Table 1.

Summary of Cluster Analysis in Patients With Sleep Apnea (or Referred for Sleep Apnea Evaluation) According to Variable Domain Used for Classification

Phenotypic Feature	Study/Year	Study Population/Sample Size/OSA Severity	Clustering Method	Main OSA Cluster Findings (Prevalence, %)	Outcomes Associated With Phenotypes/Comments
Symptoms (14 questions) ESS	Mazzotti et al,24 2019	Population (SHHS, US) N = 1,207, PSGAHI ≥ 15Hypopnea: not defined	LCA	4 clusters: 1: Disturbed sleep (12%)—predominant insomnia symptoms 2: Minimally symptomatic (33%)—lowest symptom burden of all clusters 3: Excessively sleepy (17%)—predominant sleepy, involuntary sleep, drowsy driving 4: Moderately sleepy (39%)—snoring, napping	Outcomes: Prevalent (OR) and incident CVD (HR) Adjusted for: age, sex, BMI, AHI, presence of DM, HTN, cholesterol, triglycerides, smoking status, alcohol usage, race, ethnicity, and lipid-lowering medication Prevalent: •Cluster membership not associated with CVD overall •Increased risk of HF for “Excessively sleepy” (OR, 3.1-3.7) vs all other clusters Incident:Increased risk of incident CVD or death for “Excessively sleepy” vs all other clusters (HR, 2.2-2.4)
Symptoms (16 questions) ESS Comorbidities (CVD, HTN, and DM)	Kim et al,31 2018	Population (South Korea) N = 422 HSATAHI ≥ 15Hypopnea: 30% flow decrement with 4% desaturation	LCA	3 clusters: 1. Disturbed sleep (14%) 2. Minimally symptomatic (56%) 3. Excessively sleepy (30%)	No outcomes reported No differences between clusters in AHI or BMI HTN highest among “Disturbed sleep”
Symptoms (19 questions) ESS Comorbidities (CVD, HTN, DM, and COPD)	Ye et al,20 2014	Clinical (Iceland) N = 822 HSATAHI ≥ 15Hypopnea: 30% flow reduction with 4% desaturation	LCA	3 clusters 1. Disturbed sleep (33%) 2. Minimally symptomatic (25%) 3. Excessively sleepy (42%)	Outcomes: QOL (SF-12 physical and mental components) QOL highest for “Minimally symptomatic” No differences between clusters in AHI or BMIComorbidities highest in “Minimally symptomatic”
Symptoms (17 questions) ESS 3 comorbidities (CVD, HTN, and DM)	Keenan et al,30 2018 and Pien et al,23 2018	Clinical (Iceland) N = 215 (Keenan et al30) N = 706 (Pien et al23)HSATAHI ≥ 15Hypopnea: 30% flow reduction with 4% desaturation	LCA	3 clusters: 1. Disturbed sleep (33%) 2. Minimally symptomatic (29%) 3. Excessively sleepy (38%) Nearly identical to Ye et al20/2014 regarding age, BMI, AHI, and comorbidity distribution, which did not differ among clusters	Outcomes (Pien et al23): changes in symptoms, QOL, comorbidities, anthropometrics over time; CPAP adherence Effect of CPAP on symptoms was most notable in “Excessively sleepy” on the sleepiness symptoms (eg, drowsy driving, falling asleep during the day) Both CPAP users and nonusers improved in “Disturbed sleep.” CPAP users improved in sleepiness and insomnia symptoms QOL improved in “Excessive sleepy” only “Minimally symptomatic” with highest rate of HTN and CVD at follow-up
Symptoms (17 questions), ESS 3 comorbidities (CVD, HTN, and DM)	Keenan et al,30 2018	Clinical (multi-ethnic, multinational) N = 757 PSG/HSATAHI ≥ 15Hypopnea:30% flow reduction with 4% desaturation	LCA	5 clusters: 1. Disturbed sleep (19%) 2. Minimally symptomatic (20%) 3. Upper airway with sleepiness (similar to “Excessively sleepy” from Icelandic studies) (22%) 4. UA symptoms (19%) 5. Sleepiness-dominant (similar to moderately sleepy in SHHS study) (20%) New clusters (4 and 5) composed of patients in “Minimally symptomatic” and “Excessively sleepy” in Icelandic study	Similar trends in age, BMI, and AHI among three common clusters to above studies “Upper airway with sleepiness” is younger, more obese, and sleepy than others; no clinical difference in AHI “Disturbed sleep” with highest proportion of women and highest rates of comorbidities (not consistent with SHHS, South Korean, or Icelandic studies)
