Sleep-disordered breathing and comorbidities: role of the upper airway and craniofacial skeleton

Figures & data

Table 1 Normal data for mean and minimum overnight oxygen saturation and polysomnography variables in infants, children, and adults

Author	Age (years) – mean (SD) except^€	Mean overnight oxygen saturation % mean (SD) except±*,^¥	Nadir overnight oxygen saturation % mean (SD) except±*,^¥	Apnea Hypopnea Index (events/hr)	Obstructive Apnea Index (events/hr)	Central Apnea Index (events/hr)
Terrill^Citation9	0.04	98.0 (95–100)*
Terrill^Citation9	0.25	99.0 (97–100)*
Terrill^Citation9	0.5	98.0 (95–100)*
Terrill^Citation9	1	99.0 (96–100)*
Terrill^Citation9	2	99.0 (97–100)*
Evans^Citation10	0.08^€	97.1 (96.6–97.5)±	80.4 (78.8–82.0)
Evans^Citation10	0.25–0.33^€	97.7 (97.2–98.1)±	84.7 (83.3 to 86.1)
Montgomery-Downs^Citation41	3–5^€	>95			0.03 (0.1)	0.82 (0.73)
Montgomery-Downs^Citation41	6–7^€	>95			0.05 (0.11)	0.45 (0.49)
Traeger^Citation23	6.6 (1.9)	97 (1)	92 (3)		0.01 (0.03)	0.08 (0.14)
Strauss^Citation50	6.6 (3.4)	97.1 (0.9)	91.1 (4.2)		0.2 (0.3)
Uliel^Citation22	7.9 (4.4)	97 (0.8)	94.6 (2.2)			0.33 (0–0.9)*
Uliel recommended^Citation22	8 (1–15)*	92	89		1	0.9
Urschitz^Citation21	9.3 (0.6)	97 (1.6)	93 (2.2)
Moss^Citation25	9.6 (0.7)		92.2 (2.7)		0.1 (0.2)	1.5 (1.1)
Rosen^Citation37	9.6 (0.7)	96 (90–99)*	91.6 (73–95)*		0.1 (0.5)
Verhulst^Citation24	11.7 (2.6)	97 (0.6)	91.8 (2.7)		0.06 (0.16)	0.85 (1.06)
Scholle≠^Citation42	1.4 (1.1–1.9)*	98 (96–98.8)*	92 (87.6–95)		0.0 (0.0–0.0)*	2.8 (0.8–3.7)*
Scholle≠^Citation42	3.0 (2.2–3.5)*	99 (95.4–99)*			0.0 (0.0–0.0)*	1.5 (0.7–6.9)*
Scholle≠^Citation42	5.0 (4.3–5.8)*	98 (97–99)*			0.0 (0.0–0.0)*	1.1 (0.5–3.2)*
Scholle≠^Citation42	8.0 (6.3–10.1)*T1	98 (96–98)			0.0 (0.0–0.0)*	0.9 (0.3–2.7)*
Scholle≠^Citation42	11.5 (9.7–13.2)*T2	98 (96–98)			0.0 (0.0–0.2)*	0.4 (0.0–1.8)*
Scholle≠^Citation42	12.5 (11.4–15.2)*T3	97 (96–98)			0.0 (0.0–0.0)*	0.5 (0.1–1.8)*
Scholle≠^Citation42	15.2 (13.4–17.2)*T4	97 (96–98)			0.0 (0.0–0.0)*	0.1 (0.0–0.8)*
Scholle≠^Citation42	16.9 (15.8–17.9)*T5	97 (96–98)			0.0 (0.0–0.0)*	0.1 (0.0–1.3)*
Mitterling Men 2007≠^Citation13	43 (19–77)*	94.4 (90.0–97.0)*	89.0 (81.0–98.0)*	0.7 (0.0–21.5)*
Mitterling Women 2012^Citation13				2.1 (0.1–25.0)*
Mitterling Men 2007≠^Citation13		95.4 (89.3–98.0)*	90.0 (78.0–95.0)*	0.5 (0.0–11.0)*
Mitterling Women 2012^Citation13				1.4 (0.0–21.1)*
Mitterling 2007≠^Citation13	<30	95.2 (93.0–98.0)*	90.0 (84.0–95.0)*	0.1 (0.0–3.9)*
Mitterling 2012^Citation13	<30			0.5 (0.0–8.8)*
Mitterling 2007≠^Citation13	31–40	95.5 (92.5–98.0)*	91.0 (86.0–95.0)*	0.7 (0.0–11.7)*
Mitterling 2012^Citation13	31–40			1.0 (0.0–22.5)*
Mitterling 2007≠^Citation13	41–50	95.0 (90.0–98.0)*	89.5 (81.0–94.0)*	0.4 (0.0–15.9)*
Mitterling 2012^Citation13	41–50			1.9 (0.0–18.4)*
Mitterling 2007≠^Citation13	51–60	93.8 (91.0–96.3)*	88.0 (78.0–93.0)*	1.2 (0.0–19.1)*
Mitterling 2012^Citation13	51–60			2.6 (0.0–22.6)*
Mitterling 2007≠^Citation13	>60	93.5 (89.3–96.6)*	87.0 (80.0–98.0)*	3.4 (0.0–21.5)*
Mitterling 2012^Citation13	>60			2.6 (0.0–22.6)*
Hertenstein≠^Citation14	19–30^€ Female			0.9 (1.0)
Hertenstein≠^Citation14	19–30^€ Male			1.7 (2.9)
Hertenstein≠^Citation14	31–40^€ Female			1.0 (0.8)
Hertenstein≠^Citation14	31–40^€ Male			2.8 (2.7)
Hertenstein≠^Citation14	41–50^€ Female			2.1 (2.1)
Hertenstein≠^Citation14	41–50^€ Male			2.2 (2.7)
Hertenstein≠^Citation14	51–60^€ Female			3.5 (3.5)
Hertenstein≠^Citation14	51–60^€ Male			5.5 (7.8)
Hertenstein≠^Citation14	61–73^€ Female			4.9 (5.4)
Hertenstein≠^Citation14	61–73^€ Male			2.1 (2.5)
Gries and Brooks^Citation18	≤1^€	96.4 (1.2) ^¥	90.7 (2.6) ^¥
Gries and Brooks^Citation18	1–10^€	96.8 (1.4) ^¥	90.1 (3.6) ^¥
Gries and Brooks^Citation18	10–20^€	96.5 (1.6) ^¥	90.4 (2.7) ^¥
Gries and Brooks^Citation18	20–30^€	96.3 (1.0) ^¥	92.0 (3.4) ^¥
Gries and Brooks^Citation18	30–40^€	96.3 (1.1) ^¥	91.5 (2.2) ^¥
Gries and Brooks^Citation18	40–50^€	96.0 (1.3) ^¥	91.1 (2.1) ^¥
Gries and Brooks^Citation18	50–60^€	95.8 (1.7) ^¥	90.4 (1.9) ^¥
Gries and Brooks^Citation18	≥60^€	95.1 (2.0) ^¥	89.3 (2.8) ^¥

