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Reliability of upper pharyngeal airway assessment using dental CBCT Zimmerman, Jason Noah 2017

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 RELIABILITY OF UPPER PHARYNGEAL AIRWAY ASSESSMENT USING DENTAL CBCT by Jason Noah Zimmerman DDS, University of Western Ontario, 2014 BSc (Honours), University of Western Ontario, 2009  A THESIS SUBMIITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Craniofacial Science)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)   August 2017   © Jason Noah Zimmerman, 2017       ii  Abstract  Introduction: Upper airway analysis is an often-cited use of CBCT imaging in orthodontics, however the reliability of airway measurements using this technology is not fully understood. The purpose of this study was to determine the intra-examiner and inter-examiner reliability of the complete process of volumetric and cross-sectional area assessments of the upper airway using CBCT imaging.  Methods:  Five examiners of varying levels of education and clinical experience performed manual orientation, slice and threshold selection, and measured nasopharyngeal, oropharyngeal, hypopharyngeal, and total upper pharyngeal airway volumes in addition to minimum cross-sectional area on the CBCT images of 10 patients. All measurements were repeated after 4-weeks. Intra and inter-examiner reliability was calculated using ICC and 95% CI.  Results: Threshold selection showed poor intra and inter-examiner reliability, while minimum cross-sectional area showed moderate intra and poor inter-examiner reliability. Intra-examiner reliability of volumetric measurements varied based on the anatomical region assessed with ICC ranging from 0.747-0.976, and was worst for hypopharynx and best for the oropharynx. Inter-examiner reliability of volume measurements was generally lower, with ICC ranging from 0.175-0.945, and was worst for nasopharynx and best for the oropharynx.  Conclusions: This study, for the first time, assessed the reliability of upper airway analysis with CBCT when all steps of image processing and measurement are performed by each examiner.  Reliability improved with examiner experience, though was generally low for the hypopharynx and nasopharynx volumes and overall minimal cross sectional area. The oropharyngeal volume was the only parameter to have excellent intra-examiner and inter-examiner reliability.            iii  Lay Summary  Study Question: How reliable is CBCT at assessing the upper airway’s volume and minimum cross-sectional area? Background: CBCT three-dimensional imaging is often used to look at the volume of the upper airway.  A systematic review conducted by the authors of this study found major methodological flaws in the literature. Most significantly the reliability was only assessed for the examiners’ ability to trace the upper airway, with many steps of the measurement process not considered. Methods: Five examiners positioned the CBCT images of ten patients and measured the volumes of the entire upper airway and its individual sections, as well as minimum cross-sectional area. The examiners selected the threshold sensitivity value for each scan. After 4-weeks, all measurements were repeated and reliability was calculated.  Key Results: Threshold overall had poor reliability. Reliability greatly improved with experience of the examiner, with oropharyngeal volume being the only part to have generalized excellent reliability.                 iv  Preface   This thesis is an original intellectual product of the author, J.N. Zimmerman.  The study and associated methods were approved by the University of British Columbia’s Research Ethics Board certificate H12-00951. A version of Chapter 2 has been published (Zimmerman JN, Lee J, Pliska BT. Reliability of upper pharyngeal airway assessment using dental CBCT: a systematic review. Eur J Orthod. 2016 Dec 20. pii: cjw079. doi: 10.1093/ejo/cjw079).  I was the lead investigator, responsible for all major areas of concept formation, data collection and analysis, as well as manuscript composition. Lee J contributed to data collection.  Pliska BT was the supervisory author on this project and was involved throughout the project in concept formation, data analysis, and manuscript composition. A version of Chapter 3 has been submitted for publication.  I was the lead investigator, responsible for all major areas of concept formation, data collection and analysis, as well as the majority of manuscript composition.  Pliska BT was the supervisory author on this project and was involved throughout the project in concept formation, data analysis, and manuscript composition.                v  Table of Contents  Abstract ……………………………………………………………………………………….. ii  Lay Summary ………………………………………………………………………………… iii  Preface …………………………………………………………………………........................ iv  Table of Contents …………………………………………………………………………….. v  List of Tables …………………………………………………………………………………. viii   List of Figures …………………………………………………………………........................ ix  List of Abbreviations …………………………………………………………………………. x  Acknowledgements ……………………………………………………………....................... xii  Dedication …………………………………………………………………………………….. xiii  Chapter 1: Introduction ……………………………………………………………………... 1 1.1 Computed Tomography (CT) and Three-Dimensional Imaging ……………... 1  1.1.1 Cone-beam CT and Fan-beam/Medical/Helical CT ………...................... 1 1.1.2 Hounsfield Scale and Grey Scale …………………………...................... 1 1.2 CBCT and Dentistry ……………………………………………………………... 2  1.2.1 Advantages and Disadvantages of CBCT in Dentistry ……...................... 2 1.3 CBCT and Orthodontics ………………………………………………………… 3  1.3.1 Orthodontics and OSA ……………………………………....................... 