Multiple variable domains: Symptoms Comorbidities (HTN, DM, CVD, and others) Anthropometrics (Age, sex, and BMI) AHI not included	Bailly et al,32 2016	Clinical (registry in France) N = 18,263 Sleep assessment not specifiedAHI ≥ 15Hypopnea: no specified	Multiple correspondence analysis for feature selection followed by hierarchical clustering	6 clusters: 1. Young symptomatic (10%) Low BMI, few or no comorbidities, high sleepiness, and near misses driving; medium T90% 2. Older obese (23%) Lowest ESS, few comorbidities 3. Multidisease, old, obese (19%) Symptomatic but low ESS, HTN, diabetes, CVD; highest T90% 4. Young snorers (15%) Lowest BMI, few symptoms no comorbidities; lowest T90% 5. Drowsy obese (19%) Highly symptomatic, few comorbidities 6. Multidisease, obese, symptomatic (15%) Highly symptomatic, HTN, diabetes, and CVD; high T90%	No outcomes reported Fatigue differed by cluster. Highest among “Young symptomatic” and “Multidisease symptomatic” No difference in depression scores
Multiple variable domains: Anthropometrics Sleep symptoms Insomnia report Depressive symptoms Comorbidities (HTN, CVD, and DM) AHI not included	Gagnadoux et al,34 2016	Clinical (France) N = 5,983 PSG/HSATAHI ≥ 15Hypopnea: not defined	LCA	5 clusters: 1. Female OSA with insomnia (14%) Middle-aged, obese women with insomnia and comorbidities2. Male OSA with comorbidities (15%) 3. Severe sleepy OSA without comorbidities (18%) Youngest, lack of comorbidities 4. Mild sleepiness, insomnia (32%) Non-obese with minimal comorbidities 5. Older, comorbid OSA (21%) Minimally symptomatic	Outcome: CPAP success at 6 mo (this metric defined as a combination of) Adherence (≥ 4 h daily) and (ESS decrease of ≥ 4 OR, increase of ≥ 7 points in vitality from SF-36 Adjusted for: marital, educational, and employment status; model, AHI, and baseline ESS score “Female OSA with insomnia” (OR, 0.66) “Mildly sleepy, insomnia” (OR, 0.66) and “Older, comorbid OSA” (OR, 0.38) with lower likelihood of CPAP success vs “Severely sleepy OSA without comorbidities”“Older, comorbid OSA,” despite highest CPAP use/adherence, had lowest reduction in ESS and improvement in QOLAHI differed by significance with narrow range (38-46)
Multiple variable domains: Sleepiness Demographic characteristics Anthropometrics Polysomnographic indices Lung function Blood gases Comorbidities (HTN, DM, CVD, and others)	Lacedonia et al,36 2016	Clinical (Italy) HSAT N = 198 AHI ≥ 5Hypopnea:AASM 2007 criteria (recommended or alternative not specified)Patients excluded:OHSCOPDNMD	PCA for feature selection, Network analysis with hierarchical and local optimizing clustering	3 clusters: 1. Severe, hypoxic OSA (50%) Most sleepy, obese, small lung function 2. Moderate, nonhypoxic OSA (51%) 3. Severe, minimally hypoxic OSA (9%) Large AHI vs ODI discrepancy Less sleepy	No outcomes reported No differences in comorbidities, age, or sex No differences in blood gases or lung function
Multiple variable domains: Demographic Anthropometric Symptoms Comorbidities (CHF, pulmonary HTN, and arrhythmias) AHI not included	Ferreira-Santos and Pereira Rodrigues,33 2018	Clinical (Portugal) N = 211 AHI: cutoff not definedPatients excluded:Severe lung diseasesNeurological conditions	K-modes categorical clustering	3 clusters: 1. Nonobese, young, drowsy (55%) 2. Female, poor sleep (20%) 3. Obese, older, non-drowsy (25%)	No outcomes reported No difference in AHI or comorbidities among clusters “Obese, older, non-drowsy” with highest Mallampati score and neck circumference “Female, poor sleep” with headaches and nonrestorative sleep
