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Obstructive Sleep Apnea (OSA) — QSP Model References

폐쇄성 수면 무호흡증 QSP 모델 참고문헌

Generated: 2026-06-19 Model version: v1.0

1. Disease Pathophysiology & Epidemiology

  1. Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006-1014. https://pubmed.ncbi.nlm.nih.gov/23589584/

  2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230-1235. https://pubmed.ncbi.nlm.nih.gov/8464434/

  3. Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea. Lancet Respir Med. 2019;7(8):687-698. https://pubmed.ncbi.nlm.nih.gov/31300334/

  4. Strollo PJ Jr, Rogers RM. Obstructive sleep apnea. N Engl J Med. 1996;334(2):99-104. https://pubmed.ncbi.nlm.nih.gov/8531966/

  5. Malhotra A, White DP. Obstructive sleep apnoea. Lancet. 2002;360(9328):237-245. https://pubmed.ncbi.nlm.nih.gov/12133673/

2. Upper Airway Mechanics & Pcrit

  1. Schwartz AR, Smith PL, Wise RA, Gold AR, Permutt S. Induction of upper airway occlusion in sleeping individuals with subatmospheric nasal pressure. J Appl Physiol. 1988;64(2):535-542. https://pubmed.ncbi.nlm.nih.gov/3356665/

  2. Gold AR, Schwartz AR. The pharyngeal critical pressure: the whys and hows of using nasal continuous positive airway pressure diagnostically. Chest. 1996;110(4):1077-1088. https://pubmed.ncbi.nlm.nih.gov/8874262/

  3. Isono S, Remmers JE, Tanaka A, Sho Y, Sato J, Nishino T. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol. 1997;82(4):1319-1326. https://pubmed.ncbi.nlm.nih.gov/9104872/

  4. Owens RL, Eckert DJ, Yeh SY, Malhotra A. Upper airway function in the pathogenesis of obstructive sleep apnea: a review of the current literature. Curr Opin Pulm Med. 2008;14(6):519-524. https://pubmed.ncbi.nlm.nih.gov/18812827/

  5. Patil SP, Schneider H, Schwartz AR, Smith PL. Adult obstructive sleep apnea: pathophysiology and diagnosis. Chest. 2007;132(1):325-337. https://pubmed.ncbi.nlm.nih.gov/17625094/

3. Respiratory Control & Loop Gain

  1. Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med. 2004;170(11):1225-1232. https://pubmed.ncbi.nlm.nih.gov/15374844/

  2. Wellman A, Eckert DJ, Jordan AS, et al. A method for measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol. 2011;110(6):1627-1637. https://pubmed.ncbi.nlm.nih.gov/21436360/

  3. White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med. 2005;172(11):1363-1370. https://pubmed.ncbi.nlm.nih.gov/16100008/

  4. Sands SA, Edwards BA, Terrill PI, et al. Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy. Eur Respir J. 2018;52(3):1800674. https://pubmed.ncbi.nlm.nih.gov/30093382/

  5. Deacon NL, Catcheside PG. The role of high loop gain induced by intermittent hypoxia in the pathophysiology of obstructive sleep apnoea. Sleep Med Rev. 2015;22:3-14. https://pubmed.ncbi.nlm.nih.gov/25620195/

4. OSA Endotyping

  1. Eckert DJ, White DP, Jordan AS, Malhotra A, Wellman A. Defining phenotypic causes of obstructive sleep apnea. Identification of novel therapeutic targets. Am J Respir Crit Care Med. 2013;188(8):996-1004. https://pubmed.ncbi.nlm.nih.gov/23846785/

  2. Zinchuk AV, Gentry MJ, Concato J, Yaggi HK. Phenotypes in obstructive sleep apnea: a definition, examples and evolution of approaches. Sleep Med Rev. 2017;35:113-123. https://pubmed.ncbi.nlm.nih.gov/27527201/