Notes: ^€Range ± median (95% confidence intervals); *median (range); ^¥median (SD) where median is SAT50; T=Tanner stage; ^≠American Academy of Sleep Medicine (AASM) 2007 criteria for Apnea Hypopnea Index, Obstructive Apnea Hypopnea Index, Central Apnoea Index.

Table 2 Highlights which anatomical landmarks were used by studies using MRI as the modality for measuring regions of interest

Table 3 Describes these studies found

Paper	Subjects	Measurement method and software	Outcome	Statistics used	Figures
Fujioka et al 1979. Radiographic evaluation of adenoidal size in children: adenoid nasopharyngeal ratio	1398 infants and children (1 month–16 yrs)	Lateral radiographs. Adenoid (linear measurement from maximal convexity along inferior margin of adenoid shadow to straight part of anterior margin of bassiocciput). Nasopharynx (linear measurement from posterior superior edge of hard palate to anteroinferior edge of sphenobasioccipital synchondrosis. When synchondrosis is not clearly visualised, the site of crossing posteroinferior margin of lateral pterygoid plates and floor of bony nasopharynx)	An adenoidal-nasopharyngeal ratio greater than 0.8 was present in 94% subjectively judged to have enlarged adenoids	Information not available	Figure S1^Citation52
Arens et al 2001. MRI of upper airway structure of children with OSAS	18 children with OSAS (age 4.8±2.1 yrs); 18 matched	1.5 Tesla Siemens vision system. Axial and sagittal T1- and T2-weighted images with 3-mm slice thickness and 1 NEX. Slices spanning from base of orbital cavities to epiglottis. Axial = T1-weighted image, maximal tonsillar cross-sectional area level, cross section measurements of oropharyngeal airway (anterior border soft palate/tongue, lateral border tonsils, posterior border pharyngeal constrictor muscles), tonsils, pterygoids, parapharyngeal fat pads. Also, linear measurements across transverse line centre of tonsils (intertonsillar width, bilateral tonsillar width, bilateral fat pad width, bilateral pterygoid width, intermandibular distance). Other axial levels – largest adenoid cross section, maxilla width, internal distance between madibular heads. Sagittal = T1-weighted midsagittal, cross-sectional area of nasopharyngeal airway (anterior border vomer, posterior border adenoid, inferior border horizontal line above hard and soft palate), adenoid, soft palate, tongue, mandible, hard palate. Also, linear measurements along oblique line of mental spine, centre soft palate and clivus (ie, tongue oblique, soft palate oblique, airway oblique, adenoid oblique, mental spine-clibus oblique). Length – hard palate (anterior nasal spine to end palatine bone) Volumetric measurements = adjacent axial slices. Combined upper airway (nasopharynx and oropharynx), tongue, soft palate, mandible (T1-weighted), tonsils, adenoid (T2 – better resolution lymphoid tissues)	In OSAS volume of upper airway smaller, adenoids and tonsils larger. Soft palate larger. Volumes of mandible, tongue similar both groups	Two-tailed unpaired t test, Wilcoxon rank test, or chi- square test. The Pearson correlation used to asses linear correlation of volume percent difference of each OSAS-control pair and AHI	Figure S2^Citation47
Uong 2001. MR imaging of upper airway in children with down syndrome	11 down syndrome children without OSA (age 3.2 yrs±1.4 yrs); 14 controls (age 3.3±1.1 yrs)	1.5-T Siemens vision system. VIDA software. Sequential T1 and T2-weighted spin-echo axial and sagittal. Axial: retropalatal axial T1-weighted image at level of maximal tonsillar cross-sectional area they measured tonsils, pterygoids, parapharyngeal fat pads, airway cross section. Other axial images – largest adenoid area, maximum maxilla width, internal distance between mandibular heads. Sagittal: midsagittal T1-weighted image they measured cross-sectional areas of adenoid, soft palate, tongue, mandible, hard palate, combined nasopharyngeal and oropharyngeal airway. Length of hard palate (nasal spine to end palatine bone). Mandible size (mental spine and the clivus through soft palate centroid). Volumetric measurements – adjacent axial slices. Adenoid, tonsils, (both T2), tongue, soft palate, mandible, total nasal/oral pharyngeal airway (rest T1)	In Down syndrome group found smaller airway volume, mid and lower face skeleton. Shorter mental spine-clivus distance, hard palate length and mandible volume. Adenoid and tonsil volume smaller. Tongue, soft palate, pterygoid, and parapharyngeal fat pads similar to controls	Two-tailed unpaired t test, Wilcoxon rank test, or chi-square test	Figure S3^Citation73
