NIH Sleep Research Plan

NIH Sleep Research Plan

This community and the corresponding Request for Information (RFI) have been issued to gather broad input and facilitate open discussion on the critical research opportunities and strategic goals proposed in the upcoming NIH Sleep Disorders Research Plan. We ask all the stakeholders to consider the following questions when providing input on the critical opportunities and strategic goals.

Critical Opportunities:

• Do the proposed Critical Opportunities capture current research interests in sleep and circadian rhythms biology?

• Do the proposed Critical Opportunities inspire future research directions?

• Are there noticeable gaps or missing opportunities not included herein?

Strategic Goals:

• Do the proposed Strategic Goals address the research priorities of stakeholders in the sleep and circadian rhythms fields?

• Are there priorities or needs not addressed by the proposed Strategic Goals?

Campaign Brief

Generating high-value scientific knowledge in sleep and circadian sciences, ranging from basic mechanistic biology through the clinical translational spectrum, will lead to new avenues for curing disease and promoting health, well-being, and safety. The plan presents five strategic goals, research priorities, and tactics exemplifying the potential for sleep and circadian sciences to strengthen health-care, well-being, and safety. Additionally, nine critical opportunities are identified with the potential to broadly advance the landscape of biomedical sciences. Realizing opportunities in the developing sleep and circadian disciplines will hinge on innovative strategies promoting research training of a diverse interdisciplinary workforce with the skillsets and resources to inspire innovation and tackle challenges in sleep and circadian sciences.

To submit a response, click on the "Submit New Idea" at the top of the page. To browse, comment, and vote on other responses, click on the "Browse Ideas" button in the box above. Community responses are voluntary and may be submitted either anonymously or with identifying information. Do not include proprietary, classified, confidential or sensitive information in a response. Responses must be submitted by **11:59 pm (EST) June 18, 2021.**If you are willing to do so, please indicate your primary affiliation/role or you may select to submit anonymously

STRATEGIC GOALS

These strategic goals are long-term objectives with the potential to change the landscape of sleep and circadian research over the coming years by setting research priorities and benchmarks that will improve our scientific knowledge, transform healthcare, and advance public health and safety and the well-being of the nation.

Goal 1: Elucidate the Sleep and Circadian Mechanisms Underlying Health and Disease

CDC national surveillance studies estimate that over 30% of U.S. adults and over 70% of teens nation-wide report sleep deficiency (insufficient sleep, irregular sleep, poor quality of sleep). Chronic disease and social determinants are associated with sleep deficiency and circadian misalignment. Identifying the mechanisms underlying sleep and circadian biology is essential for predicting responses to environmental influences and early detection of health-to-disease transitions. Improved understanding of the biology would enable earlier and better targeted interventions. Using new methodological and technological advances in optogenetics, functional brain imaging, wearables, and informatics ranging from single-cell models to population-based approaches will allow for new discoveries that inform the design of future studies that can be translated from the bench to populations.

This research would:

  • Promote health and resilience against disease.
  • Better define the cellular and systems biology processes that indicate health to enable early detection of transition to disease states.

