NEWS & EVENTS
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Sleep Disorders Research Advisory Board (SDRAB) Meeting – April 4-5, 2024

April 4 - 5 , 2024
Hybrid (Virtual/In-Person) Meeting In Person: Rockledge II, Room 260 C/D

Description

"The Sleep Disorders Research Advisory Board (SDRAB) convened in a hybrid format on Thursday, April 4, 2024, from 1:00 PM ET to 5:00 PM ET and on Friday April 5, 2024, from 9:00 AM ET to 1:30 PM ET. SDRAB is a Federal Advisory Committee established by the NIH Revitalization Act of 1993 and the purpose of this meeting was to update the Advisory Board and public stakeholders on the progress of sleep and circadian research activities across NIH, and the activities of Federal stakeholders and interested organizations. Dr. Esra Tasali presided over the 2-day meeting as Chair and the minutes appear below.

Meeting Summary

DAY 1

BOARD MEMBERS PRESENT
Dr. Esra Tasali, Chair
Dr. Josiane Broussard
Dr. Paula Desplats
Dr. Jeffery Durmer
Dr. Erik Herzog
Dr. Dayna Johnson
Dr. Shaun Purcell
Dr. Alberto Ramos
Dr. Tom Scammell
Ms. Alexandra Wharton

BOARD MEMBERS ABSENT
Ms. Ebony Lay

EX OFFICIO MEMBERS PRESENT
Dr. Marishka Brown, Executive Secretary
Dr. Yejun (Janet) He
Dr. Karen C. Lee
Dr. Miroslaw Mackiewicz
Dr. Donald Shell

FEDERAL EMPLOYEES
Five Federal employes attended the meeting in person and 22 were in attendance via Zoom.

MEMBERS OF THE PUBLIC
One member of the public attended the meeting in person and 51 were in attendance via Zoom (including researchers, clinicians, patients, and other stakeholders).

CALL TO ORDER
Marishka Brown, Ph.D., SDRAB Executive Secretary

  • The executive secretary called the meeting to order at 1:00 PM ET as announced in the Federal Notice [89 FR 14511] on February 27, 2024. The meeting was fully open to the public in accordance with the provisions set forth in sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act.
  • Dr. Brown introduced the chair of SDRAB, Dr. Esra Tasali.
  • The Chair welcomed everyone and SDRAB members introduced themselves.

DIRECTOR’S REPORT - National Center On Sleep Disorders Research (NCSDR)
Marishka Brown, Ph.D., Director, NCSDR

NIH PROGRAM UPDATE - HEALthy Brain and Child Development Study (HBCD)
Katherine Cole, Ph.D., Acting Director, Scientific Program Manager, HBCD Project
National Institute on Drug Abuse (NIDA)

  • Overview of the HEALthy Brain and Child Development (HBCD) Study:
    • A prospective longitudinal study of early brain and child development, involving 27 collaborative research cites across the country that are recruiting participants in their 2nd trimester of pregnancy – following children through ages 9-10
    • Multi-modal assessments of brain, cognitive and emotional development, including influence of substances and environments from birth through childhood
    • Goals:
      • Characterize neurodevelopmental trajectories from large sample (~7,200 dyads)
      • Determine how substance exposure and other environmental factors affect developmental trajectories
    • Valuable resource; large dataset will be broadly shared with annual releases starting at the end of 2024
    • Supported by the NIH Helping to End Addiction Long-term (HEAL) Initiative and by 12 NIH Institutes, Centers, and Offices (ICOs)
  • HBCD assessment domains are related to the developmental origins of health and disease that are theorized to help shape and change child cognition and neurodevelopment.
  • The visit timeline starts prenatally at visit 1 with additional in-person visits at child ages 0-1 months, 3-9 months, 9-15 months, and 15-48 months. In addition, remote assessments take place at child ages 10-17 months, 16-50 months, and 36-60 months, for a total of 8 visits. Data collected include surveys, biospecimens, biosensors, MRI, and EEG.
    • Visit 3 (3-9 months) – visit 3 adds child brain activity measurements via EEG, assessments of parent/caregiver-child interactions, and several assessments from NIH Baby Toolbox that evaluate child behavior, emotional regulation, and neurocognition.
  • One objective is to understand how prenatal and early life exposures to opioids and other substances may impact developmental trajectories
  • The sleep-associated measures could be potentially be thought of as both an exposure and an outcome in terms of how they relate to neuroimaging data. Infants sent home with wearable sensors during visit 2 (0-1 month) and visit 3 (3-9 months):
    • For 72 hours child wears sensors to detect heart rate, O2 saturation, and respiration rate
    • Parents fill out daily reports of infant behavior (typical/atypical) during this 72-hour period
    • Sensors can provide information about overall health and well-being by monitoring sleep patterns, autonomic regulation, and physical activity patterns
      • Collect data on leg movement including acceleration and angular velocity (rate of rotation) from which estimated sleep time can be derived
      • Arm band data can be used to calculate sleep staging based on pulse rate and respiration rate
      • wearable sensor data may demonstrate early markers of neurodevelopmental health that could be detected through differences in activity and sleep patterns and possibly correlated with early substance exposures
  • These are the measures of sleep that are currently available in HBCD. Study protocols for later visits are still being finalized but later visits may transition away from the infants wearables to sleep questionnaires that the parent fill out.

The discussion with SDRAB focused primarily on the demographics of the HBCD dyads.

UPDATE ON CIRCADIAN & SLEEP DISORDERS REGISTRY
Alexandra Wharton, Patient Advocate, Member of the Board of Directors for the Circadian Sleep Disorders Network

  • Ms. Wharton presented the recently published paper Registry and Survey of Circadian Rhythm Sleep-Wake Disorder Patients, authored by members of the Circadian Sleep Disorders Network (CSDN), whose mission is to:
    • Encourage research into circadian rhythm sleep-wake disorders (CRSWDs)
    • Increase awareness among medical community/general public
    • Advocate for accommodations at work and school
    • Provide emotional support and treatment options
  • In 2016, the CSDN created a patient survey and registry to:
    • fill in knowledge gaps about the disorders including information on subjective patient experience and efficacy and durability of treatments
    • find volunteers who are willing to participate in research
  • The paper publishes the results of the survey.
  • Data for this study were collected between December 2016 and August 2022. The survey remains open. Researchers are invited to extract and analyze the data published to date.

