Future Treatment of Sleep Disorders

•Sleep medicine is cataloged according to a conventional disease classification system. Disease models are rooted in the pathophysiology of sleep. Polysomnography and other tests used demonstrate pathophysiological mechanisms underlying currently known sleep disorders.•Although many patients with disorders may be adequately managed by this approach, therapeutic results insufficient some subjects, causes which lie nonspecificity symptoms, coincidental association between symptoms endotype, as well co-occurrence two or more pathologic affecting sleep.•As different pathogenetic produce phenotypes that at odds idealized description classic disorders, result standard interventions disappointing.•The expression certain traits substrate for targeted treatment. Treatable characterized biomarkers predictive value beneficial treatment response.•The challenge future gradually embrace principles systems shift gear toward managing treatable surpassing limits traditional nosologic approach. Over past decades, has evolved novel discipline health care. The development relevant medical specialties invariably been preceded major scientific advances particular areas interest. Medical surgical have traditionally organized on anatomic organ-based line growing insight organ-system physiology pathology. taxonomy human dates back nineteenth century largely ascribed work Sir William Osler, one founding fathers modern medicine.1Loscalzo J. Barabasi A.L. Systems biology medicine.Wiley Interdiscip Rev Syst Biol Med. 2011; 3: 619-627Crossref PubMed Scopus (178) Google Scholar diseases connecting affected organ system physiologic, anatomic, histologic findings called “Oslerian paradigm.”2Vanfleteren L.E. Kocks J.W. Stone I.S. et al.Moving from Oslerian paradigm post-genomic era: asthma COPD outdated terms?.Thorax. 2014; 69: 72-79Crossref (50) Syndromic patterns entities building blocks still prevails contemporary diseases. Later history, cross-sectional disciplines emerged common biological settings integrate context. Relevant “horizontal” developed age domains (pediatrics geriatrics), cell (oncology), microbiology (infectiology), name few. Sleep an essential process can readily impaired mechanisms. Evidently, various ground underpinning concept clinical we know it today. technological revolution over instigated research, thereby disclosing vast amount information producing exquisite tools diagnosing treating disorders. This evolution paved way setting up its own right.3Shepard Jr., Buysse D.J. Chesson al.History United States.J Clin 2005; 1: 61-82Crossref (97) In development, curricula established uplifting par educational standards disciplines.4Penzel T. Pevernagie D. Bassetti C. al.Sleep catalogue knowledge skills - Revision.J Res. 2021; 30: e13394Crossref (1) parallel creation professional title, textbooks, guidelines, catalogs published. International Classification Disorders (ICSD), issued American Academy Medicine (AASM), concise reference book systematically classifies sleep.5Mayer G. Nosological diagnostic strategy.in: Overeem S. Reading P. neurology. A practical 2 ed. Wiley-Blackwell, Chichester, UK2018: 41-52Crossref manual, categorized into domains, including insomnia, sleep-disordered breathing, central hypersomnia, circadian rhythm parasomnia, sleep-related movement miscellaneous conditions. themselves described associated features, predisposing precipitating factors, natural course, pathophysiology, polysomnography (PSG) objective tests. Basically, items listed ICSD modeled entities. model consists constellation signs complemented characteristic PSG (and complementary tests). merger observations testing deemed specific respect causality. connotation causality reinforced adding term “syndrome” example, “sleep apnea syndrome” “restless legs syndrome.” Moreover, provides criteria each entity. These commonly include mixture signs, findings. Diagnostic cutoffs typically based frequency and/or severity ratings characteristics. Inherently, cause-consequence relationship inferred disorder ICSD, cause being demonstrable methods consequence presentation. However, overlap often correlate poorly degree abnormality assessed tests.6Pevernagie D.A. Gnidovec-Strazisar B. Grote L. al.On rise fall apnea-hypopnea index: historical review critical appraisal.J 2020; 29: e13066Crossref (40) Not infrequently, recommended therapy fails symptomatic relief not tolerated, suggesting really these cases, there reasons believe uncertain apparent concealed confounders influence determine outcome. Thus, question arises whether practice should stick “syndromic” approach rather move management likely respond treatment? AASM revised several occasions. adjusted new data. More emphasis placed role PSG. As consequence, theoretic evolved. To illustrate conceptual adaptations time, present discussion will focus obstructive (OSA) chronic disturbance across consecutive editions also highlighting logical errors inadvertently crept in. first edition was published 1990 Association (the predecessor AASM).7ASDAObstructive syndrome (780.53-0).in: international coding manual. 