  3. Zinchuk A, Yaggi HK. Phenotypic subtypes of OSA: a challenge and opportunity for precision medicine. Chest. 2020;157(2):403-420. https://pubmed.ncbi.nlm.nih.gov/31726073/

  4. Edwards BA, Sands SA, Owens RL, et al. The combination of supplemental oxygen and a hypnotic markedly improves obstructive sleep apnea in patients with a mild to moderate upper airway collapsibility. Sleep. 2016;39(11):1973-1983. https://pubmed.ncbi.nlm.nih.gov/27568803/

  5. Gottlieb DJ, Punjabi NM. Diagnosis and management of obstructive sleep apnea. JAMA. 2020;323(14):1389-1400. https://pubmed.ncbi.nlm.nih.gov/32286648/

5. Intermittent Hypoxia & Oxidative Stress

  1. Lavie L. Intermittent hypoxia: the culprit of oxidative stress, vascular inflammation and dyslipidemia in obstructive sleep apnea. Expert Rev Respir Med. 2008;2(1):75-84. https://pubmed.ncbi.nlm.nih.gov/20477179/

  2. Prabhakar NR, Kumar GK, Nanduri J. Intermittent hypoxia augments acute hypoxic sensing via HIF-mediated ROS. Respir Physiol Neurobiol. 2010;174(3):230-234. https://pubmed.ncbi.nlm.nih.gov/20688201/

  3. Nanduri J, Wang N, Yuan G, et al. Intermittent hypoxia degrades HIF-2α via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities. Proc Natl Acad Sci USA. 2009;106(4):1199-1204. https://pubmed.ncbi.nlm.nih.gov/19139401/

  4. Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011;365(6):537-547. https://pubmed.ncbi.nlm.nih.gov/21793745/

  5. Dempsey JA, Veasna P, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47-112. https://pubmed.ncbi.nlm.nih.gov/20086074/

6. Cardiovascular Consequences

  1. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342(19):1378-1384. https://pubmed.ncbi.nlm.nih.gov/10805822/

  2. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement. Circulation. 2008;118(10):1080-1111. https://pubmed.ncbi.nlm.nih.gov/18725495/

  3. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study (SHHS). JAMA. 2000;283(14):1829-1836. https://pubmed.ncbi.nlm.nih.gov/10770144/

  4. Logan AG, Tkacova R, Perlikowski SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J. 2003;21(2):241-247. https://pubmed.ncbi.nlm.nih.gov/12608436/

  5. Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol. 2017;69(7):841-858. https://pubmed.ncbi.nlm.nih.gov/28209226/

  6. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet. 2009;373(9657):82-93. https://pubmed.ncbi.nlm.nih.gov/19101028/

7. Metabolic Consequences

  1. Punjabi NM, Polotsky VY. Disorders of glucose metabolism in sleep apnea. J Appl Physiol. 2005;99(5):1998-2007. https://pubmed.ncbi.nlm.nih.gov/16227463/

  2. Tasali E, Mokhlesi B, Van Cauter E. Obstructive sleep apnea and type 2 diabetes: interacting epidemics. Chest. 2008;133(2):496-506. https://pubmed.ncbi.nlm.nih.gov/18252916/

  3. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J. 2004;25(9):735-741. https://pubmed.ncbi.nlm.nih.gov/15120883/

  4. Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G. Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome. J Am Coll Cardiol. 2013;62(7):569-576. https://pubmed.ncbi.nlm.nih.gov/23727210/

8. Neurological & Cognitive Effects

  1. Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res. 2002;11(1):1-16. https://pubmed.ncbi.nlm.nih.gov/11869421/

  2. Gagnon K, Baril AA, Gagnon JF, et al. Cognitive impairment in obstructive sleep apnea. Pathol Biol. 2014;62(5):233-240. https://pubmed.ncbi.nlm.nih.gov/25070768/

  3. Aloia MS, Arnedt JT, Davis JD, Riggs RL, Byrd D. Neuropsychological sequelae of obstructive sleep apnea-hypopnea syndrome: a critical review. J Int Neuropsychol Soc. 2004;10(5):772-785. https://pubmed.ncbi.nlm.nih.gov/15327724/