3 vi   1.3.2 Obstructive Sleep Apnea ………………………………………………… 3  1.3.3 Pathophysiology of OSA ………………………………………………… 4  1.3.4 CBCT and Upper Pharyngeal Airway Assessment ……………………… 6 1.4 Objective …………………………………………………………………………... 6  Chapter 2: Reliability of upper pharyngeal airway assessment using dental CBCT: A systematic review ……………………………………………………………………………... 7  2.1 Introduction……………………………………………………….......................... 7  2.2 Material and Methods …………………………………………………………… 7   2.2.1 Protocol and Registration ………………………………........................... 7   2.2.2 Eligibility Criteria ……………………………………………………….. 8   2.2.3 Information Sources, Search Strategy, and Study Selection …………….. 8   2.2.4 Data Items and Collection………………………………………………... 8   2.2.5 Risk of Bias/Quality Assessment in Individual Studies ……………….… 9   2.2.6 Synthesis of Results and Risk of Bias/Quality Across Studies …………. 11  2.3 Results …………………………………………………………………………….. 11   2.3.1 Study Selection ………………………………………………………….. 11   2.3.2 Study Characteristics ……………………………………………………. 13   2.3.3 Risk of Bias/Quality of Studies …………………………………………. 13   2.3.4 Summary Description of the Studies ……………………………………. 16   2.3.5 Synthesis of the Results …………………………………………………. 16   2.3.6 Additional Analysis ……………………………………………………... 17  2.4 Discussion ………………………………………………………………………… 17   2.4.1 Limitations of the Available Evidence ………………………………….. 18   2.4.2 Clinical Implications …………………………………………………….. 19  2.5 Conclusions ……………………………………………………………………….. 20  2.6 Conflict of Interest ……………………………………………………………….. 20   vii  Chapter 3: Reliability of upper pharyngeal airway assessment using dental CBCT …… 21  3.1 Introduction ……………………………………………………………………… 21  3.2 Material and Methods …………………………………………………………… 21  3.3 Results …………………………………………………………………………….. 37  3.4 Discussion …………………………………………………………………………. 44  3.5 Conclusions ……………………………………………………………………….. 46  Chapter 4: Should Dental CBCT Be Used Today For Quantitative Assessments of the Upper Pharyngeal Airway: Final Thoughts ………………………………………………… 47  4.1 Conclusion ………………………………………………………………………… 49  Bibliography …………………………………………………………………………………... 50  Appendix A ……………………………………………………………………………………. 61                viii  List of Tables Table 2.1 Evaluation scores of the included studies (N=42) …………………………………... 14 Table 3.1 Definitions of the anatomic boundaries for each region of the upper pharyngeal airway …………………………………………………………………………………………………... 36 Table 3.2 ICC values for intra-examiner and inter-examiner reliability for all scans …………. 40 Table 3.3 ICC values for intra-examiner and inter-examiner reliability for the fast scan protocol …………………………………………………………………………………………………... 41 Table 3.4 ICC values for intra-examiner and inter-examiner reliability for the slow scan protocol …………………………………………………………………………………………………... 42 Table 3.5 Examiner variance for all parameters...………………...……………………………. 43 Table A.1 Characters of the included studies in the systematic review (N=42) ……………….. 61 Table A.2 CBCT machine settings of the included studies in the systematic review (N=42) ... 110 Table A.3 Examination characteristics of the included studies in the systematic review (N=42) …………………………………………………………………………………………………. 113 Table A.4 Raw data for threshold value ...……………………………………………………. 115 Table A.5 Raw data for measured minimum cross-sectional area in mm2….………………….116 Table A.6 Raw data for measured total upper pharyngeal airway volume in mm3.……………117 Table A.7 Raw data for measured nasopharyngeal airway volume in mm3…….……………...118 Table A.8 Raw data for measured oropharyngeal airway volume in mm3….………………….119 Table A.9 Raw data for measured hypopharyngeal airway volume in mm3….………………..120          ix  List of Figures Figure 2.1 Evaluation checklist for the included studies ………………………………………. 10 Figure 2.2 PRISMA flow diagram of the literature selection process …………………………. 12 Figure 3.1 Orientation of the axial plane using the lower border of the orbit landmarks ……… 24 Figure 3.2 Orientation of the coronal plane using the Frankfort Horizontal Plane (porion to orbitale) ………………………………………………………………………………………… 25 Figure 3.3 Orientation of the midsagittal plane using the upper incisive foramen to opisthion  …………………………………………………………………………………………………... 26 Figure 3.4 Correct sensitivity thresholding where the upper pharyngeal airway is completely filled with no “fingers” projecting out from the airway ……………………………………….. 27 Figure 3.5 Incorrect sensitivity thresholding where the upper pharyngeal airway is under-filled …………………………………………………………………………………………………... 28 Figure 3.6 Incorrect sensitivity thresholding where the upper pharyngeal airway is over-filled to the point where “fingers” can be seen projecting out of the airway …………………………… 29 Figure 3.7 Anatomic boundaries of the upper pharyngeal airway including its comprising regions …………………………………………………………………………………………………... 30 Figure 3.8 Nasopharyngeal airway volume ……………………………………………………. 31 Figure 3.9 Oropharyngeal airway volume ……………………………………………………... 32 Figure 3.10 Hypopharyngeal airway volume ………………………………………………….. 33 Figure 3.11 Total upper pharyngeal airway volume …………………………………………... 34 Figure 3.12 Minimum cross-sectional area of the upper pharyngeal airway ………………….. 