STAKEHOLDER GROUP UPDATE – American Academy of Sleep Medicine (AASM)
James Rowley, M.D., Professor of Medicine, Rush University, Chicago; President, AASM

  • Dr. Rowley shared the vision and core values (of the AASM.
  • The present AASM Strategic Plan has 4 overarching goals, which Dr. Rowley reviewed:
  • Dr. Rowley concluding his presentation by highlighting Dr. Gina Poe’s keynote address, Essential Sleep Features for Brain Remodeling – Importance for Cognition and Emotional Health, at the SLEEP 2024 meeting.
  • He also noted the AASM Strategic Plan was being updated and that the new vision would be “sleep and circadian care is fundamental to health care”.

Nisha Aurora, M.D., M.H.S., President, AASM Foundation

  • The AASM Foundation was founded by the AASM in 1998. In 2023 the Foundation awarded >$25.7 million in 329 grants in the areas of career development, strategic research, community sleep health, and disaster relief. In addition, they have trained over 409 young investigators in their training program. Over the last 4 years, they have given away grant money to medical students who are interested in a career in sleep research.
  • Earlier this year they announced their new Strategic Plan for 2024-2028 and their purpose: to invest in people, research, and communities to improve the sleep health of all people.
  • Dr. Aurora shared that 2024 application cycle closed in October 2023 and awards will be made in July 2024. There were 5 strategic research initiatives:
    • AASM Strategic Plan Goals
    • Sleep Health Disparities
    • Dissemination & Implementation Research
    • REM Sleep Behavior Disorder Research
    • Central Disorders of Hypersomnolence Research
  • Letters of Intent submissions for the 2025 application cycle will open in September 2024, and the Foundation is currently working on what the strategic research initiatives will be for this upcoming funding cycle.
  • Other activities of the AASM Foundation include:
    • Sleep Team Travel Grant – the AASM Foundation was able to offer 10 grants to support first-time attendance at the SLEEP 2024 meeting for non-physician members of the sleep team, such as sleep technologists and APPs.
    • Young Investigators Research Forum (YIRF). The next issue date for the 2025 YIRF will be on September 9, 2024, with applications for scholarships due on October 21, 2024 and awards made in January 2025. The meeting will be held April 23-25, 2025 in Bethesda, MD.
    • Community Sleep Health and Public Awareness Grant – supports a wide range of projects and initiatives dedicated to addressing sleep health needs in local, national, or global communities. This program has been so successful that the Foundation recently increased funding to up to $50,000.
    • Collaboration with several other sleep organizations:

NIH SLEEP RESEARCH COORDINATING COMMITTEE (SRCC) UPDATE – National Institute of Mental Health (NIMH) Advances in Sleep and Mental Health Research
Laura Rowland, Ph.D., Program Chief, Division of Translational Research, NIMH

  • Dr. Rowland gave an overview of the National Institute of Mental Health (NIMH)
    • NIMH is the lead federal agency for research on mental illness, and supports basic science to implementation science
    • Supports more than 3,000 research grants and contracts at universities and other institutions across the country and oversees
    • The Intramural Research Programs support approximately 600 scientists working on the NIH campuses
    • Vision – NIMH envisions a world in which mental illnesses are prevented and cured
    • Mission – to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure
    • NIMH supports work that spans mental illness trajectories, from early origins to pre-symptoms, prodrome, illness, and recovery. The institute’s priorities include:
      • Identifying risk -enhancing prediction
      • Identifying biomarkers
      • Charting illness across the lifespan
      • Developing personalized interventions
  • After this overview, Dr. Rowland shared examples of NIMH’s sleep research priorities:
    • Basic Neuroscience
      • Interactions with neural circuits supporting cognitive and emotional processes
      • Mechanism and significance of sleep-mediated synaptic plasticity
      • Neural mechanisms of sleep-associated neural dynamics and their role in behavior
      • Biologically realistic computational modeling
    • Translational/Clinical Research
      • Human neurobiology of sleep and its role in emotional regulation and cognitive processing
      • The role of sleep following trauma exposure
      • Functional relationships between changes in developmental and aging sleep patterns, brain maturation, and psychopathology
      • Sleep disturbance as prodromal and potentially etiological pathway to pathophysiology of mental illness
      • Sleep and suicide
      • Novel interventions that target sleep disturbance biomarkers to improve mental health
    • Sleep problems are strongly associated with suicidal thoughts and behaviors.
    • Much of the current sleep-related intervention research at NIMH is focused on mobile/digital applications for cognitive behavioral therapy.
  • Dr. Rowland ended her presentation by highlighting sleep research being conducted in their intramural program and by listing several resources and opportunities at NIMH.
    • Funding Opportunity: Schizophrenia and Related Disorders During Mid- to Late-Life (PAR-24-023 and PAR-24-026)
      • Specific Areas of Interest: Studies of other biological and homeostatic processes such as metabolic, sleep/arousal
      • Expires September 8, 2026
    • Optimizing Behavioral Sleep Interventions for Adolescents and Young Adults
      • This is a priority area that has gone through concept clearance and has been approved by scientific council. It may evolve into a funding opportunity.
  • SDRAB discussed with Dr. Rowland NIMH’s interest in circadian disruption. Dr. Rowland shared that NIMH is funding awards focusing at circadian disruption and cited examples in the translational program focusing on circadian disruptions during the peri-menopause transition as well as awards targeting circadian disruption to improve depression and anxiety. NIMH also funds intervention projects that focus on elderly populations at high risk for depression, such as care-takers of those with dementia.