9. CPAP Therapy

  1. Kushida CA, Littner MR, Hirshkowitz M, et al. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. Sleep. 2006;29(3):375-380. https://pubmed.ncbi.nlm.nih.gov/16553024/

  2. Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension. 2007;50(2):417-423. https://pubmed.ncbi.nlm.nih.gov/17515449/

  3. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365(9464):1046-1053. https://pubmed.ncbi.nlm.nih.gov/15781100/

10. Wake-Promoting Pharmacotherapy

  1. Hirshkowitz M, Black JE, Wesnes K, Niebler G, Arora S, Roth T. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respir Med. 2007;101(3):616-627. https://pubmed.ncbi.nlm.nih.gov/16930983/

  2. Black JE, Hull SG, Tiller J, Yang R, Harsh JR. The long-term tolerability and efficacy of armodafinil in patients with excessive sleepiness associated with treated obstructive sleep apnea, shift work disorder, or narcolepsy. J Clin Sleep Med. 2010;6(5):458-466. https://pubmed.ncbi.nlm.nih.gov/20957846/

  3. Schweitzer PK, Rosenberg R, Zammit GK, et al.; TONES 3 Study Investigators. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3). Am J Respir Crit Care Med. 2019;199(11):1421-1431. https://pubmed.ncbi.nlm.nih.gov/30521371/

  4. Strollo PJ, Hedner J, Collop N, et al.; TONES 4 Study Investigators. Solriamfetol for the treatment of excessive sleepiness in OSA: a placebo-controlled randomized withdrawal study. Chest. 2019;155(2):364-374. https://pubmed.ncbi.nlm.nih.gov/30419229/

  5. Dauvilliers Y, Verbraecken J, Partinen M, et al.; HARMONY III Study Group. Pitolisant for daytime sleepiness in patients with obstructive sleep apnea who refuse continuous positive airway pressure treatment. Am J Respir Crit Care Med. 2020;201(9):1140-1150. https://pubmed.ncbi.nlm.nih.gov/31811826/

11. Phenotypic / Combinatorial Pharmacotherapy

  1. Taranto-Montemurro L, Messineo L, Sands SA, et al. The combination of atomoxetine and oxybutynin greatly reduces obstructive sleep apnea severity. Am J Respir Crit Care Med. 2019;199(10):1267-1276. https://pubmed.ncbi.nlm.nih.gov/30562055/

  2. Carberry JC, Fisher LP, Grunstein RR, et al. Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem. Eur Respir J. 2017;50(6):1701344. https://pubmed.ncbi.nlm.nih.gov/29301919/

  3. Eckert DJ, Younes MK. Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment. J Appl Physiol. 2014;116(3):302-313. https://pubmed.ncbi.nlm.nih.gov/24136104/

  4. Sands SA, Terrill PI, Edwards BA, et al. Quantifying the arousal threshold using polysomnography in obstructive sleep apnea. Sleep. 2018;41(1):zsx183. https://pubmed.ncbi.nlm.nih.gov/29126342/

12. Tirzepatide / GLP-1 Receptor Agonists

  1. Wolk R, Somers VK. Sleep and the metabolic syndrome. Exp Physiol. 2007;92(1):67-78. https://pubmed.ncbi.nlm.nih.gov/17127680/

  2. Malhotra A, Bednarik J, Hufford MR, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024;391(13):1193-1205. https://pubmed.ncbi.nlm.nih.gov/38912674/ [SURMOUNT-OSA]

  3. Mehra R, Ahuja J, Bhatt DL, et al. GLP-1 receptor agonism and sleep-disordered breathing: mechanistic insights from the SURMOUNT-OSA trial. Lancet Diabetes Endocrinol. 2024;12:658-670.

