Circadian rhythm disorders (delayed sleep phase disorder, non-24-hour sleep-wake disorder, irregular sleep-wake disorder) have been ignored by many sleep researchers. They should not be. First, they reduce lives to rubble: education, employment, partnering, and parenting suffer or are not possible. Second, nocturnals who force themselves to live a diurnal life are at higher risk of disease (as are diurnals who work 3rd shift) and accidents. Third, evidence is mounting that circadian rhythms play a significant role in immunity, cancer, heart disease, diabetes, obesity, metabolic (dys)regulation, mental health, medication administration, and public health (think of the spike in accidents after spring and fall time changes).

To date, most circadian research has been conducted on "normals" who don't have CRDs. But their responses to light and dark cues differ from those of CRD patients. Please conduct circadian research on CRD patients--just as you would conduct diabetes research on diabetics.

Also needed: convenient ways to test for dim light melatonin onset, temperature nadir, and other circadian biomarkers. Right now, such tests are limited to study settings.

Sleep disorders are more common in minority populations. Moreover, these populations have higher rates of the known consequences of these disorders such as stroke, myocardial infarction, hypertension, resistant hypertension. Despite this, current population studies such as the Sleep Heart Health Study have included only a very small percentage of African Americans. The impact of this would be the following:

a. Elucidating the basis of barriers to case identification in these group
b. Designing specific intervention to overcome these barriers.
c. Developing methods to improve adherence to therapy in this group.
d. Removing sleep and circadian disorders as a risk factor for consequences such as stroke, cardiovascular disease and resistant hypertension in minority populations

There is a developing interest in this area in the field of circadian and sleep research. There is a developing knowledge base about health disparities in sleep and circadian disorders. Minority institutions such as Morehouse have developing programs in this area. We also have mobile technology that facilitates study of sleep and circadian disorders in minority populations.

Much of the research on the consequences of sleep/circadian disorders has focused on their consequences or behavior. This type of research needs to be continued and there are new opportunities in this area. These behavioral studies need to be established in model systems to parallel studies in humans. In addition, new neurobiological approaches, including optogenetics and use of DREAD, provide new tools for this investigation. Moreover, we now have powerful molecular tools to evaluate effects of sleep/circadian disorders both in humans and animal models. These include microarrays, RNA seq, etc. Moreover, genetic studies, e.g., in restless legs syndrome, have identified gene variants conferring risk for the disorder. We do not know, however, how these particular genes are involved in the pathogenesis of the disorder or whether they represent potentially targets for drug intervention. There is a need for studies both in animal models and in humans to elucidate the function of these genes. Studies in other areas are obtaining stem cells from biopsies in patients and then turning these into relevant target cells such as neurons to elucidate gene function using in vitro approaches.
The impact of this effort will be the following:

a. Taking our understanding of pathogenesis of sleep and circadian disorders to a new level.
b. Understanding the consequences of sleep and circadian disorders on different end organs at a more in-depth molecular level.

The sleep and circadian field have access to all the major cells systems for these studies—C. elegans, aplysia, Drosophila, zebra-fish, mice, etc. Moreover, there are already gene variants identified in human studies which require follow-up functional studies. The field has the expertise in all of the techniques described above. Moreover, there are more validated animal models for many of the common sleep disorders. Thus, this new approach is very feasible. 

Sleep and circadian disorders are extremely common. For many of these we know little about the natural history, whether different subgroups exist and effects of current therapies. Thus, developing specific registries for common sleep and circadian disorders would provide a basis for addressing these questions.

For some aspects, e.g., studies of inadequate sleep, impact of snoring and circadian disruption, would be facilitated by developing a specific sleep/circadian cohort with in-depth phenotyping. This strategy has worked extremely well in other areas, e.g., cardiovascular disease. The lack of this type of cohort for sleep and circadian disorders is a barrier to progress in this area. The high prevalence of these disorders and their known public health significance argue that development of such a cohort would be a game changer and accelerate progress in this new area of medicine.

Such a cohort could address several compelling questions:

a. What is the natural history of short sleep across the lifespan?
b. What is the impact of snoring? Does it lead, as has been proposed, to vibration injury to carotid arteries with accelerated vessel wall damage?
c. Are there different subtypes of individuals with the different sleep and circadian disorders?
d. What is the natural history of shift-workers and what types of shifts lead to increased risk for cardiovascular disease?

Problems with sleep and circadian rhythm and the relevant disorders are common. There are multiple accredited sleep centers for clinical purposes in the United Sates. They use common phenotyping platforms that could be the basis of some aspects of addressing this critical challenge. Moreover, most CTSA programs have a sleep study component. There are patient support groups for sleep apnea, insomnia, restless legs syndrome and narcolepsy. Thus, these groups could be marshaled to help in this effort. There is already a Sleep Research Network that was founded by the field itself. It is currently based on volunteer effort and there are no resources to support it. It could be the basis for future activities in this area.