PREGNANT WOMEN AND SLEEP PRESENTATION - Women’s Health & Maternal Health Research: Opportunities for Sleep Science
Gina Wei, M.D., M.P.H., Senior Scientific Advisor on Women’s Health, Associate Director for Prevention and Population Science, Division of Cardiovascular Sciences, NHLBI

  • Dr. Wei began her talk by discussion why women’s health research is important.
    • It’s a national priority
      • 1993 NIH Revitalization Act – inclusion of women and minorities in clinical research
      • 2010 Institute of Medicine (IOM) Report on Women’s Health Research – representation in research
      • 2015 NIH Policy Sex as a Biological Variable – design and inclusion
      • 2017 21st Century Cures – sex specific analysis
      • 2019 NIH Inclusion Across the Lifespan – lifespan reporting
      • 2024 President’s Executive Order – to Advance Women’s Health Research and Innovation
    • It’s an NHLBI priority
      • Women represent a significant number (more than half) of patients with heart, lung, blood, and sleep (HLBS) disorders. The impact is reflected in disease and mortality statistics, and health disparities.
  • The U.S. is the most dangerous place in the developed world to deliver a baby and the number of deaths per year is rising, as are the disparities. America’s health disparities and high maternal mortality rates:
    • Non-Hispanic Black women are 3x as likely to die as non-Hispanic White women
    • American Indian/Alaska Native women are 2x as likely to die as non-Hispanic White women
  • There is a multi-pronged agenda for women’s health at NHLBI:
    • Seize unique opportunities in specific initiatives on the health of women
    • Inclusion and reporting of women and sex-specific analyses in clinical research and trials
    • Workforce development; health education and promotion
    • Sex/gender specific studies (higher prevalence, unique conditions, differential outcomes)
    • Leverage existing resources for discovery (genomics and omics, precision medicine/data science [TOPMed])
  • The NHLBI strategic vision is undergoing a refresh and the institute is considering whether additional Compelling Question and Critical Challenges are needed to address topics that have surfaced as focus areas in the past 5 years and drive important scientific advances. Supporting women’s health through the lifespan is one of the 6 refresh focus areas.
  • Dr. Wei then transitioned her talk to discuss some exemplars of NHLBI-led and NIH-wide women’s health initiatives.
  • Among the NHLBI-led initiatives:
    • Women’s Health Initiative (WHI)
      • Launched in 1992, the original WHI study enrolled 161,808 postmenopausal
      • Several ancillary studies, one on sleep: Women’s Health Initiative Sleep Hypoxia Effects on Resilience (WHISPER)
      • Some other sleep findings from WHI include:
        • Higher sleep disturbance level was associated with increased risk of leukemia, especially for myeloid leukemia
        • Sleep disturbance was associated with approximately 10% to 30% increased Parkinson’s Disease risk
        • OSA risk factors and symptoms was associated with heart failure with preserved ejection fraction (HFpEF), but not heart failure with reduced ejection fraction (HFrEF), and largely dependent on body mass index, snoring, and hypertension
    • nuMoM2b Heart Health Study
      • Established in 2013 by NHLBI to follow participants from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-funded nuMoM2b study
      • Important findings to date:
        • Women with SDB had higher BMIs, larger waist circumferences, higher blood pressure, triglyceride, and glucose levels
      • Avenues for exploration beyond this cohort:
        • Interventions to increase physical activity in early pregnancy or in the post-partum period
        • Strategies to enhance sleep during pregnancy
        • Pre-conceptional weight reduction and management of chronic conditions
        • Enhancing periconceptional diet quality
    • ENRICH trial
      • Early Intervention to Promote Cardiovascular Health of mothers and children (ENRICH) by addressing social and behavioral determinants
      • Targeting groups with a high mortality rate - African Americans, AI/AN, Hispanic, AA/NH/PI, and age >40
      • The Goal is to determine if a cardiovascular health (CVH) module can enhance maternal and child CVH when delivered within the context of:
        • Health Resources and Services Administration’s (HRSA’s) evidence-based home visiting programs and
        • Community engaged resources
      • ENRICH includes a Sleep Health Intervention:
        • Designed to help mother and child achieve 7-9 hours of sleep each day, per AHA guidelines
        • Uses sleep education, behavior change methods and relaxation techniques
        • Education on CVH benefits of proper hours of sleep every night
        • Tips to improve sleep environment, body positioning, sleep hygiene
        • Focus on a client-centered approach to identify barriers and provide individual solutions
    • Maternal Health Community Implementation Project (MH-CIP)
      • Implementation science to improve maternal HLBS health
      • Dr. Wei noted that sleep is not yet a part of this so there are opportunities for sleep research to be more present in the implementation science space
    • Continuous Positive Airway Pressure (CPAP) for Sleep Apnea in Pregnancy (SLEEP)
      • NHLBI and NICHD partnership
      • Phase III RCT in NICHD’s Maternal Fetal Medicine Unit (MFMU)
      • n~1,500 women to assess whether treatment of OSA with CPAP in pregnancy will reduce the rate of hypertensive disorders of pregnancy
  • Dr. Wei ended her review of NHLBI initiatives by mentioning a portfolio analysis (in press) on NIH grants on Maternal Cardiovascular Health (MCH) funded from 2016-2021:
  • Among the NIH-wide initiatives:
    • Implementing a Maternal health and PRegnancy Outcomes Vision for Everyone (IMPROVE) initiative
    • White House Women’s Health Research Initiative (March, 2024)
      • Launch an NIH-cross cutting effort to transform women’s health throughout the lifespan
      • Will initially be supported by $200 million from NIH beginning in FY 2025
      • Allow NIH to launch ambitious, multi-faceted research projects such as research on the impact of perimenopause and menopause on heart health, brain health and bone health
      • In coordination with the White House Initiative on Women’s Health Research, NIH has issued a NOSI on Women’s Health Research (NOT-OD-24-079) which highlights NIH’s interest in receiving research applications focused on diseases and health conditions that predominantly affect women, present and progress in women, or are female specific, including sleep.
  • SDRAB made the following observations:
    • While access to care is an important factor in the alarmingly high and rising rate of maternal mortality rates and disparities, these numbers also present in higher socioeconomic status (SES) populations where patients report not being taken seriously by the health care providers. Dr. Wei agreed high SES is not necessarily protective against adverse health outcomes in this space and mentioned the CDC campaign Hear Her which is designed to address this issue.
    • It has been reported that women being slightly unhealthier going into pregnancy, having higher weights and what that means for SDB and circadian misalignment, has an impact on maternal and fetal outcomes. There is some evidence that there are interactions and there are some research opportunities in this space.
    • There is also a predominance of insomnia within the female population versus the male population and how that intersects with COMISA (co-morbid insomnia and sleep apnea) in particular to accelerate the effects of a SDB problem or itself be the major issue driving the health disparity. Maybe the White House Initiative could help to shine some light on this issue.