GOAL 1 High-Priority Research Areas

  • Research the various normal biological functions of sleep and circadian rhythms that define sleep health to detect and better understand the earliest origins of disease processes to, preserve health, and promote resilience.
  • Elucidate the complex interactions of circadian rhythms across various organ systems through computational and mathematical modeling (systems biology), and identify emergent phenomena that influence health and disease.
  • Explore mechanisms underlying the bidirectional relationship of the aging process and circadian rhythms.
  • Determine the brain mechanisms and effects of sleep and circadian rhythms on development, illness course, and treatment of mental health disorders, and identify the genetic-basis of such interactions.
  • Explore the mechanistic basis for circadian rhythm and/or sleep disruption as a carcinogen.
  • Identify the effects of sleep disruption on reproductive development and function.
  • Explore the role of sleep and circadian rhythms in blood brain barrier regulation as it affects drug efficacy.
  • Explore the genetic, epigenetic, molecular, cellular, and systemic mechanisms that determine sex-related differences in sleep and circadian disorders.
  • Define the sex-related differences of immune responses to sleep quality and quantity in autoimmune disease.
  • Identify the neural mechanisms and bidirectional interactions of sleep deprivation or disruption, and mental health disorders including emotional dysregulation and mood disorders.
  • Explore the effects of environmental exposures (e g. alcohol drinking, cigarette smoke, particulates, pathogens, temperature, light exposure, humidity) on sleep and circadian rhythms, and downstream consequences for organ function and disease.
  • Identify sleep and circadian influences on the biology underlying obesity and cardiometabolic risk in humans and develop preclinical models to better tailor interventions in clinical-translational studies.
  • Understand the interplay between intermittent hypoxia, sympathetic activation, microbiome, and endogenous stem/progenitor cells, and their contributions to progression of diseases.
  • Develop and test preclinical models of sleep and circadian disturbances in relation to critical illness (e.g. sepsis) and identify novel targets for drug discovery and therapeutic management.
  • Explore single-cell analytics in order to understand the cellular phenomena of sleep and circadian rhythms and enable discovery of surrogate biomarkers for sleep and circadian disorders.
  • Advance understanding of the pathways of pain, reward, sleep, and circadian rhythms to identify new therapies.
  • Investigate racism and other forms of discrimination as a major contributor to cumulative chronic stress and a driver for disparities in sleep and circadian disorders.
  • Elucidate multilevel and multifactorial causal pathways for disparities in sleep and circadian disorders, for example, examine the role of sociocultural and physical/built environmental determinants on population sleep disparities.
  • Examine mechanisms underlying sleep pathology contributing to risk for Alcohol Use Disorder (AUD).
  • Understand the effects of developmental alcohol exposure on sleep patterns later in life, and the mechanisms of alcohol-related sleep disorders.
  • Investigate the mechanisms of persistent sleep problems emerging during abstinence from alcohol use as it contributes to risk for relapse. 

Goal 2: Improve the Treatment of Sleep & Circadian Disorders and Reduce the Risk Associated with Sleep Deficiency

There is recognition of the impact of sleep and circadian disorders, and sleep deficiency outside of a disorder, as a growing economic and public health concern, that requires coordinated and well-planned prioritization of research aimed at alleviating disease burden. This entails developing and implementing tailored approaches, designed and targeted to populations. Such efforts are complementary to targeting primary and secondary prevention approaches.

Research in this area would:

  • Bring effective treatments and cures to patients with sleep and circadian rhythm disorders.
  • Identify strategies that lead to long term adherence to interventions/treatments.
  • Better understand sociocultural and physical/built environmental factors that impact interventions targeting sleep deficiency and circadian misalignment.

GOAL 2: High-Priority Research Areas

  • Determine what level of intervention for sleep-disordered breathing yields optimal outcomes and defines adherence.
  • Determine whether interventions for sleep-disordered breathing can decrease morbidity and mortality.
  • Examine the effects of sleep-disordered breathing treatment on cardiometabolic outcomes and the mediator/moderator effects of the gut microbiome in affecting such cardiometabolic outcomes.
  • Improve understanding of the influence of sleep and circadian rhythms on pain, addiction, and recovery from addiction across the lifespan.
  • Identify optimal and personalized interventions for individuals with obstructive sleep apnea through comparative effectiveness trials of available therapies (e.g. positive airway therapy versus dental devices or implantable hypoglassal stimulators).
  • Study sleep interventions and treatment of sleep disorders as an approach to improve pain control and reduce reliance on pain medications.
  • Examine the effect of sex/gender on treatment and diagnostic pathways for sleep disorders and related outcomes.
  • Conduct long-term comparative effectiveness research on medications versus cognitive behavioral therapy to treat insomnia.
  • Conduct comparative effectiveness research on complementary and alternative approaches versus cognitive behavioral therapy for insomnia – including various modalities of delivery.
  • Identify the pathobiology of sleep disordered breathing (SBD) during pregnancy and the effect of treating SDB during pregnancy on maternal and infant morbidity and mortality.
  • Develop novel approaches that are not limited by poor adherence to improve treatment for individuals with sleep and circadian disorders.
  • Understand the mechanisms by which social conditions and psychosocial stress affect sleep and circadian rhythms.
  • Develop and test novel therapies for sleep and circadian rhythm disorders that meet the definition for orphan medical conditions (e.g., narcolepsy, non-24-hour sleep wake disorder [non-sighted and sighted], fatal familial insomnia).
  • Understand the cardiorespiratory interactions of therapeutic approaches for sleep-disordered breathing in patients with underlying cardiac, respiratory, or blood disorders.
  • Understand the effect of sleep and circadian disruption on critically ill patients.
  • Develop and test interventions to improve sleep and circadian rhythms in critically ill patients and assess short- and long-term outcomes in order to distinguish causal influence from associations and epiphenomena.
  • Develop screening and treatment approaches for sleep-disordered breathing in the perioperative setting to improve patient outcomes and reduce healthcare costs.
  • Improve adoption by providers of nonmedication approaches to improve circadian rhythms in patients with comorbid medical conditions and study the effects on tangible clinical outcomes.
  • Understand the impact of sleep and circadian rhythms and their disorders on traumatic brain injury through observational and intervention-based research studies.
  • Understand the effects of chronic alcohol drinking on sleep quality and sleep-disordered breathing.
  • Understand mechanisms that underlie resilience and/or susceptibility to risks associated with circadian sleep disorders and sleep deficiency.
  • Develop multilevel interventions that incorporate social and environmental determinants of health to address disparities in sleep and circadian rhythms health care.
  • Understand the impact of medications that treat mental illnesses on sleep regulation and the impact of insomnia treatments on mental illness symptoms.
  • Develop evidence-based, culturally appropriate interventions for populations that experience sleep health disparities.