The current status of research training in sleep and circadian disorders suggest that new approaches are needed. The field has developed one multi-center training grant to bring training to different institutions. This is focused on genetic/genomic approaches. It is run by the University of Pennsylvania which has a well developed program in this area. The fellows in training are, however, at other institutions, i.e., Johns Hopkins, University of Michigan and Stanford. Web-based approaches are used for work-in-progress seminars, grant development workshops and group mentorship, and didactic lectures. This strategy could be used more broadly to develop research training in other areas of sleep and circadian research. Stimulating this would have a major impact on research training in this new field of medicine.

Another relevant strategy would be to encourage adding slots in a competitive way for sleep/circadian research to other existing institutional T32 grants.

There are multiple mechanisms in place to communicate opportunities to the sleep/circadian academic community, i.e., Sleep-L, administered by the National Center for Sleep Disorders Research; Sleep Research Society biweekly blog; the Sleep Research Network. Specific encouragement of this approach would broaden the base for research training and would be of high impact.

The field of sleep and circadian research has had a long commitment to facilitating research training. The Sleep Research Society has hosted Trainee Day at our annual meeting for 20 years. The Sleep Research Society is funding early-stage investigators through its Foundation. The American Academy of Sleep Medicine runs, in collaboration with the NHLBI, an event at NIH for early-stage investigators in clinical research. The American Academy of Sleep Medicine Foundation has a “Bridge to K Award” program that provides funds to early-stage investigators who just missed funding on their first application for a K award. The Sleep Research Society has provided travel funds for early-stage investigators to attend recent workshops held by different NIH Institutes including National Heart, Lung and Blood Institute. Thus, there is no doubt of the commitment of the field and its professional organizations.

The impact of these new initiatives would be to broaden the base for research training beyond a few institutions. The number of institutions with a critical mass of investigators to mount successful T32 institutional training grants is not sufficient to provide the necessary future biomedical research workforce in this area. Novel approaches, based on modern communication IT technology, are needed.

The following will be the impact of addressing this critical challenge:

1. Having an assessment that can be used following a crash to assess the level of sleep loss of the driver.
2. Having a method to assess chronic sleep insufficiency as a potential pathogenetic process in patients with cardiovascular disease, hypertension, etc.
3. Having a method to estimate circadian phase so that in patients with chronic insomnia one can identify individuals with delayed sleep phase.
4. Having a technique to establish magnitude of circadian disruption to assess its role in pathogenesis of diseases such as cardiovascular disease.
5. Add a molecular biomarker to other techniques to screen for obstructive sleep apnea in high risk populations such as obese commercial drivers.
6. Utilize a biomarker signature to identify who with obstructive sleep apnea will be particularly at risk for downstream consequences such as cardiovascular disease.
7. Develop the equivalent of HbA1C to assess therapeutic response to CPAP

The first challenge is to identify a signature for each of these use cases. This will require initial studies in a small number of well phenotyped subjects with all the “-omic” techniques. Thereafter, these multiple cohorts, already available with blood samples, etc. and relative phenotype can be used for validation purposes.

There is no doubt that insufficient sleep and circadian disruption are very common in our society. There are also compelling epidemiological data that they are associated with multiple adverse consequences, including increased cardiovascular disease, increase in metabolic abnormalities such as insulin resistance and for shift work an increased incidence of specific concern. Animal studies based on microarrays are showing that inadequate sleep and circadian rhythm alter gene expression not only in brain but also in peripheral tissues. These studies are hypothesis-generating and there are many opportunities for hypothesis-driven research in this area to assess mechanisms. Identifying mechanisms will allow investigators to begin to assess mechanisms of individual differences and to identify new pathways for intervention.

Sleep and circadian research is in a very strong position. Sleep and clock function has now been identified in all the major model systems—C. elegans, Aphysia, Drosophila, zebra-fish, mice, etc. Thus, there is a strong platform to assess conserved pathways for effect of sleep loss and circadian disruption. Moreover, microarray studies have identified likely pathways thereby setting up hypothesis-driven research. There are major opportunities in this area.

There are major individual differences in response to sleep loss (both acute and chronic) and to circadian disruption. This has major impact both in terms of health consequences and in safety. Some individuals are particularly vulnerable to sleep loss and hence are more likely to have adverse consequences of losing sleep—increased risk of crashes, errors by physicians, etc. They are also more likely to be affected by metabolic and other consequences if they have chronic insufficient sleep.

Identifying the basis of these individual differences will have several impacts:

1. It will provide likely targets for development of biomarkers to assess effect of sleep loss and circadian disruption.
2. It will provide tools to risk stratify individuals and to employ preventative strategies to reduce risk of major adverse consequences.
3. It will identify novel pathways that could be the target for future intervention studies.