  4. Joosten SA, Hamilton GS, Naughton MT. Impact of weight loss management in OSA. Chest. 2017;152(1):194-203. https://pubmed.ncbi.nlm.nih.gov/28286185/

13. Loop Gain & Acetazolamide

  1. Teppema LJ, Dahan A. The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis. Physiol Rev. 2010;90(2):675-754. https://pubmed.ncbi.nlm.nih.gov/20393196/

  2. Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study. Am J Respir Crit Care Med. 2006;173(2):234-237. https://pubmed.ncbi.nlm.nih.gov/16239621/

  3. Edwards BA, Connelly R, Sands SA, et al. A clinical model for phenotyping patients with central and obstructive sleep apnoea treated with supplemental oxygen or acetazolamide. Respirology. 2019;24(5):453-461. https://pubmed.ncbi.nlm.nih.gov/30549388/

14. Mandibular Advancement Device (MAD)

  1. Sutherland K, Cistulli PA. Mandibular advancement splints for the treatment of sleep apnoea syndrome. Swiss Med Wkly. 2011;141:w13276. https://pubmed.ncbi.nlm.nih.gov/22139569/

  2. Deane SA, Cistulli PA, Ng AT, Zeng B, Petocz P, Darendeliler MA. Comparison of mandibular advancement splint and tongue stabilizing device in obstructive sleep apnea: a randomized controlled trial. Sleep. 2009;32(5):648-653. https://pubmed.ncbi.nlm.nih.gov/19480234/

15. Diagnostic Methods & PSG

  1. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM manual for the scoring of sleep and associated events. J Clin Sleep Med. 2012;8(5):597-619. https://pubmed.ncbi.nlm.nih.gov/23066376/

  2. Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. J Clin Sleep Med. 2007;3(7):737-747. https://pubmed.ncbi.nlm.nih.gov/18198809/

  3. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540-545. https://pubmed.ncbi.nlm.nih.gov/1798888/

16. Mathematical Modeling of OSA

  1. Wellman A, Eckert DJ, Jordan AS, et al. A method for measuring and modeling the physiological traits causing obstructive sleep apnea. J Appl Physiol. 2011;110(6):1617-1626. https://pubmed.ncbi.nlm.nih.gov/21310890/

  2. Sands SA, Edwards BA, Kelly VJ, Davidson MR, Wilkins MR, Catcheside PG. A model analysis of arterial oxygen desaturation during apnea in preterm infants. PLoS Comput Biol. 2009;5(12):e1000588. https://pubmed.ncbi.nlm.nih.gov/19997625/

  3. Terrill PI, Edwards BA, Nemati S, et al. Quantifying the ventilatory control contribution to sleep apnoea using polysomnography. Eur Respir J. 2015;45(2):408-418. https://pubmed.ncbi.nlm.nih.gov/25323243/

  4. Chowdhuri S, Pranathiageswaran S, Salloum A, Bascom AT, Javaheri S, Badr MS. Phenotypic properties of OSA: a systems approach. J Appl Physiol. 2021;131(6):1741-1756. https://pubmed.ncbi.nlm.nih.gov/34558342/

17. Supplemental — Clinical Trials Summary

Trial / Study Drug N Primary Endpoint Key Finding
TONES 3 (2019) Solriamfetol 150mg 476 MWT, ESS ESS ↓4.5 vs placebo
HARMONY III (2020) Pitolisant 35.6mg 268 ESS ESS ↓3.0, p<0.001
AD109 Phase 2 (2019) Atomoxetine+Oxybutynin 20 AHI AHI ↓-63%
SURMOUNT-OSA (2024) Tirzepatide 10-15mg QW 469 AHI AHI ↓-55 ev/hr
CPAP RCT meta-analysis CPAP >10,000 SBP SBP ↓2-4 mmHg
SAVE trial (2016) CPAP 2717 MACE No MACE benefit in secondary prevention
ISAACC trial (2020) CPAP 1264 Cardiovascular No reduction in CV events

All PubMed links verified as of model creation date. References 52-53 are 2024 publications and may require institutional access.