Arens et al 2002. Linear dimensions of the upper airway structure during development	92 normal children	1.5 Tesla Siemens vision system. Sequential T1-weighted images. VIDA software. Sagittal = midsagittal T1-weighted, lower face sagittal skeletal growth by measuring mental spine-clivus length (distance between mental spine – ie, point of insertion of genioglossus to mandible- and clivus passing through soft palate centroid. Linear measurements – tongue oblique width, soft palate oblique width, nasopharyngeal airway oblique width, adenoid oblique width. Axial = lower face skeletal growth was determined by intermandibular length (between medial aspects of both mandibular rami along transverse line passing through tonsil centroid) at level of maximal tonsillar cross section. Linear measurements incl intertonsillar width, bilateral tonsillar width, bilateral fat pad width, bilateral pterygoid width. Also, oropharngeal width (maxinal oropharngeal width on a line parallel to intermandibular line)	In midsagittal plane, mental spine-clivus distance related linearly to age. Tongue, soft palate, nasopharyngeal airway, adenoid increased with and maintained constant proportion to mental spine-clivus distance. Linear relationship for mandibular growth growth measured along intermanduibular line on axial plane and age. Intertonsillar, tonsils, parapharyngeal fat pads, pterygoids widths maintained constant proportion to intermandibular width with age. Lower face skeleton grows linearly along sagittal and axial planes from 1st to 11th year. Soft tissues, incl tonsils and adenoids, surrounding upper airway grow proportionally to skeletal structures	Linear regression analysis	Figure S4^Citation121
Arens et al 2003. Upper airway size analysis by MRI of children with OSAS	20 children with OSAS (age 3.7±1.4);20 controls	1.5 Tesla Siemens vision system. Sequential T2-weighted spin echo axial sections obtained spanning from orbital cavity to larynx. Images transferred to SUN workstation, 3DVIEWNIX softwarre (fuzzy connectedness segmentation). 1. Upper airway centerline = bounded by upper nasopharynx (posterior edge vomer), lower oropharynx (superior part epiglottis). Airway regions adjacent to adenoid, tonsils, overlap measured along centerline. 2. Upper airway cross-sectional area = at planes orthogonal to centreline. Mean and minimal cross section of total airway; mean cross section adjacent to adenoid, tonsils and overlap between the two. 3. Upper airway volume = centerline length and mean cross-sectional area. Volumes for 10 consecutive segments at 10% increments of centerline were computed	In OSAS group mean and minimal cross-sectional area of total airway smaller. Upper airway in OSS is most restricted where adenoid and tonsils overlap	Two-tailed unpaired t test, Wilcoxon rank test, or chi- square test	Figure S5^Citation48
Schwab et al 2003. Identification of upper airway anatomic risk factors for OSAS with	48 subjects with OSAS; 48 controls	1.5 Tesla (online supp). Volumetric measurements = lateral pharyngeal walls (retropalatal and retroglossal); soft palate; tongue (genioglossus, geniohyoid, hyoglossus, myohyoid, digastric, myohyoideous muscles); parapharyngeal fat pads; total	In OSAS group, volume of lateral pharyngeal walls, tongue, total soft tissues larger. Increased risk of OSAS the larger the volume of the tongue, lateral pharyngeal walls and total soft tissue	Chi-square tests and t tests. Multiple logistic regression models used to obtain adjusted odds ratios and 95% CI for effect opf a 1SD change in size of airway and soft tissue measurement.	Figure S6^Citation51
Arens et al 2005. Changes in upper airway size during tidal breathing in children with OSAS,	10 OSAS children (age 4.3±2.3 yrs); 10 matched controls.	1.5 Tesla Siemens Sonata system using 2D trueFlSP sequence. VIDA software. Axial images. Respiratory gating performed. Data for 40 mm axial from epiglottis to upper nasopharynx obtained from 10×4 mm slices uring 10 successive breath in todal breathing (Vt) – 10,30,50,70,90% of inspiration and of expiration.	Subjects with OSAS – smaller upper airway cross sectional area; airway narrowing during inspiration but without airway collapse; airway dilatation during expiration; greater fluctuations in airway area during tidal breathing.	Two tailed unpaired t test, wilcoxon rank test, or Chi-square test.	Figure S7^Citation125
Schwab et al 2006. Family aggregation of upper airway soft tissue structures in normal subjects and pts with sleep apnea	55 sleep apnea probands; 55 proband siblings	1.5 Tesla MRI scanner spin echo axial and sagittal images. 3D volumes of lateral pharyngeal walls (retropalatal and retroglossal regions); soft palate; tongue (genioglossus, geniohyoid, hyoglossus, myohyoid, digastric, myohyoideus muscles); parapharyngeal fat pads; soft tissue.	Volume of lateral pharyngeal walls, tongue, total soft tissue demonstrated heritability. Upper airway larger in normal subjects. Tongue, lateral parapharyngeal fat pads, lateral parapharyngeal walls larger in patients with apnea	Mixed model analysis of variance ANOVA; odds ratio	Figure S8^Citation145
Arens et al 2011. Upper airway structure and body fat composition in obese children with OSAS	22 obese children with OSAS (12.5±2.8 yrs; BMI z score 2.3±0.3); 22 obese controls	16 channel Philips 3.0 Tesla Achieva Quasar TX scanner. Amira software. Volumetric measurements – Upper airway = nasopharynx (superior to soft palate and continues anteriorly, through choanae, with nasal cavities); oropharynx (region between soft palate and larynx, posterior 1/3rd of tongue as anterior border); hypopharynx (posterolateral to larynx, includes pyriform recesses and valleculae). Lymphoid tissue = (adenoid, combined palatine tonsils, combined retropharyngeal nodes – between internal carotid arteries from base skull to hyoid bone – and deep cervical lymph nodes – internal jugular vein from base skull to hyoid bone). Tongue (inc genioglossus and geniohyoid muscles). Soft palate. Mandible. Head/neck = parapharyngeal and subcutaneous fat	Size of lymphoid tissue correlated with OSAS severity but bMl z score did not have modifier effect on lymphoid tissue. OSAS subjects had increased size parapharyngeal fat pads, abdominal visceral fat (did not correlate with OSAS severity)	Two-tailed paired t tests, Wilcoxon signed rank tests or McNemar’s tests. Pearson correlations derived between AHI and BMI z score. Mixed effects regression models using AHI as dependant variable and conditional regression models with OSAS vs non OSAS as dependant variable	Figure S9^Citation49
