On November 17, 2021, Nox Medical hosted the second session of its three-part webinar series on Polysomnography. In this session titled “Endo-Phenotyping in Sleep,” Wan-Ju, Cheng MD, Ph.D., addressed several questions, including:
- What is the current state of Endo-Phenotyping in sleep research?
- Can treatments be optimized based on Endo-Phenotyping of OSA?
- What does Endo-Phenotyping mean for clinical outcomes?
Snorri Helgason, Nox Medical Director of Market Access & Product Marketing, hosted the session and facilitated questions. He introduced Dr. Wan-Ju and colleague Dr. Jon Agustsson, who gave an overview of Endo-Phenotyping.
What is Endo-Phenotyping?
“Endo-phenotypes are explaining what the physiological cause of sleep apnea is, where an endotype is defined as a subtype of a condition which is defined by a distinct functional or pathobiological mechanism,” explained Dr. Agustsson.
The four endo-phenotypes are the following:
- The upper airway collapsibility, or how easily the airway closes
- Arousal threshold, or how easily people wake up from disturbances
- Compensation, or how actively one can recruit muscles to reopen the airway when it collapses
- Loop gain, or control of ventilation
Dr. Agustsson concluded his introduction to Endo-Phenotyping by referencing the origins of Endo-Phenotyping by Harvard professors Andrew Wellman and Scott Sands,,,,. He discussed the transition from traditional endo-phenotyping and Endo-Phenotyping Using Polysomnography (PUP) and the collaboration that Nox Medical has embarked on with professors Wellman and Sands with research published in 2020. You can find more details on that collaboration here.
Dr. Agustsson then introduced Wan-Ju Cheng, MD, Ph.D., a Director of the Division of Psychiatry at China Medical University Hospital, Taichung, Taiwan, and an Associate Professor at the Department of Public Health at China Medical University. Her colleague Hang, Liang Wen, MD, Ph.D. is a Professor of School of Nursing & Graduate of Nursing at China Medical University, and Chief of the Sleep Medicine Center at China Medical University Hospital in Taichung, Taiwan.
Current State and Past Studies of Endo-Phenotyping
Dr. Wan-Ju presented her research and the origins of endo-phenotyping, covering optimal CPAP levels for different endo-phenotypes and sharing the results of research aimed to examine the CPAP treatment results of OSA patients with different endo-phenotypes. She discussed their experience collaborating with Nox Medical using the PUPpy algorithm to identify endo-phenotypes of their patients. You can read more about the PUPpy algorithm in a recent article by Finnson, Sands, Wellman et. al. in the SLEEP Journal.
Initially, she surmised, that the four Endo-Phenotypes used to be very difficult to identify in clinical settings because they required equipment that is not standard PSG equipment and it also causes discomfort to the patient.
Dr. Wan-Ju explained how in the past scientists manually dropped CPAP pressure during a PSG study and created an apnea or hypopnea and then measured the ventilation responses to determine the endotypes. With the advent of the PUPpy algorithm this is no longer necessary and scientists can get the endotypes directly from a standard PSG sleep study.
“The PUP Method, I think is really a breakthrough because it uses standard PSG and they have established a model to retrieve the four Endo-Phenotypes without any attentive equipment or invasive procedures”
She went on to explain that the PUP method has limitations as it is not fully accessible to sleep centers and is currently available for research purposes only. With the introduction of the PUPpy method, currently available for research purposes, sleep researchers now have an easier way to retrieve the four Endo-Phenotypes.
“We are very thankful to the Nox team who have developed the Python Implementation of the PUP method (PUPpy),” Dr. Wan-Ju said. “The technology pushed further because with this technology we can retrieve the four Endo-Phenotypes easily. The cloud-based platform was chosen for its scalability, making it possible to run these computationally intensive methods at scale.”