1 Association, Rochester, MN, USA1990: 52-58Google OSA did any count respiratory events nor index (AHI), but only qualitative description: “frequent episodes obstructed breathing.” criterion primarily seriousness assumed would reflected 2005, second (ICSD-2).8AASMObstructive apnea, adult.in: Sateia M. Hauri Medicine, Westchester, IL, USA2005: 51-55Google version previous AHI cutoff points were presented primary definition OSA. diagnosis could greater than equal 5/h presence 15/h even without symptoms. inspired earlier publication measurement techniques.9AASMSleep-related breathing adults: recommendations techniques research. Report Task Force.Sleep. 1999; 22: 667-689Crossref (4622) paper, introduced metric gauging severity. proposition single population survey showed prevalent hypertension.10Young Peppard Palta al.Population-based study risk factor hypertension.Arch Intern 1997; 157: 1746-1752Crossref because prospective data time publication, causal inference scientifically inappropriate. Nevertheless, then accepted measure AHI-driven remodeling converse error (Box 1).11Damer T.E. Attacking faulty reasoning.6 Wadsworth, Belmont, USA2009Google Scholar,12Heller Catch-22. Vintage, London, UK1994Google reasoning reverses order premise consequent: subjects clinically increased AHI, necessarily true. relevance become evident epidemiologic Swiss middle-aged older people urban community, shown prevalence amounted 49.7% men 23.4% women.13Heinzer R. Vat Marques-Vidal al.Prevalence general population: HypnoLaus study.Lancet Respir 2015; 310-318Abstract Full Text PDF (1159) most people, daytime sleepiness absent. Because demonstrated large percentage asymptomatic population, doubt must casted validity meaningful severity.6Pevernagie Hence follows continue distort long maintained prime predictor variable.Box 1Logical relation presentation apneaA: suggest OSAB: AHIC: causally related B (true positive)D: coincidentally (false positive)E: normal AHIF: OSAUsing relevant, responsive brings about fallacies:Set source McNamara quantitative fallacy: test result. Although state, misrepresents characteristics disorder.Set F congruent division assuming represents erroneous. Many asymptomatic.Sets C, D, (aka affirming consequent): true (set C) AHI—the opposite true.Set D false A: Box illustrates deficiencies associations assumptions.11Damer ICSD-2, sets representing profiles denominator. heterogeneous manifestations do simply fit cast set criteria. reductionist surely apply subgroups, no means all entire target group. Division fallacy wrongly individual belonging group (eg, ? 15/h) show key suffering sleepiness). It related. due coincidence, misconception. McNamara) yet another misconception decisions rely solely metric, ignoring observations.14O'Mahony fallacy.J R Coll Physicians Edinb. 2017; 47: 281-287Crossref (24) presumption itself state dose-dependent manner justified. correlation weak best. Ascribing properties obviously overqualification.6Pevernagie third (ICSD-3) further expanded model, mental, metabolic, cardiovascular comorbidities intrinsic components disorder.15AASMObstructive 3 Darien, USA2014: 53-62Google Yet, additional evidence put forward support assumption reflects Despite omission, ICSD-3 quoted rating recent guideline AASM.16Kapur V.K. Auckley D.H. Chowdhuri al.Clinical adult apnea: guideline.J 13: 479-504Crossref (851) takes step further, deleting ultimate IDSC-2 “the [ie OSA] better explained current disorder, neurologic medication use, substance use disorder.” clearly excludes need differential and, such, endorses fallacy. aforementioned fallacies far-reaching consequences research daily practice. There gold (or “ground truth”) define real causative provoking hard ascertain, high values. mentioned earlier, indicative picture labeled “false positive” practice, false-positively experience little benefit poor adherence. Trying optimize compliance individuals improve results. outcomes randomized controlled trials blurred mixing false-positive true-positive customary inclusion threshold both categories knowing who’s who. Obviously, bias addressed research.17Randerath W. C.L. Bonsignore M.R. al.Challenges perspectives apnoea: ad hoc working disordered European Society Society.Eur 2018; 52: 1702616Crossref (88) Chronic hallmarked multicomponent nonlinear processes ill-suited comprehended models.18Ahn A.C. Tewari Poon C.S. al.The reductionism medicine: offer alternative?.Plos 2006; e208Crossref (301) Instead, science offers effectively treat susceptible level. Alvar Agusti pioneered such pulmonary (COPD), highly disabling diseases.19Agusti A. Bel E. Thomas al.Treatable traits: precision airway diseases.Eur 2016; 410-419Crossref (484) Taking lung starting point, he elegantly transition reasoning. management, pathology- pathophysiology-oriented diagnosis, had point fine-tuned. identify attributes allowing stratification phenotypes. subclassification proved predict effects prognosis within stratified subgroups. Eventually, became obvious subsequent taken assessment required level.20Agusti Phenotypes characterization disease. Toward extinction phenotypes?.Ann Am Thorac Soc. 2013; 10: S125-S130Crossref (37) At present, personalized “precision”) proposed overcome limitations former strategies. defined “treatments needs basis genetic, biomarker, phenotypic psychosocial distinguish given patient similar presentations.”21Agusti path personalised COPD.Thorax. 857-864Crossref (111) main “improve while minimizing unnecessary side those less treatment.”22Jameson J.L. Longo D.L. Precision medicine--personalized, problematic, promising.N Engl J 372: 2229-2234Crossref (562) rationale observation “complex” “heterogeneous.” setting, they dynamic interactions, whereas “heterogeneous” indicates or, patient, timepoints.21Agusti An explanation concepts Table 1.Table 1Evolution conceptType ManagementUnderlying ConceptClinical ImplicationsManagementTraditional medicineMonodimensional, uniform processesSyndromic approach: denominator observed markers defines illness“One size fits all”Stratified medicineHeterogeneity entitiesPhenotyping, subtypes“One every subtype”Personalized plus complexity entitiesMultiple underly discrete Discrimination becomes obviousLabel-free, treatment-responsive Open table tab biology.23Ahn applications approach.Plos e209Crossref (143) domain studies complex space, context-sensitive interactions constitute Information lost zooming components. gain insights, dynamics analyzed integrated meta-level. Analytical derived engineering big science. transposition “systems medicine” “network medicine.”24Agusti Celli Faner What does endotyping mean disease?.Lancet. 390: 980-987Abstract (46) intricate interaction environmental, clinical, biological, genetic levels ultimately outcomes. brief, grouped basic covering genotypes, endotypes, (Table 2).24Agusti Meanwhile, reviewed appropriate opinion leaders community.25Pack A.I. Application personalized, predictive, Preventative, Participatory (P4) apnea. Roadmap improving Care?.Ann 1456-1467Crossref Scholar,26Martinez-Garcia M.A. Campos-Rodriguez F. Barbe al.Precision apnoea.Lancet 2019; 7: 456-464Abstract ScholarTable 2Definitions medicineTermMeaningExposomeThe cumulative/lifelong environmental exposures smoking, pollution, noxious substances, infections, diet.GenomeThe total composition genes defining make-up organism individual.EpigeneticsMolecular mechanisms/multilevel networks dynamically modulate outcome gene–environment interactions.GenotypeThe part genome (ie, gene genes) codes individual, determining phenotype through intermediary pathway endotypes.EndotypeThe subtype condition distinct molecular, functional, pathobiological mechanism. Studying endotypes allows mechanistic approaches beyond disease.PhenotypeObservable combination (symptoms, response therapy, outcomes, quality life).TraitA endotype subtype. trait identified recognition validated biomarkers.BiomarkerA measurable indicator (biological molecule body fluids physiologic phenomenon) gauge pathogenic Validated reliable surrogates phenotypes.ClusterA together mechanism Endotypes studied intensively decade, especially breathing.27Edwards B.A. Redline Sands S.A. al.More Sum events: apnea.Am Crit Care 200: 691-703Crossref (45) denotes metabolic systems. OSA, that, together, shape disturbed process. Members Brigham Women’s Hospital (Harvard School) explored breathing.28Eckert White D.P. Jordan A.S. al.Defining Identification targets.Am 188: 996-1004Crossref (538) Briefly, factors play upper obstruction, feature collapsibility airway, nonanatomical (genioglossus muscle responsiveness, arousal threshold, control stability—loop gain). found suitable options application positive pressure oral appliances.29Carberry J.C. Amatoury Eckert Personalized OSA.Chest. 153: 744-755Abstract (80) specifically, supplemental oxygen carbo-anhydrase inhibitors effective reducing loop gain, hypnotics increase training hypoglossal nerve stimulation compensate genioglossus responsiveness.27Edwards Scholar,30Eckert Phenotypic apnoea pathways therapy.Sleep Med Rev. 37: 45-59Crossref (161) Scholar,31Owens R.L. Edwards al.An integrative physiological non therapy.Sleep. 38: 961-970PubMed Evidence accumulating physiologically decrease thu