Night-to-Night Variability of Polysomnography-Derived Physiologic Endotypic Traits in Patients With Moderate to Severe OSA

Abstract

BackgroundEmerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA.Research QuestionDoes a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in moderate to severe OSA?Study Design and MethodsTwo consecutive in-lab polysomnography tests from a clinical trial (n = 67; male, 69%; mean ± SD age, 61 ± 10 years; apnea-hypopnea index [AHI] 53 ± 22 events/h) were used for the reliability analysis. Endotypic traits, reflecting upper airway collapsibility (ventilation at eupneic drive [Vpassive]), upper airway dilator muscle tone (ventilation at the arousal threshold [Vactive]), loop gain (stability of ventilatory control, LG1), and arousal threshold (ArTh) were determined. Reliability was expressed as an intraclass correlation coefficient (ICC). Minimal detectable differences (MDDs) were computed to provide an estimate of maximum spontaneous variability. Further assessment across four repeated polysomnography tests was performed in a subcohort (n = 22).ResultsReliability of endotypic traits between the two consecutive nights was moderate to good (ICC: Vpassive = 0.82, Vactive = 0.76, LG1 = 0.72, ArTh = 0.83). Variability in AHI, but not in body position or in sleep stages, was associated with fluctuations in Vpassive and Vactive (r = –0.49 and r = –0.41, respectively; P < .001 for both). MDDs for single-night assessments were: Vpassive = 22, Vactive = 34, LG1 = 0.17, and ArTh = 21. Multiple assessments (mean of two nights, n = 22) further reduced MDDs by approximately 20% to 30%.InterpretationEndotypic trait analysis using a single standard polysomnography shows acceptable reliability and reproducibility in patients with moderate to severe OSA. The reported MDDs of endotypic traits may facilitate the quantification of relevant changes and may guide future evaluation of interventions in OSA. Emerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA. Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in moderate to severe OSA? Two consecutive in-lab polysomnography tests from a clinical trial (n = 67; male, 69%; mean ± SD age, 61 ± 10 years; apnea-hypopnea index [AHI] 53 ± 22 events/h) were used for the reliability analysis. Endotypic traits, reflecting upper airway collapsibility (ventilation at eupneic drive [Vpassive]), upper airway dilator muscle tone (ventilation at the arousal threshold [Vactive]), loop gain (stability of ventilatory control, LG1), and arousal threshold (ArTh) were determined. Reliability was expressed as an intraclass correlation coefficient (ICC). Minimal detectable differences (MDDs) were computed to provide an estimate of maximum spontaneous variability. Further assessment across four repeated polysomnography tests was performed in a subcohort (n = 22). Reliability of endotypic traits between the two consecutive nights was moderate to good (ICC: Vpassive = 0.82, Vactive = 0.76, LG1 = 0.72, ArTh = 0.83). Variability in AHI, but not in body position or in sleep stages, was associated with fluctuations in Vpassive and Vactive (r = –0.49 and r = –0.41, respectively; P < .001 for both). MDDs for single-night assessments were: Vpassive = 22, Vactive = 34, LG1 = 0.17, and ArTh = 21. Multiple assessments (mean of two nights, n = 22) further reduced MDDs by approximately 20% to 30%. Endotypic trait analysis using a single standard polysomnography shows acceptable reliability and reproducibility in patients with moderate to severe OSA. The reported MDDs of endotypic traits may facilitate the quantification of relevant changes and may guide future evaluation of interventions in OSA. FOR EDITORIAL COMMENT, SEE PAGE 1016Take-home PointsStudy Question: Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in patients with OSA?Results: Nine endotypic traits showed moderate to good reliability, both in the short-term and long-term. The analysis was extended further to provide minimal detectable differences (MDDs) as thresholds to evaluate changes beyond spontaneous variability.Interpretation: Polysomnography-derived endotypic traits from a single-night assessment provide robust markers of the ventilatory control system and upper airway pathophysiologic features in OSA. MDDs of endotypic traits may be used to identify treatment responders and to guide clinical decisions in future clinical practice. The average of consecutive recordings can be used to reduce variance further. FOR EDITORIAL COMMENT, SEE PAGE 1016 Study