Multiple variable domains: 19 variables: Demographic Health habits BP AHI, T90 Comorbidities Medications	Quan et al,25 2018	Clinical (clinical trial, multinational) N = 2,649 Patients with CAD and/or CeVD and OSA (ODI ≥ 12) on home sleep apnea test randomized to receive CPAP or usual care	LCA	4 clusters: 1. CeVD and DM (9%) 2. CAD and DM (15%)3. CeVD (37%)4. CAD (39%)	Outcomes. Primary, composite of death from any CV cause or incident MI, stroke, hospitalization for unstable angina, HF, or TIA (HR by cluster). Adjusted for: posterior probability of cluster membershipPrimary outcome: CAD and DM (HR, 2.1)CeVD and DM (HR, 1.7)CAD and DM (HR, 1.4)CAD (referent)Rate of primary outcome by < 4 h/night vs ≥ 4 h/night CPAP use:CeVD and DM (21% vs 5%; P = .015)Other clusters with no significant differences
Comorbidities (30 conditions, ICD-9 defined)	Turino et al,40 2017	Clinical (Spain) N = 72,217 Patients on CPAP therapyAHI, hypopnea not reported	Multiple correspondence for feature selection, K-means for clustering	6 clusters: 1. Neoplastic (10%) 2. Metabolic syndrome (28%)3. Asthmatic (6%)Most women (53% of cluster)4. Musculoskeletal and joint disorders (10%)5. Few comorbidities (35%)6. Oldest CVD (10%)	Outcomes: all-cause mortality, hospitalizations, Health-care utilization “Neoplastic” and “Oldest CVD” with highest mortality (15%) and hospitalizations (> 1 visit, 30%-37%)Lowest mortality for “Metabolic syndrome” and “Musculoskeletal and joint disorders” (< 2%)
Comorbidities (19 components of Charlson comorbidity index), AHI	Vavougios et al,22 2016	Clinical (Greece) N = 1,472 Patients referred for PSGAHI: no cutoff usedHypopnea: 50% flow reduction or 30% flow reduction with arousal or 3% desaturation	PCA for feature selection, “Two-step clustering” (“preclustering” followed by hierarchical clustering)	6 clusters: 1. Mild OSA, no comorbidities (20%) Increased CAD vs no OSA2. Moderate OSA, high comorbidity (7%)Older, obese, low oxygen nadirOSA3. No OSA, no comorbidities (17%)Youngest, no sleepiness4. Severe OSA, no comorbidities (31%)Obese, sleepy5. Severe, high comorbidity (10%)Older, morbidly obese, hypersomnia6. Moderate OSA, no comorbidities (15%)Mild obesity, not sleepy, high oxygen nadir	No outcomes reported More obese, older individuals tended to be in more comorbid clusters Comorbidities cluster independently of the AHI or hypoxemia (measured by nadir oxygen saturation)
PSG characteristics (all from supine sleep) Mean event duration Minimum oxygen saturation Fraction of apneas Arousal ratio (respiratory/total) AHI	Nakayama et al,37 2019	Clinical (Japan) N = 210 PSGAHI ≥ 15Hypopnea:50% flow reduction with 3% desaturation or arousalPatients excluded:CVDPsychiatric diseaseWomenHypnotic usePLM index ≥ 15	Hierarchical and K-means	3 clusters: 1. Hyper-severe OSA, hypoxemic (20%) Obese, highest NREM 1 stage sleep, most arousals respiratory2. Severe OSA, long event durationNonobese, low NREM 1 stage, most arousals respiratory, non-hypoxemic3. Severe OSA, short event durationOverweight, higher central apneas, low fraction of apneas, low NREM 1 stage, nonhypoxemic	No outcomes reported