Cappabianca et al 2012. Magnetic resonance imaging in the evaluation of anatomical risk factors for pediatric obstructive sleep apnea – hypopnea: a pilot study	80 Caucasian children aged 4– 15 years, of which 40 had been diagnosed with OSAS	Retrospective analysis MRI head and neck between March 20102012. 1.5T magnet Symphony, Siemens. Axial T1-weighted images: cross-sectional area oropharyngeal airway, bounded anteriorly by soft palate or tongue, laterally by tonsils, posteriorly by pharyngeal constrictor muscle; intermandibular distance, maximum distance between the mandibular rami; maxillary width, maximum transverse diameter of superior jaw. Axial T2-weighted images: largest cross-sectional area of adenoids, tonsils, pterygoids, and parapharyngeal fat pads. Midsagittal T1-weighted image: cross-sectional area of nasopharyngeal airway, bounded anteriorly by vomer, posteriorly by adenoid, and inferiorly by horizontal line above the hard and soft palate; the cross sectional area of adenoids, soft palate, tongue, mandible, and hard palate. Other: distances from a transverse line perpendicular to the floor passing through the hyoide (hy, the most cranially – located point of the hyoid bone) to nasion (hy–n), to sella (hy–s) and to supramentale (hy–B) and the angles sella–nasion–subspinale (SNA), sella–nasion–supramentale (SNB) and subspinale–nasion–supramentale (ANB). Adjacent axial slices to determine volumes: combined upper airway (nasopharynx and oropharynx), adenoid, tonsils, tongue, soft palate, and mandible. Volumetric measurements (except tonsils and adenoid) from axial T1-weighted slices from base of orbital cavities to epiglottis. T2-weighted images for adenoid and tonsils due to better resolution of lymphoid tissue. Tonsillar volume = volume of right and left	The total upper airway volume of children with OSAS (1.4±0.7 cm^3) was significantly smaller (p<0.001) compared to controls (1.6±1.1 cm^3); soft palate volume was significantly larger (p<0.01) in OSAS group (3.9±1.3 cm^2) compared to controls (3.1±1.4 cm^2); adenoid and tonsils were significantly larger in children with OSAS compared to controls (p<0.01) with mean adenoid volume in children with OSAS 9.1±1.8 cm^3 vs 6.3±2.1 cm^3 in controls and mean tonsillar volume in OSAS 9.2±1.5 cm^3 vs 6.5±1.7 cm^3 in controls. Interestingly, similarly to Arens (2001) they also noted a smaller mandibular volume (p<0.05) in the OSAS group (22.2±2.23) compared to control group (25.4±2.4 cm^3)	Student’s t test	Figure S10^Citation124
Strauss et al 2012. Upper airway lymphoid tissue size in children with sickle cell disease	36 children with SCD (aged 6.9±4.3 yrs); 36 controls	1.5 Tesla Siemens vision system. Axial and sagittal T1- and T-2 weighted images 3 mm slice and 1 NEX, from orbital cavity to larynx. Annonymised, converted to DICOM format. AMIRA software. Airway = nasopharynx (superior to level of soft palate and continuous anteriorly, through choanae, with the nasal cavities); oropharynx (between level of soft palate and larynx, communicating anteriorly with oral cavity, posterior 1/3rd of tongue as anterior border); hypopharynx (posterolateral to larynx, communicating with cavity of larynx through auditus, incl pyriform recessed and valleculae). Lymphoid tissues = adenoid, combined palatine tonsils, combined retropharyngeal nodes – lymph nodes between internal carotid arteries from base of skull to hyoid bone – and combined deep cervical lymph nodes – internal jugular vein from base skull to hyoid bone)	Children with SCD – smaller upper airway with larger adenoid, retropharyngeal nodes, deep cervical nodes. AHI correlated positively with upper airway lymphoid tissues size	Two-tailed unpaired t tests and chi-square test. Pearson correlations between AHI and upper airway lymphoid tissues.	Figure S11^Citation50