35 Figure A.1 Landmarks used for hard tissue orientation of the CBCT scans …………………..121 Figure A.2 Examiner data collection form …………………………………………………… 122       x  List of Abbreviations  CT: computed tomography HCT: helical computed tomography CBCT: cone-beam computer tomography HU: Hounsfield Unit FOV: field of view 3D: three-dimensional DICOM: digital imaging and communications in medicine CSA: central sleep apnea OSA: obstructive sleep apnea µSv:  microsievert AHI: apnea-hypopnea index MRI: magnetic resonance imaging BMI: body mass index CNS: central nervous system J.N.Z.: Jason N. Zimmerman J.L.: Janson Lee B.T.P.: Benjamin T. Pliska mA: milliampere kVp: peak kilovoltage sec: seconds mm: millimeters ICC: intraclass correlation coefficient #: number ALARA: as low as reasonably achievable HIPA: Health Information Protection Act PNS: posterior nasal spine xi  CI: confidence interval SDB: sleep-disordered breathing UMN: University of Minnesota School of Dentistry, Division of Orthodontics                        xii  Acknowledgements   I would like to thank my supervisor Dr. Benjamin Pliska for his mentorship and guidance.  His direction has furthered my research skills which will benefit me in clinical practice.  I would also like to thank Dr. Fernanda Almeida, Dr. Nancy Ford, and Dr. Sid Vora for serving on my thesis committee and their support throughout the research process.  Lastly, I would like to thank Dr. Walter Siqueira who first introduced me to the world of research and without whom I would not be here today.                       xiii  Dedication   I dedicate this thesis to my family for their constant support and encouragement throughout my eleven years of university education.  I would also like to dedicate this thesis to my soon-to-be fiancé Fernanda Barona.  Your love, friendship, and wonderful sense of humour were the greatest gifts that this program has bestowed upon me and I cannot imagine going through these three years without you.  You are all the motivation that keeps me going through the many long nights and I would be nothing without all of you.  I love you all!                       1  Chapter 1: Introduction  1.1 Computed Tomography (CT) and Three-Dimensional Imaging At a time where medicine and dentistry were limited to using a two-dimensional radiograph to aid in diagnosis and treatment planning, the introduction of three-dimensional radiographic imaging through computed tomography (CT) has revolutionized radiography forever.  Where once clinicians were forced to use a two-dimensional tool to assess a three-dimensional patient, CT can provide diagnostic information that can lead to more effective and efficient treatment.  There are two principal types of CT; cone-beam CT (CBCT) and fan-beam/medical/helical (HCT).1  1.1.1 Cone-beam CT and Fan-beam/Medical/Helical CT  CBCT uses an x-ray beam that is in the shape of a cone and is the type of CT commonly used in dentistry.1  CBCT images are generated using a rotating gantry with a fixed x-ray source that creates the cone-shaped beam of ionizing radiation.  This beam is then directed through the centre of the patient onto an x-ray detector on the opposite side.  Throughout the scan, the x-ray source and detector are rotating around the centre of the patient, producing multiple consecutive planar images of the field of view (FOV).2  The scanning software collects these multiple images and reconstructs them into digital volume units called voxels containing anatomical data which can be displayed by said software.3  Where a CBCT scan integrates the entire FOV, only one rotation of the gantry is required to produce an image.2  One can achieve higher spatial resolution by applying scan settings using a longer scan time and a smaller voxel size.4   HCT, also known as medical CT uses an x-ray beam that is in the shape of a fan in a helical progression (Figure 1.1).1  This produces a series of image slices of the FOV that are then sandwiched together to create a 3D image.2  1.1.2 Hounsfield Scale and Grey Scale  The Hounsfield Scale is a standardized quantitative scale for describing radiodensity.  In a medical HCT scan, the Hounsfield Unit (HU) is proportional to the degree of x-ray attenuation by the tissue.  This standardization means that a radiodensity value from a scan on one machine can be directly compared with a radiodensity value from a scan on a different machine. There is no such standardization in reconstructed grey density values from scans derived from CBCT machines.5  The Grey Scale is a measure of x-ray attenuation in dental CBCT.  CBCT manufacturers have not introduced a standard system for displaying grey scale.  Some studies have shown a strong linear relationship between HU and gray scale.  However, grey scale differs from HU in 2  that grey scale is associated with higher noise levels, increased scattered radiation, high heel effect, and beam hardening artifacts.5  1.2 CBCT and Dentistry Two-dimensional radiographic imaging techniques have been conventionally used in dentistry for generations as a diagnostic aid to appropriately treat patients.  Then, three-dimensional radiography through dental CBCT became readily available in the late 1990’s and transformed clinical dentistry.  Its interest has expanded in both dental research and clinical practice, among general dentists and specialists alike.  Use of CBCT can range from traumatology and studying craniofacial anomalies to implantology.6  1.2.1 Advantages and Disadvantages of CBCT in Dentistry  Advantages of using CBCT include the ability to produce two-dimensional images from the 3D data, fewer metal artifacts, isotropic voxel size, has a smaller footprint and uses less energy than HCT, and is digital imaging and communications in medicine (DICOM) compatible.6 CBCT is also less expensive for the dentist to operate and is more compact than HCT, allowing for in-office imaging.  