Goal 3: Identify the Gaps and Opportunities to Accelerate the Clinical Implementation of Sleep and Circadian Research to Protect Public Health

Rapid advancements in informatics, meaningful use of electronic health records, and telemedicine in the delivery of healthcare holds great promise in addressing quality health care for all. The immense potential inherent to mobile health (mHealth) technologies to transform health care, personal health management, and basic health research offer scalable options for treating sleep and circadian deficiency/disorders at a population level. mHealth could be particularly relevant to underserved populations as cell phones and internet access become more ubiquitous – reducing barriers that limit access to quality health care and providers. Leveraging information technology and data science to deliver quality healthcare through innovative approaches is poised to continually and completely change the landscape of health care. Evidenced-based medicine is needed to guide implementation into healthcare systems and health services research, including dissemination and implementation trials, to generate the scientific data necessary to inform these new directions.

This will:

  • Embed research into healthcare delivery to enable natural experiments and continuous improvements that inform the science of healthcare delivery.
  • Reduce barriers and promote facilitators for more efficient and effective healthcare delivery.

GOAL 3: High-Priority Research Areas

  • Integrate omics and sleep-circadian data with EHRs to better predict healthcare utilization, transitions of care, and cost effectiveness.
  • Explore methods to circumvent "healthy volunteer bias" in conventional observational cohorts, clinical trials, registries and repositories, and improve representation of difficult to reach (NIH defined under-represented) populations (such as older adults [≥ 65 years age], and individuals with disabilities).
  • Gain understanding of geographic variability in healthcare delivery to patients with sleep and circadian disorders and how such healthcare delivery influences health and well-being.
  • Utilize/Develop informatics-based approaches to assist with ascertainment of clinical equipoise and implementation gaps in order to aid the development of appropriate trial designs for implementation science.
  • Leverage information technology and data science to promote health equity in prevention, identification, and treatment of disparate populations.
  • Develop multi-level strategies to disseminate and implement guideline-based and high-quality care for sleep and circadian rhythm disorders in populations with health disparities.
  • Identify and measure qualitative and quantitative measures that reveal barriers and facilitators for promoting equity in healthcare delivery for sleep and circadian disorders.
  • Promote the dissemination and implementation of a stepped-care approach for the treatment of sleep-disordered breathing in patients with prehypertension or treatment-resistant hypertension.
  • Identify patient, provider, and system-level factors that influence the detection, testing, and self-management of sleep and circadian disorders.
  • Develop and implement clinical decision support systems that can integrate into EHRs to provide high-quality care to patients with sleep and circadian disorders and reduce geographic and provider-based variations in practice – particularly in low-resourced hospital settings.
  • Develop and test innovative approaches to improve healthcare coordination in patients with sleep-disordered breathing.
  • Incorporate the Alcohol Use Disorders Identification Test (AUDIT) or AUDIT C into sleep screening to identify patients who are hazardous drinkers or have active AUD and are at risk for developing alcohol-induced sleep disorders and/or sleep-disordered breathing in order to improve patient outcome and reduce healthcare costs.
  • Perform cost-effectiveness research on the treatment of sleep and circadian disorders in integrated healthcare systems, with an emphasis on tangible patient outcomes (e.g., health-related quality of life, hospitalization, morbidity, and mortality).
  • Improve early identification and treatment of circadian rhythm disorders.
  • Identify the effect of simultaneously or sequentially treating sleep and circadian rhythm disorders in patients with comorbid medical, behavioral, and psychiatric conditions and explore the effect of such treatment approaches on patient- and system-level outcomes.
  • Develop and test multimodal medication and behavioral approaches targeting patients and providers to improve sleep, circadian rhythms .
  • Develop interventions for health care settings that serve low socioeconomic and rural populations.