STAKEHOLDER GROUP UPDATE – American Thoracic Society – Sleep and Respiratory Neurology (ATS-SRN) Assembly
Robert Owens, M.D., A.T.S.F., Professor of Medicine, University of California San Diego, Chair, ATS-SRN Assembly

  • Dr. Owens shared the mission of ATS - to accelerate global innovation in the advancement of respiratory health through multidisciplinary collaboration, education, and advocacy.
  • The ATS membership comprises more than 16,000 physicians, research scientists, and nurses and other allied healthcare professionals (32% international).
  • The ATS has four pillars:
    • Leading Scientific Discovery
    • Transforming Patient Care
    • Impacting Global Health
    • Advancing Professional Development
  • Assemblies are subdivisions of the Society and the primary assembly for the sleep community is the Assembly of Sleep and Respiratory Neurobiology (SRN)
    • >600 primary members, another 1,100 secondary members
    • Structure/Activities
      • Program – International Conference
      • Planning – Clinical Practice Guidelines, Statements, Workshops
      • Advocacy – Pulse oximetry, daylight savings, non-invasive ventilation
      • Web Committee – Pioneers in sleep medicine
      • Early Career Working Group – Mentoring
      • Sleep Program Directors/ASPIRE Fellowship – Pipeline
  • Example of some ATS-SRN Assembly output include:
    • Management of persistent, post-adenotonsillectomy obstructive sleep apnea in children: an official American Thoracic Society Clinical Practice Guideline (Zarmina Ehsan AJRCCM 2024)
    • Strategies to assess the effect of continuous positive airway pressure (CPAP) on long-term clinically important outcomes among patients with symptomatic with obstructive sleep apnea: an official American Thoracic Society workshop report (Lucas Donovan Annals ATS 2023)
    • Causes, consequences, and treatments of sleep and circadian disruption in the ICU: an official American Thoracic Society Research Statement. (Melissa Knauert AJRCCM 2023)
  • Dr. Owens then reviewed the ATS-SRN 2024 recommendations for research
    • Longitudinal studies of patients seeking care for sleep and circadian disorders – particularly OSA
    • Impact of sleep and circadian disruption on patient reported outcomes
    • Overlap of pulmonary disease with sleep/circadian disorders
  • Dr. Owens completed his presentation by affirming that the ATS and SRN have a strong commitment to health equity and to sleep as a health disparity/health equity issue
  • The SDRAB discussion that followed focused on
    • the state of the research surrounding the heterogeneity of disease and pregnancy, is an AHI of 5 that develops de novo during pregnancy something that we need to be more aggressively treating? As AHI of 5 may not the same for everybody and the research is beginning to highlight this.
    • The evidence is showing that because of the difference in anatomy in women versus men, women may not have the same kind of obstruction and the flow limitation may actually be more harmful. And this changes over time as well, from when a woman is pre-menopausal to when she is peri- and then post-menopausal. The concept of COMISA is really important and may become even more so as it is unclear what this disorder does to overnight physiological stress, whether it’s additive in terms of oxidative stress and adrenaline surges, etc. And in terms of women in general, it is challenging to understand the pathophysiology, particularly since it accelerates after menopause.
    • It’s also important to consider what kinds of technologies we are using to measure not just AHI but also what’s happening in the autonomic nervous system (ANS) in women versus men because flow limitation is all about arousal threshold.

PUBLIC QUESTIONS/COMMENTS

  • There were no questions or comments submitted by the public.

SDRAB MEMBER DISCUSSION
Lead by Dr. Esra Tasali

  • SDRAB extended discussion focused on:
    • Technology and AI development. Specifically that the research community may need to consider changing the approach to working with industry. The public is already starting to embrace some of the new sleep technologies in ways that the researchers may not be and that could be an issue in the future? Developing systems of collaboration may help these technologies become less black box and more open source, and reduce the barriers to entry for these new technologies.
    • SDRAB requested that ARPA-H (Advanced Research Projects Agency for Health) be invited to a future board meeting to discuss this further. They are dedicated to increasing the conversation with industry in research, reducing the cost, and making healthcare more affordable for people who have been traditionally minoritized and excluded.
    • Another theme that is emerging is how we adapt the tools and metrics we use to specific populations, such as women, pregnant people, children, or people of color.

The meeting adjourned at 5:00 PM ET

DAY 2

BOARD MEMBERS PRESENT
Dr. Esra Tasali, Chair
Dr. Josiane Broussard
Dr. Paul Desplats
Dr. Jeffery Durmer
Dr. Erik Herzog
Dr. Dayna Johnson
Dr. Shaun Purcell
Dr. Alberto Ramos
Dr. Tom Scammell
Ms. Alexandra Wharton

BOARD MEMBERS ABSENT
Ms. Ebony Lay

EX OFFICIO MEMBERS PRESENT
Dr. Marishka Brown, NHLBI, Executive Secretary
Dr. Yejun (Janet) He
Dr. Donald Shell

FEDERAL EMPLOYEES
Five Federal employes attended the meeting in person and 24 were in attendance via Zoom.