Dr. Wan-Ju presented details of their hopes for future studies, starting with a look at the demographic characteristics of OSA patients (old, young, male, female) and their associations with the four Endo-Phenotypes, as well as their clinical symptoms, personal treatment responses and the relationship between these Endo-Phenotypes, comorbidities and mortalities. For example, how do old and young patients, as well as men and women, have the four Endo-Phenotypes distribution.
“We have seen in the clinical literature that OSA patients may have insomnia or hypersomnia, or have no symptoms. What is the relationship of those clinical symptoms with Endo-Phenotyping?” she said. “Most importantly in clinical practices, we want to have a personalized treatment for patients. These four Endo-Phenotypes may contribute to different treatment outcomes and there have been some reports emerging in recent years.”
Dr. Wan-Ju explained in their sample and research methodology that, unlike much of the world, PSG and CPAP titration are covered by national health insurance, so the home PSG market is not very big in Taiwan. Also, studies of this ethnic group of Han Chinese are quite rare. Sample data was collected since 2007 and includes 2,000 PSG cases annually of all age groups that are manually scored by certified technicians.
Can treatments be optimized based on Endo-Phenotyping?
Clinicians are most interested in knowing if treatments for obstructive sleep apnea can be optimized based on Endo-Phenotyping. According to other literature findings, Dr. Wan-Ju cited specialized treatments including upper airway surgeries, hypoglossal nerve stimulation and other medications and sedatives.
Dr. Wan-Ju then presented preliminary findings from their research in collaboration with Nox Research to analyze the Endo-Phenotypes of their patients.
“The preliminary results analyzed the Endo-Phenotyping of 558 patients older than 20 years from May 2020-August 2021,” she explained. “310 patients had AHI larger than 15 per hour and 46% (143) had received CPAP titration. Then, we studied those 143 patients to see how their Endo-Phenotypes are associated with the sleep architecture improvement and their optimal CPAP titration pressure in this condition.”
After looking at the various preliminary results, Dr. Wan-Ju surmised,
“A higher optimal CPAP titration pressure was needed to treat patients with high upper airway gain compared to those with lower upper airway gain. Additionally, patients with high collapsibility, high arousal threshold, high upper airway gain and high loop gain had larger improvements in sleep architecture with CPAP titration.”
Dr. Wan-Ju concluded by offering the next steps for their future studies including larger, cross-country population studies in Asia and Europe for high and low endotype value determination, as well as interactions between endotypes on symptoms, treatment outcomes, and mortality and morbidities.
The session wrapped with a Q&A with host Snorri Helgason, Dr. Agustsson and Dr. Wan-Ju where they answered compelling questions like:
- What is the interaction between endotypes and are there any clues on which center types are more connected to each other?
- Can the PUPpy method be used in home PSG, rather than an in-lab environment?
- Will it be possible in the future for patients to upload their own home PSG into the cloud and see their own endotype?
- Regarding patients who have recurrent hypopnea and a low number of apneas on home sleep apnea testing, do those patients have potentially low arousal threshold and is this an indication of that?
- What is AHI to start treatment by CPAP treatment if you have snoring patients that don’t meet the criteria for CPAP treatment ?
Missed the webinar? Catch up on the full presentation below.
The photo included in this article features the Nox A1® PSG System by Nox Medical and ResMed AirSense™ 10 AutoSet™ CPAP machine.
 Wellman A, et al. A method for measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol (1985). 2011;110(6):1627–1637.
 Wellman A, et al. A simplified method for determining phenotypic traits in patients with obstructive sleep apnea. J Appl Physiol (1985). 2013;114(7):911–922.
 Sands SA, et al. Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2018;197(9):1187–1197.
 Terrill PI, et al. Quantifying the ventilatory control contribution to sleep apnoea using polysomnography. Eur Respir J. 2015;45(2):408–418.
 Sands SA, et al. Quantifying the arousal threshold using polysomnography in obstructive sleep apnea. Sleep. 2017;41(1). doi: 10.1093/sleep/zsx183
Topic: Research & Publications