Question: Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in patients with OSA? Results: Nine endotypic traits showed moderate to good reliability, both in the short-term and long-term. The analysis was extended further to provide minimal detectable differences (MDDs) as thresholds to evaluate changes beyond spontaneous variability. Interpretation: Polysomnography-derived endotypic traits from a single-night assessment provide robust markers of the ventilatory control system and upper airway pathophysiologic features in OSA. MDDs of endotypic traits may be used to identify treatment responders and to guide clinical decisions in future clinical practice. The average of consecutive recordings can be used to reduce variance further. OSA is characterized by repetitive upper airway (UA) collapse during sleep, concomitant intermittent hypoxia, arousals from sleep, increased risk for cardiovascular and metabolic comorbidities, and a compromised quality of life.1Bonsignore M.R. McNicholas W.T. Montserrat J.M. Eckel J. Adipose tissue in obesity and obstructive sleep apnoea.Eur Respir J. 2012; 39: 746-767Crossref PubMed Scopus (92) Google Scholar However, the heterogeneity of clinical presentations cannot be captured by the traditional classification of disease severity based on frequency of respiratory disturbances.2Pevernagie D.A. Gnidovec-Strazisar B. Grote L. et al.On the rise and fall of the apnea-hypopnea index: a historical review and critical appraisal.J Sleep Res. 2020; 29: e13066Crossref PubMed Scopus (121) Google Scholar Pathophysiologic mechanisms, including high upper airway collapsibility, insufficient muscle compensation, ventilatory instability, and low arousal threshold have been described as potential underlying causes.3Eckert D.J. White D.P. Jordan A.S. Malhotra A. Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets.Am J Respir Crit Care Med. 2013; 188: 996-1004Crossref PubMed Scopus (708) Google Scholar Yet, standard methods to quantify these pathways require complex sleep study protocols, limiting clinical accessibility. To overcome these limitations, an advanced modelling technique has been developed to estimate the key endotypic traits from routinely collected signals in clinical polysomnography.4Sands S.A. Edwards B.A. Terrill P.I. et al.Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea.Am J Respir Crit Care Med. 2018; 197: 1187-1197Crossref PubMed Scopus (127) Google Scholar, 5Sands S.A. Terrill P.I. Edwards B.A. et al.Quantifying the arousal threshold using polysomnography in obstructive sleep apnea.Sleep. 2018; 41: zsx183Crossref PubMed Scopus (87) Google Scholar, 6Terrill P.I. Edwards B.A. Nemati S. et al.Quantifying the ventilatory control contribution to sleep apnoea using polysomnography.Eur Respir J. 2015; 45: 408-418Crossref PubMed Scopus (153) Google Scholar Several studies applied this approach to address responses to various OSA treatments,7Edwards B.A. Sands S.A. Eckert D.J. et al.Acetazolamide improves loop gain but not the other physiological traits causing obstructive sleep apnoea.J Physiol. 2012; 590: 1199-1211Crossref PubMed Scopus (197) Google Scholar,8Taranto-Montemurro L. Sands S.A. Edwards B.A. et al.Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation.Eur Respir J. 2016; 48: 1340-1350Crossref PubMed Scopus (81) Google Scholar the potential to predict treatment success,9Op de Beeck S. Dieltjens M. Azarbarzin A. et al.Mandibular advancement device treatment efficacy is associated with polysomnographic endotypes.Ann Am Thorac Soc. 2021; 18: 511-518Crossref PubMed Scopus (26) Google Scholar or the effectiveness of therapeutic intervention in cohorts of mixed disease expressions.10Bosi M. Incerti Parenti S. Sanna A. Plazzi G. De Vito A. Alessandri-Bonetti G. Non-continuous positive airway pressure treatment options in obstructive sleep apnoea: a pathophysiological perspective.Sleep Med Rev. 2021; 60101521Crossref PubMed Scopus (11) Google Scholar Using this method to investigate the pathophysiologic features of OSA in clinical practice may lead to recognition of clinical phenotypes and eventually may enable steps toward precision medicine and personalized treatment in this disorder.11McNicholas W.T. Pevernagie D. Obstructive sleep apnea: transition from pathophysiology to an integrative disease model.J Sleep Res. 2022; 31e13616Crossref Scopus (20) Google Scholar The use of endotypic traits for clinical classification of patients with OSA requires a high intraindividual stability and repeatability, which was investigated recently,12Alex R.M. Sofer T. Azarbarzin A. et al.Within-night repeatability and long-term consistency of sleep apnea endotypes: the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study.Sleep. 