CBCT also has a lower radiation dose due to a shorter exposure time compared with HCT.1   However, limitations of CBCT include a limited detector size, low contrast range, a restricted FOV, limited inner soft tissue information, increased scatter radiation and reduced contrast resolution, and the inability to be used for the estimation of HU.6  Compared to conventional 2D radiography, CBCT is also associated with a higher level of radiation exposure for patients.7  It is estimated that the effective dose of a conventional panoramic radiograph is 24.3 µSv and for a cephalometric radiograph is 5.6 µSv.8  The effective dose of CBCT for a small FOV is 48-652 µSv and for a large FOV is 68-1073 µSv, which is relatively small compared to a conventional CT scan which is 534-2100 µSv.9,10  Therefore the effective doses do differ significantly across CBCT machines and is substantially higher compared to conventional panoramic radiographs, but are still considerably less compared to conventional CT.11 Nonetheless, efforts have been made to reduce radiation dosage associated with CBCT including narrow collimation12 and changing the rotational angle from 360o to 180o 13.  Some potential improvements to reduce patient radiation exposure associated with CBCT include reducing patient dose with high resolution, varying FOV, enhancing image quality, and reducing scan time.2    3  1.3 CBCT and Orthodontics In the specialty of orthodontics, CBCT can have many uses such as assessing the location of supernumerary or impacted teeth and potential root resorption associated with these conditions.6  Some studies have suggested the use of CBCT for fabrication of surgical guides for the placement of orthodontic mini-implants.14  Furthermore, changes in the condyles, rami, chin, maxilla and dentition can be assessed by superimposing the CBCT scans taken before and after orthognathic surgery.15  More recently, orthodontics has employed the use of CBCT for airway assessment.  1.3.1 Orthodontics and OSA The relatively recent involvement of orthodontists with obstructive sleep apnea (OSA) in both children and adults has furthered the interest of CBCT in the assessment of the upper airway. Nasal obstruction and sleep disordered breathing has been shown to be associated with altered craniofacial growth in some patients.16  More recently, common facial orthopaedic treatments have demonstrated effectiveness for paediatric OSA.17  As such the relationship of upper airway anatomy to sleep disordered breathing development and treatment continues to be an area of ongoing research.  1.3.2 Obstructive Sleep Apnea  Sleep apnea is a life threatening condition with two subcategories; central sleep apnea (CSA) and obstructive sleep apnea (OSA).  CSA is triggered by the brain temporarily ceases to send signals to the respiratory muscles which regulate breathing.  This results in multiple cessation episodes of respiration during sleep.18,19  OSA is a disorder that is a result of complete or partial collapse of the airway, leading to disturbances in respiratory parameters and abnormal sleep.19  In an adult, an apnea is described as a complete cessation of airflow for a minimum of 10 seconds.  A hypopnea is characterised by a decrease in airflow below 70% for a minimum of 10 seconds with a 4% or greater blood oxygen desaturation.  A hypopnea can instead be defined as a reduction of airflow below 50% for a minimum of 10 seconds with a 3% desaturation, or the event is associated with arousal.20  The apnea-hypopnea index (AHI), which is the standard for diagnosing OSA, is the combined total number of apneas and hypopneas per one hour of sleep.19,21  In adults, a diagnosis of OSA can be made when the AHI of a patient is 5 or greater and demonstrates symptoms of excessive daytime sleepiness, fatigue, disturbed sleep with choking or gasping, experiencing non-refreshing sleep, or if the bed partner reports loud snoring or pauses in respiration while the patient is sleeping.22,23  A reported AHI of 5-15 events per hour is described as mild OSA, between 15-30 as moderate OSA, and 30 or greater as sever OSA.24  The prevalence of OSA has been reported to be 2% of women and 4% of men ages 30-60 years old, with OSA patients being most commonly middle-aged men who are also 4  overweight.25,26  However it is important to note that there may be many patients who go undiagnosed.18,19  This is because OSA can be asymptomatic and the prevalence of these patients with OSA who do not exhibit a clinical syndrome can be up to 30% among the middle-aged population.19,21   Other risk factors for OSA seen in adult patients include an increased body mass index (BMI), an increased neck circumference, race, family history, alcohol use, smoking, use of sedatives, and nasal congestion.27,28  However, since OSA is less common in women, other factors including neuromuscular pathways may contribute to protecting the airway from constriction.29,30  OSA is not limited to patients who are overweight, but can also occur in those of normal bodyweight who have anatomic abnormalities.    1.3.3 Pathophysiology of OSA The pharynx is a funnel-shaped tube which is fibromuscular, is approximately 15 centimeters in length, and functions as a conduit for food and air.31,32  It is located superior to the larynx, esophagus, and trachea, and dorsal to the oral and nasal cavities.32–36  The pharynx can be divided into 3 components; the nasopharynx, oropharynx, and hypopharynx from superior to inferior.  The nasopharynx is located posterior to the nasal cavity while the oropharynx is posterior to the oral cavity.32,37,38  The hypopharynx extends from the tip of the epiglottis to the lowest portion of the airway at the larynx.  A large number of muscles affect this portion of the airway, often acting in concert with or opposition to other related muscles.20 A patient experiences an OSA event when the pharyngeal airway narrows or closes with respiratory effort during sleep.  