Goal 4: Advance the Scientific Understanding of Sleep & Circadian Contributions to Health Disparities, Populations, and Public Safety

Sleep health disparities (SHDs), are defined as differences in one or more dimensions of sleep health (duration, efficiency, timing, regularity, alertness, and quality)—on a consistent basis—that adversely affect designated disadvantaged populations. There are pronounced SHDs among racial/ethnic, rural, low socioeconomic status and sexual gender minority populations in the U.S. The incidence and prevalence of sleep deficiencies at a population level are influenced by many of the same determinants for other health outcomes with known health disparities. Thus, a nuanced integration between health disparity causal pathways and sleep and circadian-related mechanisms tailored for the specific population(s) and sensitive to the sociocultural context(s) is needed to understand and address SHDs.

Strategies to address SHDs where identified by the community and described in detail in the workshop report and include a) develop and promote integrative research on SHDs, b) investigate the causes and health consequences of SHDs, c) and develop interventions to address SHDs.

This research would:

  • Improve sleep health by targeting populations that experience health disparities.
  • Enable more patient-centered approaches to diagnose and treat sleep and circadian rhythm disorders.
  • Advance effective public health and safety policies that address sleep health disparities.

GOAL 4: High-Priority Research Areas

  • Develop education-based studies to increase societal awareness of the importance of sleep and circadian rhythms, in addition to adequate nutrition and physical activity, to promote optimal health among underserved US populations.
  • Develop studies to investigate how increased social awareness of the effects of short- and long-term chronic drinking on sleep quality impact behavior.
  • Improve understanding of sex and gender differences in sleep quantity and quality in relation to demographic and social determinants.
  • Understand the relative contribution of environment/geolocation, racial discrimination, and adverse childhood experiences on sleep and sleep disorders across race/ethnicity.
  • Enable data-driven health policies aimed at promoting sleep and circadian rhythms and management of sleep and circadian disorders in populations with health disparities.
  • Enable community-based research to facilitate comparative-effectiveness, dissemination, and implementation research in sleep and circadian disorders.
  • Study the characteristics of social and physical environments in schools, colleges, healthcare facilities, and workplaces that promote good sleep and aligned circadian rhythms, and the effects on health, health-related quality of life, healthy development, healthy behaviors, and mental health across all life stages among underserved populations.
  • Develop studies to investigate how increased awareness of sleep and circadian rhythms disorders play a role in the health and well-being in underserved populations, including shift workers and patients with sleep and circadian rhythm disorders.
  • Develop and test "real-world" interventions through novel, system-level redesigns aimed at promoting improved sleep and circadian rhythms in shift work workers and study the effect on health, well-being, patient and public safety, especially in population that experience sleep health disparities.
  • Integrate sleep and circadian research into big-data analytics and social media outside healthcare systems (including public-private partnerships) to enable the study of sleep and circadian influences on population health.
  • Explore the effect of sleep and circadian disorders on the workplace with respect to absenteeism, presenteeism, costs to employers, and workplace safety.
  • Develop novel approaches for multi-modal detection of sleepiness and fatigue, with an emphasis on biomarkers in the transportation and related industries.
  • Develop and implement mechanisms for preventing fatigue and sleepiness related accidents in homes, transportation, healthcare, and other industries.
  • Study the bi-directional relationships between social, environmental, and policy level factors (e.g. discrimination, noise) and sleep and circadian health among U.S. underserved populations.