PSG characteristics (AHI metrics stratified by position and sleep state [REM vs NREM]), arousals, age, BMI, sex, ESS	Joosten et al,35 2012	Clinical (Australia)N = 1,064 PSGAHI 5-30 per hour Hypopnea: > 50% reduction in the oronasal pressure signal, or a smaller reduction in association with oxygen desaturation of 3% or an arousal	K-means	6 Clusters: 1. Mild supine predominant OSA (32%) Youngest, nonobese2. Moderate supine predominant OSA (21%)Older3. Moderate supine isolated OSA (4%)Younger, nonobese4. REM predominant OSA (12%)Most female, most obese5. Mild REM-supine OSA (20%)Oldest6. Moderate REM-supine OSA (13%)Younger	No outcomes reported
PSG characteristics only 29 variables in domains of: Respiratory disturbance Sleep architecture Autonomic dysfunction Hypoxia	Zinchuk et al,21 2018	Clinical (US veterans) N = 1,247 Patients referred for OSA evaluationPSGAHI: no cutoff usedHypopnea: > 30% reduction in nasal pressure with a 4% desaturation	PCA and hierarchical clustering for feature selection, K-means for clustering	7 clusters: 1. Mild (43%) Lowest apneas/hypopneas2. PLMS (20%)3. NREM and poor sleep (15%)Highest ratio of arousals per AHI, minimal hypoxemia4. REM and hypoxia (15%)Relatively preserved sleep architecture5. Hypopnea and hypoxia (6%)6. Arousal and poor sleep (3%)Highly fragmented sleep, minimal hypoxemia7. Combined severe (10%)Apneas with arousals and desaturations, severe hypoxemia	Outcome: incident CVD or death by cluster (HR, compared with “Mild” cluster) Adjusted for: Framingham risk score, regular CPAP use, ethnicity, alcohol use, home oxygen useMultiple clusters in each conventional severity category:Mild: 1 and 2Moderate: 3 and 4Severe: 5, 6, and 7“PLMS” (HR, 2.0)“Hypopnea and hypoxia” (HR, 1.7)“Combined severe” (HR, 1.7)Risk of outcome in regular vs nonregular CPAP users, cluster“PLMS” (OR, 0.38)“Hypopnea and hypoxia” (OR, 0.22)
CPAP adherence trajectories Hours of CPAP use per day by each patient over 180 d	Babbin et al,45 2015	Clinical (clinical trial, multinational) N = 161 AHI ≥ 5Hypopnea: not defined	Time series analysis and dynamic cluster analysis	4 Clusters 1. Great users (17%) 2. Good users (33%)3. Low users (23%)4. Slow decliners (27%)	Outcomes: CPAP adherence (hours/night), symptoms (ESS), QOL (FOSQ), attention (PVT) “Good users” more vigilant (FOSQ) vs “Low users” or “Slow decliners” “Good users” with higher productivity (FOSQ) vs “Low users” and “Great users”“Great users” and “Good users” higher sleep quality vs “Low users”Over time, self-efficacy waned in “Low-users”

OR and hazard ratio (HR) reported only for significant associations between clusters and outcome. AASM = American Academy of Sleep Medicine; AHI = apnea-hypopnea index; CAD = coronary artery disease; CeVD = cerebrovascular disease; CHD = coronary heart disease (myocardial infarction; coronary revascularization procedure); CHF = congestive heart failure; CV = cardiovascular; CVD = cardiovascular disease (CHD, stroke, and heart failure); DM = diabetes mellitus; ESS = Epworth Sleepiness Scale; FOSQ = Functional Outcomes of Sleep Questionnaire; HF = heart failure; HSAT = home sleep apnea testing; HTN = hypertension; ICD-9 = International Classification of Diseases, Ninth Revision; LCA = latent class analysis; MI = myocardial infarction; NMD = neuromuscular disease; NREM = non-rapid eye movement; ODI = oxygen desaturation index; OHS = obesity hypoventilation syndrome; PCA = principal component analysis; PLMS = periodic limb movements of sleep; PVT = Psychomotor vigilance test; QOL = quality of life; REM = rapid eye movement; SF = Short-form quality of life questionnaire; SHHS = Sleep Heart Health Study; T90% = percent recording time spent at arterial oxygen saturation below 90%; TIA = transient ischemic attack; UA = unstable angina.