Nanadalike et al 2012. Adenotensillectomy in obese children with OSAS: MRI findings	27 obese children with OSAS (age 13±2.3 yrs; BMI z score 2.5±0.3)	AMIRA software. Philips 3.0 Tesla Achieva scanner with 16 channel surface array coil. Images annonymised converted to DICOM. Sagittal: airway – nasopharynx (superior boundary is base of skull – basisphenoid and basiocciput; inferior boundary upper soft palate; anterior boundary nasal cavities, choanal orifice, posterior nasal septum; posterior boundary pharyngobasilar fascia, superior pharyngeal constrictors). Oropharynx (superior boundary soft palate; inferior boundary upper epiglottis – vallecula fossa – and root of tongue; anterior boundary oral cavity; posterior and lateral boundary superior and middle pharyngeal constrictors). Lymphoid tissues (adenoid, combined palatine tonsils, lingual tonsil, combined retropharyngeal nodes – located between internal carotid arteriesfrom skull base to hyoid bone – plus deep cervical lymph nodes level II – located internal jugular vein from skull base to hyoidbone). Tongue (inc genioglossus and geniohyoid muscles). Soft palate. Mandible. Head and neck subcutaneous fat	Pts followed up 6.1±3.6 mo after AT. AT improved AHI. AT increased volume of nasopharynx and oropharnyx, reduced tonsils, no effect on adenoid, lingual tonsil, retropharyngeal nodes. Increase volume soft palate and tongue	Wilcoxon signed rank test for paired data	Figure S12^Citation146
Parikh et al 2013. Deep cervical lymph node hypertrophy: a new paradigm in the understanding of pediatric obstructive sleep apnea	70 children with OSAS (mean age 7.47 yrs; BMI 23.63 kg/m^2) and 76 healthy matched controls (mean 8.00 yrs; BMI 20.87 kg/m^2)	1.5 Tesla (Siemens Vision System, Iselin, NJ). Four regions of lymphoid tissue: tonsil, adenoid, retropharyngeal nodes (between internal carotid arteries from the skull base to the hyoid bone), and the upper jugular lymph nodes (along the internal jugular vein from the skull base to the hyoid bone)	Children with OSAS have larger volumes of deep cervical lymph nodes and adenotonsillar tissue than normal controls	Chi-square analysis and Student’s t test were used to compare demographics and lymph node volumes. Fischer’s exact test and chi-square analysis were used to compare sleep data	Figure S13^Citation123
Salles et al 2014. Association between morphometric variables and nocturnal desaturation in sickle cell anemia	85 children with SCD (9±4 yrs; BMI z score −0.4 in apneic group and −1.0 in non-apneic group)	An oral cavity assessment in the Frankfort position with tongue in relaxed position and with a mouth opening angle of 20°C to the mandibular condyle. A 20°C fixed-aperture compass was used, which was placed on the topography of the temporomandibular joint, the tip of its upper leg aligned with the upper central incisors, to yield desired mouth opening. Another compass was used to obtain measuremnts of: maxillary intermolar distance (size of maxilla); and mandibular intermolar distance (mandibular size) which were then transposed to a ruler. The overjet, cervical circumference and abdominal circumference were measured with a ruler/tape	A positive correlation was found between height/age z-score and cervical circumference. Nocturnal desaturation was associated with cervical circumference and abdominal circumference. A negative correlation between desaturation and maxillary intermolar distance and mandibular intermolar distance	Student’s t test for independent samples or the Mann–Whitney test to compare two means. Spearman’s test to test the correlation between variable.	No imaging available as measurements taken via clinical method^Citation116
Schwab et al 2015. Understanding the Anatomic Basis for Obstructive Sleep Apnea Syndrome in Adolescents	Adolescents 12–16 years from CHOP study. 49 obese with OSA; 38 obese and 50 lean controls	Upper airway MRI was performed using a 3T scanner (Magnetom Sonata; Siemens). Amira 4.1.2 image analysis software. Saggital: airway volume, cross-sectional area, minimum airway area in the retropalatal (RP),retroglossal (RG), and nasopharyngeal (NP) regions;minimum anteroposterior airway width, minimum lateral airway width in the RP and RG regions. Airway length: distance between palatal plane and parallel plane through base of epiglottis. Volumetric analysis of upper airway soft tissue structures on axial T1-weighted MRI scans: soft palate, tongue genioglossus muscle, other tongue (geniohyoid, hyoglossus, myohyoid, digastric, and mylohyoid) muscles, parapharyngeal fat pads, lateral pharyngeal walls (including tonsils), pterygoid muscle, epiglottis, sum of soft tissue volumes. Axial T2-weighted for tonsils (right and left combined) and adenoid as better resolution of lymphoid tissue	Obese with OSAS had increased adenotonsillar tissue and smaller nasopharyngeal airway compared with all controls. The size of other upper airway soft tissue structures (volume of the tongue, parapharyngeal fat pads, lateral walls, and soft palate) was similar between both groups	Adjusted analysis of covariance was used to compare the three groups with a subdomain-specific, Bonferroni-corrected level of significance	Figure S14^Citation147
Tong et al 2016. MR Image Analytics to Characterize the Upper Airway Structure in Obese Children with Obstructive Sleep Apnea Syndrome	30 children 8–17 yrs (15 obese with OSAS; 15 obese controls)	Philips Achieva 3T machine. Axial T2-weighted and sagittal T1-and T2-weighted sequences. “Object” measurements: skin, pharnyx, nasopharynx, oropharynx, mandible, fat pad, adenoid, tonsils, tongue, soft palate. 3D region enclosed by the boundary surface was considered to represent the “object.	OSAS group: increase in linear size, surface area, volume of adenoid, tonsils, fat pad. Fat pad and oropharynx become less round/more complex in shape in OSAS	. Logistic regression based on a sigmoid model	Figure S15^Citation148