Goal 5: Foster the Development of a Strong and Diverse Workforce for Sleep and Circadian Research

Building a diverse scientific workforce, as well as recruiting and retaining researchers in the fields of sleep and circadian biology are a high priority. The diverse workforce is inclusive of all underrepresented groups as highlighted by the Notice of NIH's Interest in Diversity as well as scientific backgrounds and perspectives. Diversifying the sleep and circadian workforce should start as early in the education pipeline as possible to ensure that talented individuals receive the opportunity to engage in research to strengthen the fields. The fields of sleep and circadian research are rapidly growing and include basic research areas all the way through to population sciences in every cell and organ –affording the field access to a research pool that is shared by few other scientific disciplines. The increase in both the number of awards and the number of Institutes, Centers, and Offices across NIH that fund sleep and circadian research, signifies the evolution and expansion of the fields into new areas, highlighting the potential.. Major advancements in the field have opened opportunities into new areas such as implementation research, public health, nursing, medicine, and bioinformatics, which are all perspectives that could advance human health and safety.

TACTICS for Addressing Research Areas in Sleep and Circadian Research:

There are methodological and technical barriers to advancing the science and practice of sleep and circadian rhythms medicine. Solving such issues can have a transformative effect on the field and improve the ease and pace of research in sleep and circadian rhythms. These issues need to be addressed by methodological studies and are necessary to help advance the science of sleep and circadian sciences.

  • Develop, validate, and test a wider variety of cellular and animal models of health and disease states of sleep and circadian rhythms, and develop consensus on the strengths and weaknesses of such models.
  • Develop, validate, and set standards for wearable technologies that can measure sleep and circadian rhythms, and integrate such measures with other physiological data into electronic health records or data clouds.
  • Utilize AI techniques to enable predictive modelling and the interoperability of multidimensional sleep and circadian rhythms data; improve disease surveillance; identify positive deviance; promote treatment adherence; promote early and effective engagement of patients, public and stakeholders; and support platforms for comparative effectiveness research and clinical decision support systems.
  • Engage research sponsors (NIH Institutes, inter-agency efforts, foundations and industry) to encourage the collection and reporting of timing of samples in observational studies and interventions in clinical trials, in order to generate hypotheses for chronotherapies in every organ system, including emergent phenomena such as sleep and circadian rhythms.
  • Develop accessible, harmonized, reference data science approaches to better understand circadian contributions to health and disease
  • Undertake greater representation of patients with circadian rhythm sleep disorders in sleep and circadian science research.

 

CRITICAL OPPORTUNITIES (CO)

Timely research directions with the potential to significantly impact sleep, circadian, and biomedical sciences were identified across the translational spectrum from knowledge generation and discovery science to medicine and public health. These opportunities map to multiple strategic goals and were selected as examples informing the overall research agenda. These examples do not exclude other research directions or limit the consideration of any investigator-initiated line of study.

CO1: Identify biomarkers in sleep and circadian physiology to indicate the severity of medical conditions and the effectiveness of therapeutic interventions.

Molecular and cellular indicators of normal biological processes, disease processes, and responses to an exposure or intervention (biomarkers) are tools critical to translating advances in sleep and circadian sciences to medical and public health applications. Objective tools to efficiently measure the magnitude of genomic and clinical abnormalities produced by sleep deficiency and poor circadian health are essential to enable the discovery of potentially modifiable risk factors, identify sleep and circadian-related susceptibility to disease, and provide the evidence/foundation on which to develop therapeutic recommendations.

The collection of physiological and pathological findings indicate a close inter-relationship between known networks of multi-omic layers linked to physical and mental health with sleep and circadian function. Existing computational technologies are poised to systematically interrogate these interactions for indicators of sleep or circadian function and promising biomarkers of mood disorders and emotional dysregulation. Multi-omic-data resources through which daily patterns of metabolic profiles, epigenomics, and protein and RNA expression patterns can be studied are needed to enable this achievement. Advances in these areas would thus support the development of sleep and circadian biomarkers to offer researchers an opportunity to better study or to have a greater impact on modifiable sleep-related risk and health outcomes across the lifespan.

CO2: Elucidate the significance of sleep and circadian biology to immune function and the microbiome.

