Key Dates

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National Institute of Mental Health (NIMH)

National Institute on Drug Abuse (NIDA)

The National Institute of Mental Health, in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute on Drug Abuse (NIDA), intends to promote a new initiative by publishing a Notice of Funding Opportunity (NOFO) to solicit applications for research  to understand the heterogeneity of central nervous system (CNS) outcomes in people with HIV employing quantitative assessments that are linked to psychopathology, to identify distinct disease phenotypes, known as biotypes. .

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects. 

The NOFO is expected to be published in Spring 2023 with an expected application due date in Summer 2023.

This NOFO will utilize the P01 activity code. Details of the planned NOFO are provided below.

 The Biotypes of Central Nervous System Complications in People with HIV (PWH)

Central Nervous System (CNS) complications, including mild to moderate cognitive impairment and adverse mental health outcomes are significant comorbidities among individuals living with HIV on antiretroviral therapy (ART). Despite two decades of clinical studies and many clinical trials aimed at improving outcomes related to CNS complications associated with HIV, results have been largely disappointing, with most trials showing minimal or no improvement in neurocognitive function. Researchers are now recognizing that, in addition to inflammation at the cellular level, various patient-level factors such as comorbid conditions (e.g., cardiovascular, metabolic), concomitant neurological diseases, persistent CNS viral reservoirs, long-term effects of chronic HIV infection, immune system dysfunction, social and structural factors, concomitant drug use and ART-related toxicity can influence CNS pathogenesis and resulting outcomes.

The complexity of these multifactorial pathogenic pathways leads to heterogeneity in outcomes. There has been a shift in psychiatry towards incorporating a neurobiological understanding of CNS disease and patient outcomes, rather than solely focusing on clinical phenomenology. To better understand the heterogeneity of CNS outcomes in individuals living with HIV, it is necessary to collect and analyze biological measures related to the etiologies and pathophysiological pathways involved in causing such complications. This effort can help identify biologically distinct disease phenotypes (based on mechanisms), known as biotypes, and allow for the development of personalized treatment strategies (precision medicine) to mitigate negative CNS outcomes in people living with HIV.

Research Scope and General Structure of This P01 Funding Opportunity

Applications responding to the Notice of Funding Opportunity (NOFO) must include the research components (listed below) along with an administrative core, a clinical core and a data management core. Applicants may also propose up to three resource and analytics cores; however, these are optional. All proposed components and cores are expected to be integrated and work together as part of a whole project with a singular goal to identify biotypes of CNS outcomes in PWH. 

• Data collection, integration, and harmonization of existing data from studies of PWH
• Development, Testing, and validation of  biologically linked assessments to identify biotypes of CNS complications in PWH
• Machine learning and deep learning-based clustering analysis to identify phenotypic clusters of patients with similar underlying pathophysiology

The research study will commence with the collection, integration, harmonization, and analysis of existing datasets of NeuroHIV studies from various research sites, to identify broad phenotypic clusters of patients with similar underlying pathophysiology, with the data management core being responsible for managing this process. Based on these clusters, the team will determine a common set of measures for initial screening (Tier 1) and longitudinal assessments (Tier 2) involving CNS outcomes specified below. Tier 1 assessments can include brief biologically linked Research Domain Criteria (RDoC), NIH-Toolbox, and Neuro-Qol-based neurobehavioral assessments to study constructs relevant to underlying pathobiology and should be of a limited duration, while Tier 2 assessments will consist of a comprehensive battery of measures, including multimodal assessments of behavioral outcomes, neuronal pathophysiology, virological features, immune dysfunction, co-morbid conditions (e.g., cerebrovascular, metabolic), social and structural factors, concomitant drug use and possible ART-related toxicity. The end goal of the research is to employ machine learning and deep learning algorithms to identify the various actionable biotypes of CNS complications among people with HIV using the data obtained from these tiered assessments in combination with existing research data. Datasets selected for identifying the phenotypic clusters should be well-described and appropriate for answering the stated research questions, including appropriate data types and measures. Procedures for selecting datasets that are representative of the population, with the goal of minimizing potential bias, should be described in the application. 

The individual research components must be part of a cohesive whole where the success or failure of each component is tightly linked to that of all the other components. The datasets that are analyzed and the assessments being developed must include components of the below mentioned multifactorial etiologies and pathogenesis pathways that influence CNS outcomes in PWH:

• Demographics, anthropomorphic measurements, socioeconomic status, clinical history including ART medication history, neuromedical factors including concomitant medication use and the presence of other related comorbidities as well as neurological disorders
• Laboratory data collection and analysis including CBC, CD4+ T cell enumeration, plasma HIV load, alongside measures of viral dynamics in the CNS (CSF) and periphery including state of the science assays to quantify viral reservoirs 
• Neuropsychiatric assessments using the RDoC framework that can aid in identifying the biological phenotypes of CNS outcomes to evaluate domains of interest including Negative Valence, Positive Valence, Cognitive systems, Social Processes, Arousal and Sensorimotor systems
• Assessments of neurological and neurobehavioral function using NIH Toolbox and/or Neuro-QoL frameworks
• Longitudinal structural, functional, and task-based neuroimaging assessments to comprehend alterations in neuronal circuits, as well as neuroimaging measures of chronic cerebrovascular and BBB dysfunction.
• Collection and Analyses pertaining to pathway linked biological measures such as signaling pathways, neuroinflammation, neurotransmitters, immune profiles, neuroendocrine pathways, cerebrovascular dysfunction, and neurodegeneration (e.g., Neopterin, NfL, p-tau, GFAP)
• Host and viral genetic/ epigenetic data that can aid in identifying biotypes of CNS complications 
• All the above in the context of substance use (nicotine, cocaine, methamphetamine, stimulants, opioids, prescription drugs, and cannabinoids) and substance use data across the lifespan.