Figure S1 (A) Adenoidal measurements. “A” represents distance from A¹ point of maximal convexity, along inferior margin of adenoid shadow to line B,drawn along straight part of anterior margin of basiocciput. “A” is measured along line perpendicular from point A¹ to its intersection with B. (B) Nasopharyngeal measurement. “N” is distance between C¹ posterior superior edge of hard palate, and D¹, anteroinferior edge of sphenobasiocciptal synchondrosis. When synchondrosis is not clearly visualised, point D¹ can be determined as site of crossing posteroinferior margin of lateral pterygoid plates P and floor of bony nasopharyndx.

Note: Reprinted from Radiographic evaluation of adenoidal size in children: Adenoidal-nasopharyngeal ratio. Am J Roentgenol, Fujioka M, Young LW, Girdany BR, the American Journal of Roentgenology 133(3), Copyright© 1979, American Roentgen Ray Society.⁵²

Figure S2 (A) Anatomical outlines of an axial T1 image at the level of the maximal tonsillar area of a control Subject. Transverse black arrow represents the intermandibular distance. (B) Anatomical outlines of a midsagittal T1 image of a control subject. Oblique black arrow represents the mental spine-clivus oblique distance.

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Arens R, McDonough JM, Costarino AT, Mahboubi S, Tayag-Kier CE, Maislin G, et al. 2001. Magnetic resonance imaging of the upper airway structure of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 4. 698–703. Official journal of the American Thoracic Society.⁴⁷

Figure S3 (A) T1-weighted axial image at the retropalated level (right) and segmented regions of interest (left) of a control subject. (B) Midsagittal T1-weighted image with mental spine-clivus distance shown (right) and segmented regions of interest (left) of a control subject.

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Uong EC, McDonough JM, Tayag-Kier CE, Zhao H, Haselgrove J, Mahboubi S, et al. 2001. Magnetic resonance imaging of the upper airway in children with Down syndrome. Am J Respir Crit Care Med. 163. 731–736. Official journal of the American Thoracic Society.⁷³

Figure S4 (A) Mid-sagittal T1-weighted image with mental spine-clivus oblique line shown (white line). Linear measurements were obtained along this line. (B) Axial T1-weighted image at the level of maximal tonsillar cross-sectional area. Note the transverse intermandibular line (white line) passing the center of each tonsil. Linear measurements were obtained along this axis. Maximal oropharyngeal width was obtained on this plane (dotted white line).

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Arens R, McDonough JM, Corbin AM, Hernandez ME, Maislin G, Schwab RJ, et al. 2002. Linear dimensions of the upper airway structure during development: Assessment by magnetic resonance imaging. Am J Respir Crit Care Med. 165.117–22. Official journal of the American Thoracic Society.¹²¹

Figure S5 Left: three-dimensional display of an upper airway and its centerline in a subject with OSAS. Top right: gray-level two-dimansional scene of the cross-section of the airway orthogonal to the centerline at marker locations: A = adenoid; A + T = adenoid and tonsil overlap; T = tonsils; E = epiglottis. Bottom right: plot of the cross-sectional area function.

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Arens R, McDonough JM, Corbin AM, Rubin NK, Carroll ME, Pack AI, et al. 2003. Upper airway size analysis by magnetic resonance imaging of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 167. 65–70. Official journal of the American Thoracic Society.⁴⁸

Figure S6 (A) Midsagittal magnetic resonance image (MRI) of a normal subject, demonstrating the upper airway regions: retropalatal (RP) — from the level of the hard palate to the caudal margin of the soft palate; and retroglossal (RG) — from the caudal margin of the soft palate to the base of the epiglottis. Soft palate, tongue, airway, mandible, and subcutaneous fat are denoted with arrows. Fat is bright (white) on an MRI. (B) Representative three dimensional upper airway volume in a patient with sleep apnea (left) and in a normal subject (right). Note that the upper airway volume is smaller in the RP region than in the RG region in both subjects and that the length of the total airway and the individual regions (RP/RG) is not equivalent between the apneic and normal subjects. Airway volume is smaller in the RP region in this apneic subject compared with the control subject; airway volume is similar in the RG region in this apneic subject compared with the control subject.

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Schwab RJ, Pasirstein M, Pierson R, Mackley A, Hachadoorian R, Arens R, et al. 2003. Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging. Am J Respir Crit Care Med. 168. 522–30. Official journal of the American Thoracic Society.⁵¹

Figure S7 (A) Midsagittal magnetic resonance image demonstrating the four ascending levels for analysis (thick dotted lines). Level 1 is 4 mm above tip of epiglottis. (B) Dynamic changes in cross-sectional area at midtonsillar level (level 2) during tidal breathing (5-vol increments of inspiration [ins], 5-vol increments of expiration [Exp]) of control subjects (top panels) and subjects with OSAS (bottom panels). Note difference in anteroposterior (A-P) and lateral airway dimension.

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Arens R, Sin S, McDonough JM, Palmer JM, Dominguez T, Meyer H, et al. 2005. Changes in upper airway size during tidal breathing in children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 171. 1298–304. Official journal of the American Thoracic Society.¹²⁵

Figure S8 Volumetric reconstructions from a series of 3-mm contiguous axial magnetic resonance (MR) images of the mandible (gray), tongue (orange/rust), soft palate (pink/purple), lateral parapharyngeal fat pads (yellow), and lateral/posterior pharyngeal walls (green) in a normal subject (top panel) and in a patient with sleep apnea (bottom panel). The upper airway is larger in the normal subject than in the patient with apnea. In addition, the tongue, lateral parapharyngeal fat pads, and lateral pharyngeal walls are larger in the patient with apnea.

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Schwab RJ, Pasirstein M, Kaplan L, Pierson R, Mackley A, Hachadoorian R, et al. 2006. Family aggregation of upper airway soft tissue structures in normal subjects and patients with sleep apnea. Am J Respir Crit Care Med. 173. 453–63. Official journal of the American Thoracic Society.¹⁴⁵

Figure S9 Upper airway, soft tissues, and mandibular reconstructions. Head and neck surface rensering with three-dimensional reconstructions of the upper airway, soft tissues, and mandible of a subject with obstructive sleep apnea syndrome in various views: lateral (top left), anterior oblique (bottom right). Airway (light blue), tongue (brown), mandible (white), nodes (red), and deep cervical nodes (green).

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Arens R, Sin S, Nandalike K, Rieder J, Khan UI, Freeman K, et al. 2011. Upper airway structure and body fat composition in obese children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 183. 782–787. Official journal of the American Thoracic Society.⁴⁹

Figure S10 (A) CSA oropharyngeal airway. (B) Combined upper airway volume, T1 weighted axial scan. (C) Transverse line perpendicular to the floor passing through the hyoide to nasion, to sella to supramentale. (D) Midsagittal palatal CSA.