2022; 45zsac129Crossref PubMed Scopus (15) Google Scholar whereas test-retest has not been is to these endotypic traits by of OSA severity and physiologic during of apnea-hypopnea index in obstructive sleep apnea using Physiol. PubMed Scopus Google Scholar the study of moderate to severe of endotypic traits and the thresholds for differences to from spontaneous detectable The data used for the evaluation was from a clinical trial described in J. D. et trial and of in sleep apnea.Am J Respir Crit Care Med. 2022; PubMed Scopus (20) Google Scholar this was a and study a potential treatment for sleep apnea. were to and apnea-hypopnea index [AHI] and with of or both at the (n = two consecutive polysomnographic sleep recordings at and an two nights of and test-retest reliability was performed on the two consecutive assessments for analysis evaluation was performed using the (n = 22) to potential long-term analysis was of of study is in The study was performed to the of the of for clinical and and were from the The was in the and the analysis was by the and polysomnography recordings were in with by the of Sleep et for the of Sleep and and of Sleep Scholar The polysomnography recordings and and and and respiratory body and were recordings were by a single sleep in with the of Sleep et for the of Sleep and and of Sleep Scholar was were by the of a an or The frequency of and was captured and as the of were used to the index The sleep sleep sleep and sleep expressed as of (eg, Endotypic traits were to described by Sands and S.A. Edwards B.A. Terrill P.I. et al.Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea.Am J Respir Crit Care Med. 2018; 197: 1187-1197Crossref PubMed Scopus (127) Google S.A. Terrill P.I. Edwards B.A. et al.Quantifying the arousal threshold using polysomnography in obstructive sleep apnea.Sleep. 2018; 41: zsx183Crossref PubMed Scopus (87) Google Scholar and Terrill and P.I. Edwards B.A. Nemati S. et al.Quantifying the ventilatory control contribution to sleep apnoea using polysomnography.Eur Respir J. 2015; 45: 408-418Crossref PubMed Scopus (153) Google Scholar using an analysis Using the pressure was to respiratory and used as with and arousal The was of which were used to the endotypic traits gain was computed as the to a and at the frequency muscle was by the at and eupneic ventilatory drive and as as at the ventilatory drive to the arousal threshold Endotypic traits were during and sleep and in the and endotypic traits were in both and sleep, was on from sleep, studies were performed in this sleep Nine endotypic traits were computed and used in the the ventilatory control system arousal ventilatory to and and pathophysiologic features and and muscle = Vactive of the of endotypic The ventilatory control system is by a analysis of of based on the ventilatory airway based on a of based on the at of ventilatory drive as a of upper airway muscle and analysis were performed using for was applied on endotypic traits Vactive and Vpassive to described and S.A. Edwards B.A. Terrill P.I. et al.Phenotyping pharyngeal pathophysiology using polysomnography in patients with obstructive sleep apnea.Am J Respir Crit Care Med. 2018; 197: 1187-1197Crossref PubMed Scopus (127) Google Scholar a was applied to both Vactive and and for the were reported L. L. 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Identification of novel therapeutic targets.Am J Respir Crit Care Med. 2013; 188: 996-1004Crossref PubMed Scopus (708) Google Scholar between OSA severity and and of collapsibility and were and may the between fluctuations in these other relevant were that the were of physiologic fluctuations between that both Vactive and Vpassive showed between nights at low high in may the of muscle and may the increased of this However, which was as a of collapsibility in a D. L. Azarbarzin A. et polysomnographic methods for pharyngeal collapsibility in obstructive sleep apnea.Sleep. 2022; Scopus (11) Google Scholar was and reliable for assessment of as by of suggest that pathophysiologic using a developed method markers that may overcome fluctuations and to the evaluation of this is the study to address of the of endotypic traits to sleep or body S.A. S.A. Sands S.A. et loop gain the body position during sleep in patients with obstructive sleep PubMed Scopus Google Scholar, S.A. 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