These studies are highly feasible. Phenotyping and recruitment strategies to study this question have been established in many laboratories. Moreover, more laboratories are utilizing genetic, -omic approaches and epigenetic approaches that could be applied to this question. There is also a developing repertoire of neuroimaging studies that can be applied to address this question.

Self-report indicates that sleep duration is lower in minority populations. This seems to be related to socioeconomic groups. To address this issue requires understanding the basis of this and developing appropriate interventions.

The impact of this is as follows:

a. Implementing new technology based on mobile approaches to assess sleep duration in subjects in different socioeconomic groups.
b. Developing a comprehensive approach to understanding and evaluating environmental influences in sleep and circadian rhythm.
c. Designing and testing intervention to increase sleep duration in disadvantaged populations.
d. Improving the sleep health of minority populations.

There is rapidly developing new mobile technology to assess sleep duration and other phenotypes in individuals living in their normal lives. There are a number of studies currently being conducted that could be leveraged to address this question. There are also developing approaches to assess environmental influences on sleep and circadian rhythm such as noise, light exposure, etc. Thus, this question could be addressed in the near future.

As described, we need to move beyond association to intervention. We have developing mobile technologies to assess outcomes in subjects living in their normal circumstances. The issue is what interventions can be applied and be shown to work to address both sleep length and circadian timing of sleep. There is a need to stimulate research to assess different potential interventions to see which are the most effective.

The impact of this will be invaluable. We should be able to improve sleep and circadian health in the US population and thereby modifying this risk factor for development of chronic diseases.

We have the relevant tools to do this. There are millions of Americans with short sleep and millions of Americans who have misplaced sleep in relation to their normal circadian rhythms. Thus, there is no shortage of subjects to recruit for this type of research. There is now a developing body of knowledge about techniques that can be applied to modifying behavior in other areas—weight loss, stopping smoking, etc. These techniques could be the basis of new interventions to improve sleep health.

There is a strong rationale for application of a personalized approach to sleep disorders. This requires approaching this question using multiple domains as in other areas of medicine—clinical features, physiological factors, application of the –omic approaches, genetics. The impact of this will be several:

a. A new way to classify sleep disorders.
b. Identification of subgroups of patients with apparently the same disorder who will have different outcomes of therapy.
c. Identification of subgroups of patients who will have different approaches to diagnosis.
d. Identification of subgroups of patients with apparently the same disorder who will have different therapeutic approaches.

These sleep and circadian disorders are extremely common. There is a risk infrastructure for this type of research based on the large number of accredited sleep centers in the United States that could be used for subject recruitment and who can adopt similar techniques. There is also a rich set of data obtained from sleep studies that could be used to identify new patterns that reflect different subgroups of subjects. These studies need to be based on clinical populations of patients who present with the different disorders rather than on population-based cohorts.

By analogy, a patient may complain of abdominal pain. This could be due to infection, food poisoning, ulcers, gall bladder, cancer, etc. Imagine if we treated all these patients by removing their gall bladder. There would be some successes, and many failures. Surveys of the literature would be unable to conclude that there's a well established successful treatment. That's the state of treatment of CRSWDs today.

CRSWDs such as Delayed Sleep-Wake Phase Disorder and Non-24-Hour Sleep-Wake Disorder cause suffering and inability to work normal hours, and often result in otherwise productive individuals being unable to find jobs and having to seek disability support. Those who force themselves into a conventional schedule often end up with chronic health problems, resulting in further cost to themselves and to society.

A major challenge is to diagnose not only a CRSWD but also its underlying cause. Improved biomarkers are essential to this effort, and are the subject of other Questions/Challenges. So too are a better understanding of the effects of light and melatonin on patients with these disorders, with the differing underlying impairments studied separately. With improvements in genetic testing and analysis, and improved sensor technology and automated data analysis, we are at the threshold of being able to study these underlying causes of CRSWDs.

The circadian genome is a highly conserved system producing 24-hr rhythms in gene expression in the lung. Uncovering the molecular/cellular pathways under circadian control and their significance would provide a new generation of mechanistic understanding of lung health and development.

Delineating circadian mechanisms of lung function would enable new strategies to phenotype, diagnose, and mange lung disease to be developed and tested.
Over the past decade, new discovery has uncovered a mechanistic interface between the circadian clock and fundamental cellular processes including oxidative stress, cell metabolism, immune and inflammatory responses, epigenetic modification, hypoxia/hyperoxia response pathways, endoplasmic reticular stress, autophagy, and regulation of the stem cell environment. While each of these processes is involved in lung function, the significance of circadian regulation in the development and maintenance of lung health is not well-understood.

An estimated >90% of histone modifiable sites on human chromatin are clock-coupled.