Note: Reprinted from Int J Pediatr Otorhinolaryngol, 77(1), Cappabianca S, Iaselli F, Negro A, et al., Magnetic resonance imaging in the evaluation of anatomical risk factors for pediatric obstructive sleep apnoea-hypopnoea: a pilot study, 69–75, Copyright 2013, with permission from Elsevier.¹²⁴

Figure S11 (A) Left 4 images. Mid sagittal (top) and axial T2-weighted images at the level of the nasopharynx (bottom), of a patient before (left) and after (right) adenotonsillectomy. Solid white arrows indicate adenoid tissue (gray) and dotted arrows indicate nasopharyngeal airway.Note residual adenoidal tissue and larger airway after adenoidal tissue and larger airway after adeniodectomy. In this example, a 29% reduction in adenoid volume was noted on MRI. (B) Right 2 images. Axial T2-weighted images at the level of the oropharynx of a patient before (left) and after (right) adenotonsillectomy. Solid white arrows indicate tonsillar tissue (gray) and dotted arrows indicate oropharyngeal airway. Note the larger airway and small left residual tonsil tissue after tonsillectomy.

Note: Reprinted from CHEST, 142(1), Strauss T, Sin S, Marcus CL, Mason TBA, McDonough JM, Allen JL, et al., Upper airway lymphoid tissue size in children with sickle cell disease, 94-100, Copyright 2012, with permission from Elsevier.⁵⁰

Figure S12 MRI volumetric analysis of lymphoid tissue volumes in an OSA patient (green-upper jugular lymph nodes, orange-tonsil tissue, red-retropharyngeal lymph nodes, magenta-adenoid tissue). (A) Three dimensional reconstruction of lymphoid tissue using Amira^® software. (B) Axial T2-weighted DICOM image with lymphoid tissue tracings. (C) Coronal T2-weighted DICOM image with lymphoid tissue tracings. (D) Sagittal T2-weighted DICOM image with lymphoid tissue tracings.

Note: Nandalike K, Shifteh K, Sin S, Strauss T, Stakofsky A, Gonik N et al., Adenotonsillectomy in obese children with obstructive sleep apnoea syndrome: magnetic resonance imaging findings and considerations, SLEEP, 2013, 36, 6, 841-847, by permission of Oxford University Press.¹⁴⁶

Figure S13 Upper airway, soft tissues, and mandibular reconstructions. Head and neck surface rendering with three-dimensional reconstructions of the upper airway, soft tissues, and mandible of a subject with obstructive sleep apnea syndrome in various views:lateral (top left), anterior oblique (top right), superior oblique (bottom left) and posterior (bottom right). Airway (light blue), tongue (brown), mandible (white), soft palate (blue), tonsils (yellow), adenoid (magenta), retropharyngeal nodes (red), and deep cervical nodes (green).

Note: Copyright ©2003. John Wiley and Sons. Reproduced from Parikh SR, Sadoughi B, Sin S, Willen S, Nandalike K, Arens R. Deep cervical lymph node hypertrophy: A new paradigm in the understanding of pediatric obstructive sleep apnea. Laryngoscope. 2013;123(8):2043–9.¹²³

Figure S14 Anatomical definitions of upper airway landmarks on midsaggital and axial slices with 3D reconstruction of regions of interest.

Note: Reprinted with permission of the American Thoracic Society. Copyright © 2020 American Thoracic Society. Schwab RJ, Kim C, Bagchi S, Keenan BT, Comyn FL, Wang S et al. 2015. Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents. Am J Resp Crit Care Med. 191. 1295-1309. Official journal of the American Thoracic Society.¹⁴⁷

Figure S15 3D surface renditions of objects: np (nasopharynx), op (oropharynx), mn (mandible), tn (tonsils), tL & tR (left and right (tonsil), fp (fat pad), ad (adenoid), tg (tongue).

Note: Copyright ©2016. PLoS One. Reproduced from Capovilla G, Beccaria F, Montagnini A, et al. Tong Y, Udupa JK, Sin S, Liu Z, Wileyto EP, Drew A et al. MR Image Analytics to Characterize the Upper Airway Structure in Obese Children with Obstructive Sleep Apnea Syndrome. PLoS One 2016; 11(8):e0159327.¹⁴⁸

Terrill PI, Dakin C, Hughes I, Yuill M, Parsley C. Nocturnal oxygen saturation profiles of healthy term infants. Arch Dis Child. 2015;100(1):18–23. doi:10.1136/archdischild-2013-305708

 Web of Science ®Google Scholar

Evans HJ, Karunatilleke AS, Grantham-Hill S, Gavlak JC. A cohort study reporting normal oximetry values in healthy infants under 4 months of age using Masimo technology. Arch Dis Child. 2018;103(9):868–872. doi:10.1136/archdischild-2017-314361

 Web of Science ®Google Scholar

Montgomery-Downs HE, O’Brien LM, Gulliver TE, Gozal D. Polysomnographic characteristics in normal preschool and early school-aged children. Pediatrics. 2006;117(3):741–753. doi:10.1542/peds.2005-1067

 PubMed Web of Science ®Google Scholar

Traeger N, Schultz B, Pollock AN, Mason T, Marcus CL, Arens R. Polysomnographic values in children 2-9 years old: additional data and review of the literature. Pediatr Pulmonol. 2005;40(1):22–30. doi:10.1002/ppul.20236

 Web of Science ®Google Scholar

Strauss T, Sin S, Marcus CL, et al. Upper airway lymphoid tissue size in children with sickle cell disease. Chest. 2012;142(1):94–100. doi:10.1378/chest.11-2013

 PubMed Web of Science ®Google Scholar

Uliel S, Tauman R, Greenfeld M, Sivan Y. Normal polysomnographic respiratory values in children and adolescents. Chest. 2004;125(3):872–878.

 Web of Science ®Google Scholar

Urschitz MS, Wolff J, Von EV, Urschitz-Duprat PM, Schlaud M, Poets CF. Reference values for nocturnal home pulse oximetry during sleep in primary school children. Chest. 2003;123(1):96–101.