Inflammatory homeostasis and the immunological response to damaged or unhealthy cells are closely coupled to preservation of sleep and circadian rhythms that sustain cellular physiology. The number of immune cells, such as lymphocytes and antigen presenting cells, and the expression of cytokines increase to maximal values during sleep and decrease during wakefulness. This homeostasis cannot be maintained during disturbances in sleep and circadian function, producing an array of abnormalities in innate and adaptive immunity. Resilience to infection is reduced, damaged or unhealthy cells are not removed, and inflammatory equilibrium becomes disrupted. Sleep and immunity are also bidirectionally linked: the release of inflammatory factors promote deep slow-wave sleep, which is critical to optimal host defense.

Scientists are able to map circadian rhythms in previously unimaginable detail due to technological advancements in the 24-hour measurement of gene activity and proteomics in the microbiome. A better understanding of the biological interactions between the microbiome and immune function would allow us to more clearly define normal healthy function and measure their perturbation by the environment, pathogens, or early disease processes.. A better understanding of these cross-cutting interactions in normal biological processes, would allow us to more clearly define health and measure their perturbation by the environment, pathogens, or early disease processes. The ability to detect and prevent abnormalities associated with early disease processes hastens the development of new therapies and strategies for health promotion and resilience.

CO3: Elucidate the relationships between sleep and circadian rhythms to clinical dementia outcomes and related pathologies, including Alzheimer's dementia and related dementias as well as pathobiology associated with AD/ADRD.

Over the past decade, seminal findings linking sleep and circadian biology with neurodegeneration have offered compelling evidence for the importance of sufficient sleep for optimal brain health. The discovery of the role of the glymphatic system in clearing accumulated neurotoxic waste products from the brain during sleep, and the strong association between sleep deficiency, sleep disorders and the vasculature, are key examples that not only highlight a new role for sleep in maintaining brain health at the individual level, but also demonstrate the impact of sleep and circadian sciences at the population and societal levels. Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, and Traumatic Brain Injury are all associated with disrupted sleep and circadian rhythms. However, evidence pointing to the bidirectionality of this relationship is mounting: not only do these conditions impact sleep, but sleep-wake and circadian disruptions can also lead to neurodegenerative pathologies. Although changes in sleep and circadian rhythms typically occur with aging, there are distinct differences between the changes in sleep in healthy aging versus those found in neurodegenerative diseases.

CO4: Identify the neurobiological mechanisms underlying the perception of sleep quality, sleepiness, and fatigue.

Improved understanding of the neurobiological mechanisms of why organisms feel sleepiness and fatigue, or the urge to sleep, could be transformative for not only sleep and circadian sciences, but other fields. Emerging technologies of brain imaging, molecular imaging, and wearables, combined with the recognition of the public health impact of an epidemic of sleep loss, sleepiness, and fatigue may offer new solutions to an obstinate challenge. fMRI studies indicate that sleep and circadian factors shape the function of brain centers underlying emotional regulation, cognitive function, coping, and interoceptive perception of pain and fatigue. For example, the study of interoception, which refers to the representation of the internal world, and includes the processes by which an organism senses, interprets, integrates, and regulates signals from within itself is extremely relevant to sleep and fatigue. Both sleep and interoception are tightly connected to physical and mental well-being, with complex, dynamic relations between sleep and sensory processes within each modality of interoception (e.g., thermoception, nociception, visceral sensations, and subjective feelings about these sensations). A better understanding of these interrelations may facilitate management of functional somatic symptoms, chronic pain, insomnia, and other sleep and mental disorders.

CO5: Develop chronotherapeutic approaches to prevent and treat chronic diseases.

The biology of natural, physiological rhythms and cyclical phenomena in human cellular, molecular, and emergent systems unlocks a powerful tool that can be leveraged to treat obesity, cardiovascular disease, metabolic, and respiratory diseases, cancer, rheumatoid arthritis, and mental health disorders. Translating evidence-based associations and applying them to develop or refine interventions as chronotherapy,( or chronomedicine), the alignment of treatment based on the body's circadian rhythms, could enhance therapeutic efficacy. Research has shown a time-of-day dependency for medical treatments in areas such as asthma, hypertension, cancer, and cardiovascular disease. For example, the blood brain barrier (BBB), which is circadian regulated, has also been shown to be impacted by chronic sleep disruption. Sleep loss disrupts BBB permeability via systemic low grade inflammation as a result of increased accumulation of inflammatory molecules that may in turn result in cognitive impairment. While its circadian regulation can help us understand why certain drugs work better at certain times of day, effective therapeutic regimens can be developed by optimizing time-dependent drug delivery as per BBB permeability by modulating the drug efficacies. Optimizing medication based on time-of-day could be transformative for healthcare as discoveries in chronotherapeutics could create a paradigm shift in medical approaches for preventing and treating major medical conditions.