The pharyngeal airway is unique in that it has no rigid support, instead being muscle and ligament formed and supported.  While the patient is awake, muscle tensions keep the lumen patent. While the patient is asleep however, the muscles relax and the pharyngeal walls become more flexible and more collapsible.  Furthermore, in the reclined position the effects of gravity distort the pharyngeal walls, especially by retropositioning of the tongue while the patient is supine, resulting in a narrowed lumen.  Since the required volume exchange of air remains the same, a higher velocity is necessary through the smaller passageway. This airflow is turbulent, causing vibration and flutter of the flexible walls and soft palate, resulting in (often loud) snoring.  The narrower the lumen, the faster the velocity and the lower the pressure.20   Once a critical point is reached, this combination of physical conditions will result in an occluded airway.  Although respiratory effort will continue, with the diaphragm contracting downward forcefully enough that the chest walls may be drawn inward, there will be no air exchanged until there is sufficient arousal (lighter level of sleep) to regain enough muscle tension and reopen the pharyngeal airway.  This sequence of loud snoring, sudden silence, and loud resuscitative “snort” is not only virtually pathognomonic for OSA, but is frequently what drives the patients and their families to seek treatment.20 5  The resultant and repetitive apnea events characteristic of OSA can be associated with many symptoms including loud irregular snoring,20 long pauses in breathing during sleep,20 excessive daytime sleepiness,20,22,23,26,39 obesity,20 fatigue,20 impotence,20 morning headaches,20 and changes in cognitive functions such as alertness, memory, personality, or behavior.20  This can lead to motor vehicle,20,21,25,26,40,41 reduced quality of life,20,21,26 decreased work performance,20 along with many consequences to the patients’ health.  These can include cardiovascular disease,18,42–44 hypertension,20,22,23,25,27 coronary artery disease,20,25,26,39,45 deep vein thrombosis,18,43,46,47 stroke,18–20,27,46 and sudden death.19–21,40,44  In patients with more chronic cases, OSA has been associated with cor pulmonale,27,41 pulmonary hypertension,47,48 polycythemia,21,49,50 and metabolic syndromes.48,51  Therefore OSA can be quite incapacitating and life-threatening. According to imaging techniques including lateral cephalograms, magnetic resonance imaging (MRI), and CBCT, the airway constriction associated with OSA most often occurs in the retropalatal and retroglossal regions of the oropharynx.33–36,52–54  This region of the pharynx is particularly vulnerable in OSA patients compared to normal control patients due to decreased collapsing pressures and airway dimensions, which is observed in patients under general anesthesia with complete muscle paralysis.55–58 Hard tissue craniofacial abnormalities commonly associated with OSA as revealed by radiography include a short anterior cranial base,56–58 a retrognathic and retruded maxilla and mandible in relation to cranial base,26,52,53,57,59–63 an increased mandibular plane angle,26,53,57 a large gonial angle,53,62,64,65 a decreased upper to lower facial height ratio,57,64 an increased lower facial height,53,58,66 and an inferior and counter-clockwise translation of the hyoid bone.29,62,64,65  All of the above can result in the development of a compromise in airway dimension.  The soft tissue can also significantly contribute to upper pharyngeal airway risk factors related to OSA.  Studies using lateral and posteroanterior cephalometry assessed restricted posterior airway space and discovered that thickening of the velum and velopharyngeal lumen can compromise the airway.30,64,67  Furthermore, an increased tongue size, a longer soft palate, and lateral pharyngeal wall size can also contribute to OSA.37,38,53,58–63,66,67   Neurologic control of the upper pharyngeal airway also plays an interconnected part in OSA.  The normal physiological process of respiration involves signals being sent from the medulla to the respiratory centres, which through the inspiratory phase stimulates the genioglossus to prepare the upper pharyngeal airway for the development of negative intrapharyngeal pressure.  Airway patency is maintained by the pharyngeal abductor and dilator muscles.30,67  Once the central nervous system (CNS) signals the upper pharyngeal airway and diaphragm the muscles go into a hypotonic state, and the size of the pharynx and soft tissue determine airway stability while the patient is sleeping.53,67,68  Airway obstruction occurs if the negative intraluminal pressure created during inspiration surpasses the support of the soft tissues in the airway.30,69  As a result, the CNS attempts to maintain airway patency by signaling the muscles to go into a hypertonic state to resume respiration, which leads to a lighter level of sleep.30,70      6  Patients with obstructive sleep apnea have been shown to have a significantly reduced total airway volume, airway area, airway width, and a significantly larger airway length compared to patients who do not suffer from obstructive sleep apnea.71  This is important because the frequency of airway collapse increases in patients who have narrower and longer airways.72  Obstructive sleep apnea patients have also been shown to have a significantly larger tongue for a given maxillomandibular size than patients who do not have obstructive sleep apnea.73    1.3.4 CBCT and Upper Pharyngeal Airway Assessment The ability to assess the upper airway in three-dimensions and the lower radiation dose compared to medical CT imaging makes CBCT an attractive potential tool for the assessment of OSA patients.74   However it remains to be determined if CBCT can provide anything beyond a qualitative assessment of upper airway anatomy. In order for CBCT to become a resource for quantitative airway assessment, its reliability as a measurement tool must first be established. For the purpose of this thesis, reliability is defined as the agreement between measurements for the same examiner (intra-examiner) or between different examiners (inter-examiner).  