MEMBERS OF THE PUBLIC
One member of the public attended the meeting in person and 51 were in attendance via Zoom (including researchers, clinicians, patients, and other stakeholders).

CALL TO ORDER
Marishka Brown, Ph.D.

  • The executive secretary called the meeting to order at 9:00 AM ET as announced in the Federal Notice [89 FR 14511] on February 27, 2024. The meeting was fully open to the public in accordance with the provisions set forth in sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act.
  • Board members were reminded they are required to absent themselves if their presence constitutes or appears to constitute conflict of interest.
  • The SDRAB chair asked members introduced themselves and provide their backgrounds, expertise, interests and activities.

DISCUSSION/ACTION ITEMS FROM DAY 1

  • Dr. Tasali summarized the presentations and discussions from the first day
  • Dr. Brown encouraged the SDRAB to consider what suggestions it could make to NIH concerning sleep and circadian research priorities based on the discussions so far. The following emerged:
    • The focus on the health of women is going to be an important direction to address. When studying sex differences research may need to beyond the dichotomy of male and female but recognize that even within females there is variability. Research that focuses on pre-pubescent differences between the sexes would be an important approach to consider.
    • Should consider going beyond the sex as a biological variable (SBV) policy and study the different physiology, pathophysiology, and presentations in girls and women.
    • In addition, there could be more research on disorders and diseases that are specific to women. For example, polycystic ovarian syndrome where you see women with high testosterone levels very early on in pre-menopausal states at high risk for diabetes and CV disease. Studying what is different in that population could help us better understand the relationship between sleep and cardiometabolic disease.
    • Research focused on sleep health disparities remain a priority.
    • It’s important to consider social determinant and structural factors beyond socioeconomic status that are contributing factors to health inequities. This is potentially true when considering the relationship between sleep and maternal and infant mortality. SDoH should be collected in research studies that could help us understand the experiences of minoritized individuals.
    • Datasets mentioned in Dr. Wei’s presentation may present an opportunity to understand how sleep is contributing to health inequity and examine sleep as an intervention point to reduce some adverse health outcomes in women.
    • The SDRAB could consider putting out position papers on the highest priorities in sleep and circadian research.

PROGRAM PRESENTATION - Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b)
Aaron Laposky, Program Director, NCSDR/NHLBI

  • NCSDR/ NHLBI/ are invested in advancing research that is focused on understanding the impact of sleep on the health of women, particularly in the context of heart, lung, and blood diseases.
  • The importance of recognizing SBV is underscored by research showing that symptoms of sleep deficiency, sleep and circadian phenotypes, as well as the consequences of poor sleep differ between women and men. Furthermore, women experience specific life course transitions, including pregnancy and menopause, where sleep is a significant factor for both quality of life and health.
  • While difficulty sleeping during pregnancy occurs in the majority of women, it should not be disregarded as just a normal occurrence or something that will simply go away after delivery. Research now shows that sleep deficiency and sleep disorders during pregnancy are associated with adverse maternal and potentially neonatal outcomes as well.
  • About 15 years ago an accumulation of studies indicated that self-reported symptoms of SDB were common in pregnant women and these studies linked SDB symptoms to CV risk, including gestational hypertension, preeclampsia, gestational diabetes. And the overlap between pregnancy pathophysiology and SDB and those involved in pregnancy complications, such as sympathetic overdrive, oxidative stress, neuroendocrine changes, etc., pointed to the biological plausibility that SDB is an adverse exposure in pregnancy for maternal health.
  • These observations were important, especially given the high rate of maternal morbidity and mortality in the U.S. and the urgent need to identify modifiable risk factors and preventive therapeutic strategies to mitigate these adverse pregnancy outcomes. The possibility that SDB is a modifiable risk factor in pregnancy could have a meaningful clinical impact for the approximately half a million women who experience SDB during pregnancy.
  • Therefore, NIH identified this as an important area that was in need of more definitive research and catalyzed what has been an enduring program on SDB and maternal health.
  • In 2010, the NICHD funded a prospective cohort study of 10,000 nulliparous women called the nuMoM2b study to investigate clinical markers and causes of adverse pregnancy outcomes. This led to a collaboration between NICHD, NHLBI and ORWH to fund the nuMom2b SDB study which added objective measures of breathing during sleep using in-home monitoring in about 1/3 of the nuMom2b cohort.
    • Results from the nuMom2b SDB study showed that overall ~10% of women exhibited sleep apnea and the prevalence was ~25% in women who were overweight/obese. Among women with sleep apnea, the risk association was quite high:
      • Gestational hypertension: 75% increase in adjusted odds ratio (aOR)
      • Preeclampsia: 100% increase in aOR
      • Gestational diabetes: 200% increase in aOR
    • One of the most interesting things about these results was that the SDB was mostly mild, in the AHI of 5-10 range, and none of the women had severe sleep apnea.
    • The study produced the definitive data that SDB is an associated independent CV risk factor during gestation and pointed to SDB as a potential modifiable factor that could impact the health of women during pregnancy.
  • In a follow-up to the original nuMoM2b cohort, NHLBI, along with several other ICOs, funded the nuMoM2b Heart Health study, an outcome of the growing recognition of pregnancy as a window to future health in women.
    • Published report begins to address some questions about heterogeneity of sleep apnea and what different phenotypes could mean
  • Based on these observation studies and other research, in 2018 NHLBI partnered with NICHD and their Maternal-Fetal Medicine Units (MFMU) Network to fund a multi-site, phase 3 RTC to test the efficacy of a sleep apnea intervention during pregnancy to reduce the risk for developing hypertensive disorders.
  • Other areas of NHLBI interest in the sleep and maternal health space:
    • Clinical predictors of sleep apnea
    • Heterogeneity of SDB phenotypes
    • SDB and gestational CV disorders mechanisms
    • Other sleep deficiency
      • Duration, timing, quality
    • in utero/neonatal impact of poor maternal sleep
  • SDRAB noted in the discussion how striking the effects of even mild OSA during pregnancy were and how important it is to make health care providers aware of the risk. They also noted the need to better understand the optimal time for SDB assessment and treatment during pregnancy and mentioned the need for more strategic approaches to research in these areas s.

