as well as the limitations, that should be addressed in the application.

The goals of this FOA include, but are not limited to the following:

Inform the development of novel treatments, improve efficiency, and enhance clinical impact of existing treatments

• Examine on and off-label response rates to treatments
• Identify on and off-label side effects
• Identify characteristics/profiles of those who do or do not respond to off-label treatments including treatment for co-occurring mental and physical health conditions that may impact posttraumatic conditions
• Interrogate promising findings from smaller pilot trials in larger, more diverse, and real-world clinical care settings
• Integrate various sources of claims and outcomes-based data (this may include but is not limited to Federal and private health insurance or other claims that are beyond any provider group claims data)
• Apply, test, and validate predictive modeling to anticipate and predict treatment outcomes
• Use latent class analysis to cluster differential post-trauma outcome trajectories following TBI
• Understand outcomes related to mood dysregulation, cognitive decline, psychosocial change, pain, and substance abuse following TBI
• Understand mental health outcomes of patients treated for conditions whose symptoms overlap with posttraumatic disorders
• Identify high value interventions and strategies that measure or model the actual or potential impact of specific interventions, approaches, or strategies on health-related behaviors, healthcare utilization, and health outcomes
• Enhance understanding of the epidemiologic contexts for targeted interventions (e.g., accurate rates of diagnosis, linkage to services, and comorbid conditions that indicate gaps and targets for intervention)
• Use EHR to promote use of standardized outcomes measures and measurement-based care in treatment of post-traumatic conditions
• Examine approaches to improve treatment fidelity and treatment adherence and examinations of the effects on treatment outcomes
• Leverage EHR to learn about the status of Veterans who chose to use non-VA health care services rather than using VA provided health care
• Investigate how access to both internal and external health records may improve the health of all Veterans

Examine services delivery to improve the quality and outcomes of care

• Understand factors affecting mental health services outcomes using computational and predictive analytic approaches
• Inform how to best replace or discontinue interventions, especially those that are less effective or ineffective as compared to best evidence-based practices (i.e., deimplementation)
• Develop methods to improve the value of information gleaned from EHRs, to further EHR development and case identification approaches and approaches to determine ?response to treatment, and to improve generalizability of findings
• Understand how healthcare system changes (e.g., success of program implementation of specific treatments or clinical practice guidelines) impact service utilization and outcomes

Research on innovative service delivery models to reduce or eliminate known health disparities related to race, ethnicity, geography, sexual and gender minority status, socioeconomic status

• Understand the benefit of varying contexts for delivery of care (e.g., training of healthcare provider, care provided in individual vs group settings, delivery in person vs telehealth) where evidence does not currently exist
• Understand health disparities in health care practice, access, and treatment response
• Identify mutable factors that impact access, continuity, utilization, quality, value, and outcomes, including health disparities in outcomes, or scalability of mental health services in the United States that may serve as targets in future service delivery intervention development

1. Eligible Applicants

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

• 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)

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.

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

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications

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

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

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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