1.4 Objective The aim of this study was to determine the reliability of volumetric and cross-sectional area assessments of the upper pharyngeal airway using dental CBCT.  This would be accomplished by first conducting a systematic review of the literature, followed by an original study to fill in the subsequently revealed knowledge gaps.          7  Chapter 2: Reliability of upper pharyngeal airway assessment using dental CBCT: A systematic review75  2.1 Introduction  Dental cone beam computed tomography (CBCT) became readily available in the late 1990’s and revolutionized dental radiography.  Its interest has expanded in both dental research and clinical practice, among general dentists and specialists alike.  Use of CBCT can range from traumatology and studying craniofacial anomalies to implantology.  In the specialty of orthodontics, CBCT can have many uses such as assessing the location of supernumerary or impacted teeth and potential root resorption associated with these conditions.6   The relatively recent involvement of orthodontists with obstructive sleep apnea (OSA) in both children and adults has furthered the interest of CBCT in the assessment of the upper pharyngeal airway. Nasal obstruction and sleep disordered breathing has been shown to be associated with altered craniofacial growth in some patients.16  More recently, common facial orthopaedic treatments have demonstrated effectiveness for paediatric OSA.17  As such the relationship of upper airway anatomy to sleep disordered breathing development and treatment continues to be an area of ongoing research. The ability to assess the upper pharyngeal airway in three-dimensions and the lower radiation dose compared to medical CT imaging makes CBCT an attractive potential tool for the assessment of OSA patients.74  However it remains to be determined if CBCT can provide anything beyond a qualitative assessment of upper airway anatomy. In order for CBCT to become a resource for quantitative airway assessment, its reliability as a measurement tool must first be established. For the purpose of this review, reliability is defined as the agreement between measurements for the same examiner (intra-examiner) or between different examiners (inter-examiner).  Therefore, the purpose of this study is to systematically review the literature to evaluate the reliability of upper pharyngeal airway assessment using dental CBCT.  2.2 Material and Methods  2.2.1 Protocol and Registration The protocol for the present systematic review was constructed a priori according to the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 and is available upon request. This systematic review follows the PRISMA statement,76 its extension for abstracts,77 and was not registered.   8  2.2.2 Eligibility Criteria  The following selection criteria were used for the systematic review: 1. Human studies involving patient data (not phantoms or simulated anatomy)  2. Use of CBCT imaging 3. Assessment of the upper pharyngeal airway 4. Reliability reported  2.2.3 Information Sources, Search Strategy, and Study Selection  The electronic databases of MEDLINE, EMBASE and Web of Science were searched through June 2015. The search tree used for the MEDLINE database is provided in Appendix 1, and similar trees were used for the subsequent databases.  The studies included were restricted to those written in the English language.  A limited gray literature search was conducted using Google Scholar by limiting the examination to the first 100 most relevant hits.  Authors were contacted to identify unpublished literature or ongoing studies, and to clarify data as needed.  The reference lists of the included studies were also searched for any relevant studies.    Assessment of the literature for inclusion in the systematic review, and the extraction of data were completed independently and in duplicate by two investigators (J.N.Z. and J.L.).  Any discrepancies were resolved by consultation with the third author (B.T.P.).   Risk of bias/quality assessment was also completed independently and in duplicate by two investigators (J.N.Z. and B.T.P.), with the third author (J.L.) resolving any discrepancies.  The investigators were not blinded to the authors or the results of the research.  2.2.4 Data Items and Collection  Three different data extraction tables were developed.  The first (Table A.1) recorded whether or not the study was randomized, sample size, age of the sample, whether or not the sample was syndromic, whether or not a control was used, if a gold standard was used, what kind of segmentation was used, the airway region measured, the measurements recorded (volume and/or minimum cross-sectional area), the reliability test used and statistics, imaging software used, and the threshold values used (if any).  The second data extraction table (Table A.2) recorded the CBCT machine used, field of view, tube current (mA), tube potential (kVp), exposure time (sec), and resolution/voxel size (mm).  The third data extraction table (Table A.3) recorded the number of examiners, the number of times the measurements were repeated, the time period between repeated measurements, and the qualifications of the examiner(s).  