OVERVIEW OF FOOD & DRUG ADMINISTRATION (FDA) OFFICE OF WOMEN’S HEALTH
Kaveeta Vasisht, M.D., Pharm.D., Associate Commissioner for Women’s Health, Director, Office of Women’s Health, Office of the Commissioner, FDA

  • Dr. Vasisht began by sharing that the mission of the Food and Drug Administration (FDA), which is to protect the public health, by ensuring the safety and efficacy and security of human drugs, veterinary drugs, biologics, and many other consumer products.
  • Dr. Vasisht outlined the history of the FDA’s Office of Women’s Health (OWH), which was mandated by Congress in 1993.
  • Although located in the Office of the Commissioner, the FDA OWH works across all the FDA offices to advance the health of women. They do this by generating policy, funding research, supporting education and training, and providing consumer information.
  • The mission of the OWH is to:
    • Promote the inclusion of women in clinical trials and the implementation of guidelines concerning the representation of women in clinical trials and the completion of appropriate data analysis​
    • Identify and monitor the progress of crosscutting and multidisciplinary health initiatives that impact the health of women​
    • Serve as the principal advisor to the Commissioner and other key Agency officials on scientific, ethical, and policy issues relating to the health of women
  • FDA OWH achieves its mission through the foundational principle that Sex is a Biological Variable (SABV).
  • In 1998, the FDA established the “demographic rule”. This was a pair of regulations that require the reporting of new drug applications to present the clinical trial data by gender, age, and race.
  • In 2015 the FDA Center for Drug Evaluation and Research (CDER) published the Drug Trials Snapshots Summary Report, with the goal of making demographic data more broadly available.
    • Dr. Vasisht noted that the drug trial Snapshots in the sleep disorder spaces that although women were fairly well represented, there was little racial/ethnic diversity.
  • In 2020, the FDA released guidance for industry to enhancing the diversity of clinical trial populations, asserting representatives of both sexes should be included in clinical trials in numbers to allow detection of clinically significant sex-related differences in drug response.​ Also that year, in collaboration with the NIH ORWH, the FDA OWH launched a diverse women in clinical trials campaign to encourage diversity across age, race/ethnicity, and comorbidities.
  • In 2022, the FDA released additional guidance for industry to enhance the enrollment of participants from underrepresented racial and ethnic population in clinical trials. The FDA followed-up on this with the Omnibus Reform Act that required sponsors to submit a diversity action plan (race, ethnicity, sex, and age groups) for Phase 3 or other pivotal trials.
  • In addition to regulation, the FDA OWH advances scientific knowledge through both intramural and extramural research that informs the regulatory decision making.
  • In 2015, they created the first FDA Women’s Health Research Roadmap – a strategy for science and innovation to improve the health of women that outlined several priority areas for research
  • The FDA has several external mechanisms to support emerging science:
    • FDA Broad Agency Announcement (BAA)
    • Cooperative Research and Development Agreements (CRADAs)
    • Centers of Excellence in Regulatory Science and Innovation (CERSI) Program
    • Memorandum of Understanding (MOU)
  • Dr. Vasisht noted there is a lack of information on medical products in pregnancy and lactation and bridging those gaps and knowledge is a big priority area for the FDA. In addition to putting out guidance on pregnancy and lactation, the OWH has a pregnancy registries webpage including post-marketing commitments from drug companies
  • The FDA OWH is also engaged in numerous educational efforts
    • In collaboration with the NIH ORWH, developed a free online course for clinicians and researchers called Bench to Bedside – Integrating Sex and Gender to Improve Human Health.
    • Regularly bring in external speakers to discuss why sex differences matter, or what the latest cutting edge sciences are in women's health
    • Host public scientific workshops
    • Sponsor public continuing education webinars
  • Dr. Vasisht ended her talk by sharing some of the FDA OWH resources:
  • A Q&A with the SDRAB followed
    • Dr. Vasisht reiterated that the OWH’s priority is looking at conditions that are unique to women, that disproportionately impact women or that impact women differently. They are open to any research that falls under that umbrella, including sleep-related product development.
    • Dr. Vasisht affirmed that patient and advocacy group input is very important to OWH and there are several ways that the FDA engages with those stakeholders, including having Patient Affairs Staff and Advisory Committees
    • SDRAB suggested that sleep and circadian influences be taken into account when choosing speakers for the OWH workshops

BASIC SCIENCE PRESENTATION - Gestational Sleep Deficiency: Fetal/Neonatal Cardiorespiratory and Metabolic Outcomes
Tracy Baker, Ph.D., Professor, Department of Comparative Biosciences, University of Wisconsin, Madison