CO6: Develop tools and/or methods for the early prediction, detection, and treatment of sleep deficiency and sleep and circadian disorders in children and adolescents to promote lifelong health and wellbeing, and prevent disease.

Sleep is critical to pediatric and adolescent development and daily functioning and impacts performance and health trajectories. As the effects of insufficient sleep in children persist into adulthood, this has wide-ranging implications for health and life outcomes. Recent findings suggest that epigenetic and metabolic effects of sleep deficiency and circadian abnormalities may be persistent and enduring across the lifespan. Maternal sleep deficiency has been linked to increased adiposity in offspring and alterations in postnatal neurodevelopment, emotional regulation, and metabolic and cardiac risks are associated with childhood sleep deficiency. Sleep deficiency and untreated sleep disorders increase blood pressure, atherosclerotic inflammation, and cardiometabolic disease risks at all ages.

Studies have also linked neighborhood conditions with adolescent sleep loss. Sleep is particularly reduced in low-income and developmentally delayed children from 3 – 6 years of age, and thus contributes to known health disparities that have far-reaching consequences. Evidence is emerging that environmental factors at the household- and neighborhood-level can alter healthy sleep. Social vulnerability – the potential negative effects on communities as a result of external stressors on health – and adverse childhood experiences (ACEs), which are stressful or traumatic life events that occur during the first 18 years of life, are linked to sleep disturbance in adults. Investigating the impact of sleep and circadian disruption early in life, and how these exposures affect disease and health trajectory across the lifespan could potentially offer opportunities for early-stage interventions to prevent disease.

CO7: Demonstrate how dissemination and implementation of high-quality care for sleep and circadian disorders can be improved by data science approaches in adaptive healthcare systems.

The application of artificial intelligence (AI) is becoming increasingly common in healthcare setting. Leveraging analytic approaches for big data by incorporating the complex information from multiple sources including electronic medical records (EHR), cohorts, clinical research studies, registries, smartphones, and wearable devices could be used to not only advance our understanding of sleep and circadian disorders, but could also provide information about prevalence, assist in the personalization of treatments, improve the allocation of resources, and inform healthcare policies. AI approaches could also be used to better understand sources of inequity in healthcare and health research related to sleep and circadian disorders; however, a major challenge is the lack of representation of diverse populations in big datasets. As innovation is not typically done through a health equity lens, it will be critical for the sleep and circadian communities to consider this perspective in any approach that is developed. Recognizing the importance of information management and data sharing practices in publicly funded research projects, the NIH has announced more expansive policies aimed at improving transparency, reproducibility, and availability of scientific data.

CO8: Embed omics-based approaches in real-world healthcare settings to facilitate personalizing treatments and cures for sleep and circadian rhythm disorders.

Personalized medicine and its considerable goal of harnessing an individual's own data to refine (or personalize) care from diagnosis, to treatment, to monitoring, remains a prominent ideal in medical research and a highly sought objective. One pathway to personalizing medicine is the collective methods and tools used to investigate the structures, functions, activities and interactions of different molecules within an organism, or omics-based approaches.

Technological breakthroughs, combining multiple "omics "approaches and artificial intelligence platforms, have revealed intriguing possibilities. Pragmatic research approaches within adaptive healthcare systems that embed knowledge generation processes in daily practice to continually improve care, could transform healthcare delivery not only within sleep and circadian medicine, but other medical fields as well. Furthermore, embedding the collection and time-stamping of biological samples during normal clinical workflows could create the foundational infrastructure for precision medicine in sleep and circadian sciences.

CO9: Identify people-driven approaches to improve awareness of sleep and circadian rhythms and promote healthy sleep behaviors for the benefit of public health and safety.