9  2.2.5 Risk of Bias/Quality Assessment in Individual Studies  Faced with a lack of an appropriately validated tool that is clearly indicated for risk of bias/quality assessment for reliability studies, it was decided to search for a method that was as systematic and objective as possible.  A previously conducted systematic review on a similar topic was identified78 and their assessment tool was used with minimal and appropriate adjustments to systematically assess the selected studies (Figure 2.1).  There were three main parameters evaluated: study design, study measurements, and data analysis.  Each of these three parameters were divided further into sub-sections.   Study design was divided into whether or not the sample was randomized, whether or not the sample size was greater than or equal to thirty subjects, whether or not a control was used, whether a human sample was used, and the method of segmentation. Study measurements was divided into the gold standard used, the portion of the airway studied, and the measurement assessed.  Data analysis was divided into the type of reliability assessed and the statistical test used. Each study was awarded a given number rating for fulfilling the sub-parameters, where each sub-parameter had a maximum rating that could be awarded.78  If any of the sub-parameters were not fulfilled, then a zero was entered for that particular sub-parameter.  The sum up to a maximum of 20 represented the overall quality of the study, with a higher rating signifying a higher quality of the study.               10  Figure 2.1 Evaluation checklist for the included studies Parameters of evaluation   Maximum score 1. Study design (a) (b) (c) (d) (e) Randomized sample (*) Sample size ≥30 (*) Control group included (*) Human sample (*) Method of segmentation: Algorithm (*) Commercial software (*) 1 1 1 1 1 2. Study measurements (f)   (g)     (h) Gold standard: Physical model (***) Manual segmentation (****) Portion of airway: Nasopharynx (*) Oropharynx (*) Hypopharynx/Velopharynx (*) Total upper pharyngeal airway (*) Type of measurement: Volume (**) Minimum cross-sectional area (*) 4   4     3 3. Data analysis (i)   (j) Reliability: Intra-examiner (*) Inter-examiner (*) Statistical test used: ICC (**) Other appropriate statistical test (*) 2   2 Total   20             11  2.2.6 Synthesis of Results and Risk of Bias/Quality Across Studies  It was determined a priori that if the data extracted from each study was adequately homogeneous and the combination of the extracted data was valid, a meta-analysis would be conducted.  2.3 Results  2.3.1 Study Selection  Of the 1241 studies that were screened, 43 articles satisfied the inclusion criteria.74,79–120  However due to the inability to make contact with the authors of one study120 in order to obtain the required data, this study had to be excluded.  A flowchart following the PRISMA format is provided (Figure 2.2), outlining the selection process employed.                   12  Figure 2.2 PRISMA flow diagram of the literature selection process            13  2.3.2 Study Characteristics  The selected studies included the CBCT scans of 956 patients evaluated for reliability of upper pharyngeal airway assessment.  The studies exhibited considerable variations in sample size (ranging from 4-71 scans), mean patient ages (ranging from 8-48 years old), imaging software, machine settings, and examiner protocols (Tables A.1-A.3).  The assessed scans were of a wide spectrum of patients, including those with various syndromes and patients receiving orthodontic treatment (Table A.1).  The studies also used examiners with an array of qualifications including dental students, general dentists, orthodontic residents, orthodontists, physicians, maxillofacial surgeons, and dental radiologists (Table A.3).  The most commonly used CBCT machine was i-CAT (Imaging Sciences International), and the most frequently used imaging software was Dolphin Imaging®.   A majority of the studies used intraclass correlation coefficient (ICC) as the reliability statistic, followed by Dahlberg’s formula being the next most common statistical analysis.  2.3.3 Risk of Bias/Quality of Studies  There were 42 studies that were assessed for methodological quality (Table 2.1).  A score of ≥13/20 was deemed as a high quality study.  Only 5 of the 42 studies fulfilled this criteria.81,87,89,94,105  The major methodological limitation was the lack of a gold standard used in the study.  The next two biggest limitations were sample size and lack of a control group.  Randomization of the sample was another key limitation indicating the potential risk of bias.            14  Table 2.1 Evaluation scores of the included studies (N=42)   Parameters of scoring (x: maximum score) Study design Study measurements Data analysis Total score, n (% out of 20) Studies evaluated (a) = 1 (b) = 1 (c) = 1 (d) = 1 (e) = 1 (f) = 4 (g) = 4 (h) = 3 (i) = 2 (j) = 2   Alves et al.79  1 0 0 1 1 0 1 3 1 2 10 (50) Alves et al.80  1 0 0 1 1 0 1 3 1 2 10 (50) Bandiera et al.81  1 1 1 1 1 0 3 3 1 2 14 (70) Brunetto et al.82  0 0 0 1 1 0 4 3 1 2 12 (60) Burkhard et al.83  1 0 0 1 1 0 1 3 2 1 10 (50) Celikoglu et al. 84 1 0 1 1 1 0 3 2 1 2 12 (60) Chang et al.85  0 0 0 1 1 0 1 1 1 2 7 (35) Cheung and Oberoi86  1 0 1 1 1 0 1 3 1 1 10 (50) De Souza et al.87  0 1 0 1 1 0 3 3 2 2 13 (65) Di Carlo et al.88 1 0 0 1 1 0 4 2 1 2 12 (60) El and Palomo89 1 1 0 1 1 4 2 2 1 2 15 (75) Enciso et al.90 1 0 1 1 1 0 1 3 1 2 11 (55) Feng et al.91 1 0 0 1 1 0 1 2 2 2 10 (50) Glupker et al.92 1 0 0 1 1 0 2 3 1 2 11 (55) Grauer et al. 93 1 0 0 1 1 0 1 2 1 1 8 (40) Guijarro-Martinez