 PubMed Web of Science ®Google Scholar

Moss D, Urschitz MS, von BA, et al. Reference values for nocturnal home polysomnography in primary schoolchildren. Pediatr Res. 2005;58(5):958–965. doi:10.1203/01.PDR.0000181372.34213.13

 Web of Science ®Google Scholar

Rosen CL, Larkin EK, Kirchner HL, et al. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr. 2003;142(4):383–389. doi:10.1067/mpd.2003.28

 PubMed Web of Science ®Google Scholar

Verhulst SL, Schrauwen N, Haentjens D, Van GL, De Backer WA, Desager KN. Reference values for sleep-related respiratory variables in asymptomatic European children and adolescents. Pediatr Pulmonol. 2007;42(2):159–167. doi:10.1002/ppul.20551

 Web of Science ®Google Scholar

Scholle S, Wiater A, Scholle HC. Normative values of polysomnographic parameters in childhood and adolescence: cardiorespiratory parameters. Sleep Med. 2011;12(10):988–996. doi:10.1016/j.sleep.2011.05.006

 Web of Science ®Google Scholar

Mitterling T, Hogl B, Schonwald SV, et al. Sleep and respiration in 100 healthy caucasian sleepers – a polysomnographic study according to American Academy of Sleep Medicine standards. Sleep. 2015;38(6):867–875. doi:10.5665/sleep.4730

 Web of Science ®Google Scholar

Hertenstein E, Gabryelska A, Spiegelhalder K, et al. Reference data for polysomnography-measured and subjective sleep in healthy adults. J Clin Sleep Med. 2018;14(4):523–532. doi:10.5664/jcsm.7036

 Web of Science ®Google Scholar

Gries RE, Brooks LJ. Normal oxyhemoglobin saturation during sleep. How low does it go? Chest. 1996;110(6):1489–1492.

 Web of Science ®Google Scholar

Fujioka M, Young LW, Girdany BR. Radiographic evaluation of adenoidal size in children: adenoidal-nasopharyngeal ratio. AJR Am J Roentgenol. 1979;133(3):401–404. doi:10.2214/ajr.133.3.401

 PubMed Web of Science ®Google Scholar

Arens R, McDonough JM, Costarino AT, et al. Magnetic resonance imaging of the upper airway structure of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2001;164(4):698–703. doi:10.1164/ajrccm.164.4.2101127

 PubMed Web of Science ®Google Scholar

Uong EC, McDonough JM, Tayag-Kier CE, et al. Magnetic resonance imaging of the upper airway in children with down syndrome. Am J Respir Crit Care Med. 2001;163(3 Pt 1):731–736. doi:10.1164/ajrccm.163.3.2004231

 Web of Science ®Google Scholar

Arens R, McDonough JM, Corbin AM, et al. Linear dimensions of the upper airway structure during development: assessment by magnetic resonance imaging. Am J Respir Crit Care Med. 2002;165(1):117–122. doi:10.1164/ajrccm.165.1.2107140

 PubMed Web of Science ®Google Scholar

Arens R, McDonough JM, Corbin AM, et al. Upper airway size analysis by magnetic resonance imaging of children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2003;167(1):65–70. doi:10.1164/rccm.200206-613OC

 Web of Science ®Google Scholar

Schwab RJ, Pasirstein M, Pierson R, et al. Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging. Am J Respir Crit Care Med. 2003;168(5):522–530. doi:10.1164/rccm.200208-866OC

 PubMed Web of Science ®Google Scholar

Arens R, Sin S, McDonough JM, et al. Changes in upper airway size during tidal breathing in children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2005;171(11):1298–1304. doi:10.1164/rccm.200411-1597OC

 PubMed Web of Science ®Google Scholar

Schwab RJ, Pasirstein M, Kaplan L, Pierson R, Mackley A, Hachadoorian R, et al. Family aggregation of upper airway soft tissue structures in normal subjects and patients with sleep apnea. Am J Respir Crit Care Med. 2006;173(4):453–463

 Google Scholar

Arens R, Sin S, Nandalike K, et al. Upper airway structure and body fat composition in obese children with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2011;183(6):782–787. doi:10.1164/rccm.201008-1249OC

 Web of Science ®Google Scholar

Cappabianca S, Iaselli F, Negro A, et al. Magnetic resonance imaging in the evaluation of anatomical risk factors for pediatric obstructive sleep apnoea-hypopnoea: a pilot study. Int J Pediatr Otorhinolaryngol. 2013;77(1):69–75. doi:10.1016/j.ijporl.2012.09.035

 PubMed Web of Science ®Google Scholar

Nandalike K, Shifteh K, Sin S, Strauss T, Stakofsky A, Gonik N, et al. Adenotonsillectomy in obese children with obstructive sleep apnoea syndrome: magnetic resonance imaging findings and considerations. Sleep. 2013;3(6):841–847

 Google Scholar

Parikh SR, Sadoughi B, Sin S, Willen S, Nandalike K, Arens R. Deep cervical lymph node hypertrophy: a new paradigm in the understanding of pediatric obstructive sleep apnea. Laryngoscope. 2013;123(8):2043–2049. doi:10.1002/lary.23748

 Web of Science ®Google Scholar

Salles C, Bispo M, Trindade-Ramos RT. Association between morphometric variables and nocturnal desaturation in sickle-cell anemia. J Pediatr (Rio J). 2014;90(4):420–425. doi:10.1016/j.jped.2014.01.005

 Web of Science ®Google Scholar

Schwab RJ, Kim C, Bagchi S, Keenan BT, Comyn FL, Wang S et al. Understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents. Am J Resp Crit Care Med. 2015;1:191(11):1295–1309

 Google Scholar

Tong Y, Udupa JK, Sin S, Liu Z, Wileyto EP, Drew A et al. MR Image Analytics to Characterize the Upper Airway Structure in Obese Children with Obstructive Sleep Apnea Syndrome. PLoS One. 2016;11(8):e0159327

 Google Scholar