People-driven approaches to public health promotion are required to access difficult-to-reach populations for both primary and secondary prevention, treatment, and cures. The persistent barriers faced by under-represented minorities, rural populations, children, geriatric populations, individuals with disabilities, and other underserved groups, limit the ability of healthcare system-based approaches to improve national health. Sleep health disparities are an important focus for the promotion of health equity that can be effectively addressed through community- engaged and people-based approaches. Moreover, the sizable costs associated with delayed care during advanced disease could be shifted to a preventative disease model through people- or community-driven approaches for sleep and circadian disorders for better health in individuals with other medical and psychiatric conditions.

 

EMERGING OPPORTUNITY: COVID-19 PANDEMIC

Most of the acute effects of SARS-CoV-2 infection have been focused on the upper airway, lungs, and the cardiovascular system. Research has shown that the health and function of these systems are mediated by sleep and circadian rhythms biology. This relationship is further supported by recent evidence indicating that the risk of illness severity and death may be higher among COVID-19 patients with untreated sleep apnea. Furthermore, widespread reports of cognitive impairment in symptomatic patients indicate that the virus exerts direct and/or indirect effects on the central nervous system. The evidence for a neurological component to COVID-19 is further supported by documentation of the most common symptoms experienced by individuals after COVID-19: debilitating fatigue, difficulty breathing, cognitive dysfunction or "brain fog", and sleep disturbances including insomnia. For example, evidence suggests that in some cases respiratory failure and consequent mortality caused by the virus is not solely mediated through damage to the lungs, but may also involve impaired brainstem circuitry that regulates breathing.

Sleep and circadian biology are intrinsically tied to immune function and play a fundamental role in both mental and physical health. Extensive research has established that poor sleep and circadian misalignment undermines the immune system's ability to fight infections, may impair the effectiveness of some vaccines and may delay recovery from critical illness. Early reports suggest that sleep is affected by SARS-CoV-2 infection, and fatigue/sleep deficiency is a common complaint from those experiencing post-acute sequelae of SARS-CoV-2 (PASC) or "Long COVID". In addition to the significant impact on the health of the millions of individuals who have been infected by the virus, the COVID-19 pandemic has led to long-term behavioral, psychological, social, and economic consequences that need to be addressed in the coming years. Adequate sleep duration, sleep quality, and regular sleep schedules are essential for coping with physiological and psychosocial stressors, such as the COVID-19 pandemic.

While accumulating research demonstrates that sleep disruption is a prevalent feature of COVID-19, research is urgently needed to determine whether sleep is directly involved in COVID-19 susceptibility, immune response, and related pathophysiology. Sleep deficiency is modifiable, and a potential target to improve COVID-19 prevention, management and long-term outcomes.

Comments are strongly encouraged on opportunities that have been identified below:

• The role of sleep and circadian disruption in risk of infection and severity of acute COVID-19 across vulnerable populations.

• Sleep and circadian disruption as modifiers of COVID-19 pathobiology.

• The contribution of sleep deficiency to COVID-19 long-term effects on the cardiovascular, pulmonary, hematological systems, cancer and other diseases.

• Examine the bidirectional relationship between alcohol misuse and sleep disruption as modifiers of COVID-19 outcomes.

• Examine the effects of chronic alcohol drinking on sleep quality and their contribution to other symptoms such as cognitive impairment, pain, and anxiety that are associated with Post-Acute Sequelae of COVID-19 (PASC).

• Determine how shift work and chronic sleep disruption combined with alcohol misuse and alcohol use disorder (AUD) may exacerbate COVID-19.

• Disruption of sleep on women – due to factors such as care-taking responsibilities or burnout – and sleep disruption in pregnant populations.

• Research questions relating to the role of sleep and circadian disruption in the effects of COVID-19 across the cancer continuum, from cancer risk factors to diagnosis and treatment to survivorship.

• The impact of mitigation efforts in response to the COVID-19 pandemic on sleep, mental health, and wellbeing

 

Inquiries

If contact information is provided, NIH Program staff may contact respondents and may invite some respondents to present concepts for discussion at an ideation summit or other workshop. There will be no obligation to do so.

This community is intended for information and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the federal government. The NIH does not intend to make any awards based on responses gathered through this community or the RFI, or to otherwise pay for the preparation of any information submitted or for the government's use of such information.

Please direct all inquiries to:

Marishka Brown , Ph.D., NCSDR Director, NHLBI; Telephone: 301-435-0199; Email: NCSDR@nih.gov