  • Dr. Baker began by noting that the intra uterine environment has a profound impact on the offspring health and risk for disease and adulthood. Her lab is investigating the health outcomes of offspring in a model of sleep apnea during pregnancy.
  • There are many maternal factors, such as stress, consumption of drugs or alcohol, nutrition, obesity underlying health conditions or infection that are associated with an increased risk for a variety of disorders in the offspring. One thing that these maternal factors have in common is that they all activate the maternal immune system (MIA).
  • Sleep apnea is an increasingly common source of MIA during pregnancy
  • To begin to understand the health consequences of maternal sleep apnea in pregnancy to the offspring, Dr. Baker’s lab developed a rat model
  • Offspring were followed and various physiological and neurological endpoints were studied at different stages in their life cycle. Found that male GIH offspring exhibit early-apparent deficits in cardiorespiratory, metabolic and cognitive function that persist into adulthood​. Deficits in the female offspring were either non-existent, or mild and they are apparent only transiently.
  • Dr. Baker then highlighted some research investigating the impact of GIH on cardiorespiratory control and metabolic function.
  • Dr. Baker highlighted several collaborative projects including with Sathish Kumar at University of Wisconsin, involving arterial blood pressure in unanesthetized rats using a tail cuff radio telemetry system and the results of that study as well as a collaboration with Richard Kinkead at Laval University where they investigated FosB immunoreactivity as a marker of neuronal activity in the paraventricular nucleus (PVN) of the hypothalamus where the stress response and blood pressure homeostasis are regulated.
  • Dr. Baker concluded her presentation –by addressing the question of evidence in humans that sleep apnea during pregnancy adversely impacts the health of adult offspring and reviewed the literature. She found that the available data in humans does appear to track with what is seen in the animal models.
    • Many of the pregnancy complications associated with sleep apnea are strongly associated with increased risk for chronic disease in offspring
  • During the Q&A SDRAB suggested it would be informative to consider the potential consequences of sleep fragmentation and the role of estrogen.

REMARKS FROM NHLBI – Division of Lung Diseases (DLD)
Gustavo (Gus) Matute-Bello, M.D., Deputy Director, DLD

  • Dr. Matute-Bello assured the group that sleep disorders and circadian biology are important priorities for the NHLBI.
  • NCSDR activities are closely integrated with the Institute and with DLD in synergistic and mutually beneficial ways through the integration of sleep medicine and circadian biology into our pediatric and adult lung research and critical care portfolios, as well as the heart, lung, and blood portfolios and the translation activities of the Center for Translation, Research and Implementation Science (CTRIS).
  • In addition, NCSDR benefits from administrative and logistic support from DLD and NHLBI ancillary resources that has helped the Center grow and extend its impact.
  • Dr. Matute-Bello ended his remarks by thanking the Board members for their contributions, noting SDRAB plays a key role in helping identify research areas towards our common goal of catalyzing transformative research that will improve and hopefully someday cure sleep and circadian disorders.

Sumita Khatri, M.D., M.S.C.R. Chief Medical Research Officer, DLD

  • Dr. Khatri shared that as Chief Medical Research Officer (CMRO), she oversees DLD’s clinical trial portfolio by ensuring adherence to the highest standards of safety and scientific rigor.
  • Being a clinician, she is always focused on the care and well-being of the research participants.
  • As a former critical care doctor and asthma specialist, Dr. Khatri worked in the intensive care unit (ICU) and remembers being concerned about how the nursing staff would be able to stay healthy working nights and how the patients could get adequate rest with all the lights and machines. She is excited to join the DLD as CMRO and learn about the impact of sleep and circadian disorders.
  • Dr. Khatri ended her remarks by encouraging the Board to continue to personalize their work and think about the shift workers, and the patients, and all the people whose health is affected by these disorders.

BASIC SCIENCE PRESENTATION - Time to Deliver: Maternal-fetal circadian communication
Erik Herzog, Ph.D., Professor of Biology, Washington University, St. Louis

  • Dr. Herzog began his presentation with an overview of central circadian pacemaker, the superchiasmatic nucleus (SCN), how it coordinates rhythms and cells across the body and how disruption of these rhythms impact health. He highlighted that daily rhythms:
    • Are intrinsic to maternal and fetal tissues
    • Change reliably during pregnancy
    • Synchronize between mom and fetus before a healthy birth
  • Dr. Herzog research expands that concept of SCN coordination to consider that the maternal clock may be coordinating the daily rhythms in the fetus Asking the question of what might be the function for circadian rhythms in early development?
  • Dr. Herzog’s lab is also studying the role of circadian misalignment in pre-term birth (PTB).
    • PTB defined as <37 weeks
      • Extremely early PTB: <28 weeks
    • #1 cause of death of babies in the U.S. and is associated with high-rate of short and long-term health complications
    • Rate of PTB in the U.S. is ~10.0% (380,000 babies born prematurely each year)
    • In some localities, such as St. Louis, PTB is also associated with your zip code, as are maternal and infant mortality
    • PTB associated with many factors and there are many pathways of PTB, including inflammation/infection and maternal/fetal stress.
  • Studies in mice showed that by the third day of gestation, there is a significant change in the onset of daily locomotor activity and this becomes more dramatic as the pregnancy progresses, then resolves prior to delivery.
  • A pilot study was conducted in women who were monitored via actogram before and throughout their pregnancy and a similar trend was seen - the end of daily wake activity progressed earlier in the first and second trimesters, and then resolved. When quantified over a group of women, there was a significant advance in chronotype of pregnant women. Those results have been replicated in a second cohort of women.
  • Dr. Herzog next explored whether the onset of daily sleep is normal for pregnancy, underlies a healthy pregnancy, and/or what daily sleep patterns might relate to poor pregnancy outcomes.
  • Actigraphy data was presented from a cohort of 1,250 woman from diverse racial and SES backgrounds that were recruited over 5 years.
  • Conclusions from studies of circadian synchrony in pregnancy:
    • Networked circadian cells generate daily rhythms in physiology and behavior
    • Circadian pacemakers develop in utero and synchronize to the mother prior to birth
    • Impaired maternal or fetal daily rhythms associates with poor birth outcomes
  • A robust Q&A with the Board followed.
    • Dr. Herzog informed the Board he is working to get all the actigraphy data from the 1,000+ women cohort uploaded to the National Sleep Research Resource (NSRR) so that they will be available to the community.