Applications should include the following items:

Multidisciplinary Team: 

Because this effort involves bringing together different modalities of assessments and diverse expertise, applicants must form multidisciplinary teams. It is expected that each team would include experts with knowledge and experience in the NeuroHIV field related to: 

• Neuropsychiatry, clinical neurology and neuroimaging 
• Substance use and co-morbidities 
• Data curation, data science and machine learning
• Virology and immunology
• Management of multimodal clinical studies

Diverse Clinical Sites: 

HIV is a global pandemic and CNS complications in PWH are prevalent in populations across diverse settings. Consequently, for this project it is expected to have diverse clinical sites and data sets obtained from at least one international site and a minimum of three distinct domestic sites with sufficient cases for identifying phenotypic clusters of CNS complications in people with HIV. Furthermore, a similar configuration of sites should be utilized in the development, testing, and validation of Tier 1 and Tier 2 assessments. Using datasets from geographically diverse populations can provide a wider range of demographic, cultural and socioeconomic backgrounds to help capture the true heterogeneity of CNS complications in PWH. All the clinical sites proposed must have access or have the capability to facilitate state of science approaches such as the ability to measure viral dynamics in the CNS, Serum/CNS biomarker quantification and advanced neuroimaging.

Clinical Benefit of identified biotypes: 

This NOFO supports development, testing and validation of RDoC,  NIH-Toolbox, and Neuro-Qol-based biologically linked Tier 1 and Tier 2 assessments that measure constructs dimensionally, along a spectrum of functioning to identify biotypes of CNS complications in PWH. The assessments should be developed using iterative design process to meet acceptable standards of reliability, sensitivity, validity, generalizability, accessibility, and engagement across participants.  The applicants should have a strong supporting rationale for the approach they use to develop the Tier 1 and Tier 2 assessments and how these assessments represent a significant improvement over the current state of the science. Further, the applicants must demonstrate, their methodology for developing the Tier 1 and Tier 2 assessments can provide insights for conceptualizing personalized treatment strategies to alleviate CNS complications in PWH.

Milestones: 

Annual Go/No-Go milestones must be proposed in the overall Integrated Development Plan to reflect progress on each of the above-mentioned research components. Applicants should clearly outline how the research components are interrelated and the order in which each research component needs to be successfully completed before initiation of other components. A discussion of the milestones relative to the progress of specific research components and the implications of successful completion of the milestones for the other research components should be included. Milestones should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Specific aims or a list of activities are not considered milestones because they would not enable evaluations of specific goals. 

The clarity and completeness of the outlined milestones regarding specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties.  Evaluation of the proposed milestones will be a significant criterion of the scientific peer review. The annual administrative review of Milestones will place a high priority on the following:

• Successful achievement of milestones
• Assessment of the overall feasibility of program advancement, considering data that may not have been captured in milestones
• Availability of funds

Cores

Administrative Core (required): Each application must contain an Administrative Core that is responsible for the overall management, communication, coordination, and oversight of the program.

Clinical Core (required): Each application must contain a Clinical Core as one of the components that will be involved in developing, testing, and validating Tier 1 and Tier 2 assessments to identify biotypes of CNS complications in PWH. The clinical Core must be composed of a multidisciplinary team of investigators and have representatives from all the clinical sites where the Tier 1 and Tier 2 assessments are being conducted. The clinical core may include a Scientific Advisory Committee to provide overall direction and guidance to develop, test and validate biologically linked (RDoC, NIH-Toolbox, and Neuro-Qol-based) Tier 1 and Tier 2 assessments. 

Data Management Core (required): Each application must contain a Data Management Core as one of the  components that will provide reliable data management, data analysis and communication among  the proposed P01 research sites, as well as a reasonable plan to develop a data science framework for facilitating the workflow for data aggregation and analysis between the proposed research components. The data management team should include appropriate data science staff with expertise in advanced machine learning and software engineering support. The Data Management core may include a Scientific Advisory Committee to provide overall direction and guidance related to data science approaches to identify biotypes of CNS complications in PWH. The Data Management Core should provide details on plans to identify best practices, standards, tools, workflows, and computational infrastructures, and to reuse those already in use by the research community, where applicable.

Resource and Analytic Core (Optional): Applicants may propose up to three Resource and Analytic cores (e.g., Biomarker Core, Neuroimaging Core, Comorbidities Core) to provide guidance, analytics support, and resources necessary for accomplishing the goals of the three individual research components. Each of these cores, when proposed, can include a Scientific Advisory Committee to provide overall direction and guidance in specific areas of expertise essential for achieving the proposed goals of the grant. A Resource and Analytic Core must not duplicate resources already available at the institution(s). While the addition of Resource and Analytic Core(s) is optional, if included in the application, the core(s) should be critical to the success of the P01 project.
 

TBD

Applications are not being solicited at this time. 

Please direct all inquires to:

Vasudev R Rao, MBBS, MS.
National Institute of Mental Health (NIMH)
Telephone: 301-825-3259
Email: [email protected]

Yu Lin, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1318
Email: [email protected]