PROGRAM PRESENTATION - Environmental Influences on Child Health Outcomes (ECHO) Cohort

Christina Park, Ph.D., M.H.S., Program Officer, ECHO

  • Dr. Park began by describing the Environmental Influences on Child Health Outcomes (ECHO) program and asking the SDRAB consider areas in maternal and child sleep research that ECHO can address to inform clinical practice, policies, or other programs.
  • ECHO’s mission is to enhance the health of children for generations to come and consist of both an observational and intervention arm.
  • The ECHO cohort’s overall scientific goal is to answer solution-oriented questions about effects of broad range of early environmental exposures on child health and development.
    • ECHO subscribes to the theory of developmental origins of health and development so exposures are studied from preconception to age 5 years, although the program covers up to age 21 years in terms of outcomes and covariates.
    • Cohort is diverse by geography (U.S. only), sex, age, SES, and race/ethnicity
  • The ECHO Cycle 1 Cohort spanned 7 years from Sep 2016 – Aug 2023. It leveraged and pulled together existing pregnancy and pediatric cohorts, consequently much effort was required to develop the ECHO protocol that allowed data harmonization.
  • The ECHO Cycle 2 Cohort spans the 7 years from Sep 2023 – May 2030
    • Extends and expands the ECHO Cohort to further investigate the influences of a broad range of early exposures, from society to biology, including the preconception period, on child health among diverse populations.
  • Cycle 2 ECHO Cohort status as of 3/28/2024
    • Enrollment began in mid-January 2024
    • 1,282 pregnancies enrolled (715 other than non-Hispanic white)
    • 4,991 children re-enrolled from Cycle 1 (1,795 other than non-Hispanic white)
    • Data being actively collected via in-person measurements and mostly online surveys using centralized REDCap (Research Electronic Data Capture) system.
    • Biospecimens collection is ramping up
    • Standardized data & biospecimen collection protocol (unlike Cycle 1, but basic core data elements are the same)
  • Types of data collected
    • Early developmental data – including growth, feeding, milestones, physical activity, and sleep
    • Demographic information
    • Environmental data
    • Pregnancy and birth information
    • Data on health conditions
    • Public health crisis
  • ECHO Cohort data and study materials are being made available as a nationwide research resource to the public in the NICHD DASH repository
  • Dr. Park then pivoted to focus specifically on the maternal and child sleep health data in the ECHO Cohort.
  • ECHO Cycle 1 Sleep Health Data Elements
    • Maternal/Caregiver
      • Maternal sleep quality in pregnancy; caregiver sleep quality
      • Maternal sleep health in pregnancy; caregiver sleep health
      • Maternal sleep-related impairment in pregnancy; caregiver sleep-related impairment
    • Child
      • Child Sleep Quality
      • Child Sleep Health
      • Child Sleep-Related Impairment
      • Child Sleep Ecology
  • ECHO Cycle 2 Sleep Health Data Elements - combined critical variables into one instrument called sleep health
    • Maternal/Caregiver
      • Maternal sleep quality in pregnancy; caregiver sleep quality
      • Device-measured physical activity, sleep in pregnancy
  • Child
    • Child Sleep Health
    • Device-measured physical activity, sleep in pregnancy
  • Timing of sleep data collection (Cycle 2)
    • Sleep Health in Pregnancy
    • Accelerometer
    • Caregiver sleep health
    • Child Accelerometer
    • Sleep health
  • Dr. Park then shared examples of the sleep data that has been collected.
  • Dr. Park ended her presentation by sharing some examples of sleep-related papers published by ECHO cohort investigators:
  • There was an active discussion following Dr. Park’s presentation.
    • The biospecimens collected in ECHO are timestamped, which is beneficial for analyses.
    • Regarding Dr. Parks request to the Board to consider other areas in maternal and child sleep research that ECHO can address to inform clinical practice, policies, or other programs, ideas that were suggested included:
      • inclusion of a measure of chronotype, for example by administering the Munich ChronoType Questionnaire (MCTQ), or level of desynchrony in the mothers either before or during the pregnancy.
      • The ECHO program is collecting accelerometer data for 7 days. It could be beneficial to extend the assessments into later pregnancy and extending the amount of time the accelerometer data is collected.
      • There could be an opportunity in ECHO to harmonize the data with other cohorts to ensure that the data is processed with models that are already validated for newborns and infants.
      • The centralized REDCap could be used to ask more question about sleep/circadian health, SDB, OSA, and sleep habits in the ECHO children to better understand, in a prospective fashion, the role of insufficient sleep in ADHD outcomes in this rich cohort.
      • It would also be helpful to collect things that are not normally collected like ferritin levels as a component of the analysis to see if there's a risk potentially for the underlying issue of restless leg syndrome (RLS) which then gets to dopamine dysfunction and potentially ADHD as well.

PUBLIC QUESTIONS/COMMENTS

  • There were no questions or comments submitted by the public.

SDRAB MEMBER DISCUSSION
Lead by Dr. Esra Tasali

  • The board discussed research opportunities and directions that should be considered by the community.
  • Adding sleep and circadian metrics to large cohorts like HBCD, ECHO, and other studies could be accelerated if there were a platform for sharing the data and the algorithms for their analysis.
  • The Board also considered whether it might be necessary to create specific initiatives or somehow incentivize the community, young investigators in particular, to make use of all this rich data.
  • The Board discussed the risks and benefits of the role of professional societies such as the AASM and others, in compiling and evaluating resources in terms of available devices and algorithms.
  • The NIH already has a model of public/private partnership in the Accelerating Medicines Partnership (AMP) Program that includes the NIH, biopharmaceutical and life sciences companies, and non-profit organizations. Perhaps this structure could be used for sleep and circadian research as well.
  • The Board discussed the importance of supporting more interventional sleep trials and generating efficacy data, in particular physiological data, that can be used to justify the usefulness of various interventions.

UPCOMING EVENTS/CLOSING REMARKS

  • The chair thanked the board for their time and participation.
  • The NCSDR director thanked all the board members for their passion and inspiration and for enabling all board members to speak with compassion.
  • The next meeting of the Board is scheduled for August 1, 2024 and it will be fully virtual.

The meeting adjourned at 1:30 PM ET