and Swennen94 0 1 0 1 1 0 3 3 2 2 13 (65) Hart et al.95 0 1 0 1 1 0 3 3 1 2 12 (60) Hong et al.96 1 0 0 1 1 0 1 3 1 1 9 (45) Iannetti et al.97 0 0 0 1 1 0 1 2 2 1 8 (40) Iwasaki et al.98 1 0 1 1 1 0 3 2 1 2 12 (60) Jiang et al.99 1 0 0 1 1 0 1 3 1 2 10 (50) 15   Parameters of scoring (x: maximum score) Study design Study measurements Data analysis Total score, n (% out of 20) Studies evaluated (a) = 1 (b) = 1 (c) = 1 (d) = 1 (e) = 1 (f) = 4 (g) = 4 (h) = 3 (i) = 2 (j) = 2  Kim et al.100 1 0 0 1 1 0 4 3 1 1 12 (60) Kim et al.101 (30) 1 0 0 1 1 0 4 3 1 1 12 (60) Kochel et al.102 1 0 0 1 1 0 4 3 1 1 12 (60) Lenza et al.74 1 0 0 1 1 0 4 3 1 1 12 (60) Li, L. et al.103 0 1 1 1 1 0 1 1 1 1 8 (40) Li, YM. et al.104 0 0 0 1 1 0 3 2 1 2 10 (50) Mattos et al.105 1 0 0 1 1 0 4 3 2 2 14 (70) Oh et al.106 0 1 0 1 1 0 1 3 1 2 10 (50) Sears et al.107 1 0 0 1 1 0 3 2 1 1 10 (50) Starbuck et al.108 1 0 0 1 1 0 1 2 1 2 9 (45) Stefanovic et al.109 0 1 1 1 1 0 2 3 1 2 12 (60) Valladares-Neto et al.110 1 0 0 1 1 0 3 3 1 1 11 (55) Vizzotto et al.111  0 0 0 1 1 0 2 1 1 2 8 (40) Weissheimer et al.112 0 1 0 1 1 3 1 2 1 2 12 (60) Xu et al.113 0 1 1 1 1 0 1 3 2 2 12 (60) Yoshihara et al.114 1 0 1 1 1 0 3 3 1 1 12 (60) Zhao et al.115 (44) 0 1 1 1 1 0 2 3 1 2 12 (60) Zheng et al.116 1 0 0 1 1 0 4 3 1 1 12 (60) Aboudara et al.117 1 0 0 1 1 0 1 3 1 2 10 (50) Haskell et al.118 0 0 1 1 1 0 1 3 1 2 10 (50) Iwasaki et al.119 1 0 1 1 1 0 2 3 1 2 12 (60)  16  2.3.4 Summary Description of the Studies  All of the included studies assessed intra-examiner reliability.  However, only 7 of the 42 included studies (~17%)83,87,91,94,97,105,113 and only 3 of the 5 high quality studies (60%)87,94,105 assessed inter-examiner reliability.  From the high quality studies, upper airway volume showed good to excellent intra-examiner reliability (0.880-0.990) and minimum cross-sectional area showed moderate to excellent intra-examiner reliability (0.780-0.999).  Upper airway volume demonstrated excellent inter-examiner reliability (0.986-0.998) while minimum cross-sectional area demonstrated moderate to excellent inter-examiner reliability (0.696-0.988).  Both intra- and inter-examiner reliability varied depending on which section of the upper pharyngeal airway was assessed.  According to the high quality studies, intra-examiner reliability for total airway volume ranged from 0.987-0.990, and inter-examiner reliability from 0.950-0.992.  Intra-examiner reliability for nasopharyngeal airway volume ranged from 0.880-0.992 while inter-examiner reliability was 0.986.  Intra-examiner reliability for oropharyngeal airway volume ranged from 0.990-0.999 and inter-examiner reliability was 0.998.  Intra-examiner reliability for hypopharyngeal airway volume ranged from 0.994-0.996 and inter-examiner reliability was 0.994.    Only 19 of the 42 included studies (~45%)74,85,88,89,92,94,95,97,98,104–106,108,110–112,114,115,117 identified the qualifications of the examiners, with only 2 of the 5 high quality studies (40%)89,105 doing so.  Furthermore, only 1 of the studies105 used more than 2 examiners.  The intra- and inter-examiner reliabilities of both airway volume and minimum cross-sectional area did vary depending on the qualifications of the examiners.  A majority of the studies did not assess the upper pharyngeal airway in its entirety, with only 8 of the 42 included studies (~19%)74,82,88,100–102,105,116 and 1 of the 5 high quality studies (20%)105 doing so.  Additionally, many of the studies did not assess both airway volume and minimum cross-sectional area.  Only 28 of the 42 included studies (~67%)74,79–83,86,87,90,92,94–96,99–102,105,106,109,110,113–119 and 4 of the 5 high quality studies (80%)81,87,94,105 measured both.  Most importantly, not a single study had the examiners orient the scan on their own.  Equally as critical, none of the studies had the examiners assign the appropriate sensitivity threshold value for each scan on their own.  2.3.5 Synthesis of the Results  The studies generally show high intra-examiner reliability with lower inter-examiner reliability.  Furthermore, airway volume demonstrated greater intra- and inter-examiner reliability than did minimum cross-sectional area.  Many of the studies only assess intra-examiner reliability, and do not address inter-examiner reliability.  A majority of the studies do not assess the upper pharyngeal airway in its entirety, and several of the studies do not evaluate both airway volume and minimum cross-sectional area.  Less than half of the studies provide the qualifications of the examiners evaluating the scans.  Furthermore, none of the studies allows for 17  manual image orientation or manual selection of the airway sensitivity threshold by the examiners themselves.  2.3.6 Additional Analysis  Considering the significant heterogeneity between study protocols in terms of field of view, scan settings, indication for image acquisition and the machine type used, a meta-analysis of the results was not possible.  2.4 Discussion  This systematic review was performed to assess the reliability of CBCT measurement of the upper airway, a process that has become increasing more common in the field of orthodontics. The practical aspects of airway analysis of a DICOM file generated from a CBCT scan of a patient generally involves several steps, each with its own potential for error. Orientation of the image is typically the first step following opening of the file in a software program used for the analysis.  As the boundaries for the airway are most commonly based on lines parallel to horizontal plane of the image instead of internal landmarks, a standardized method of orientating the field of view in the frontal, sagittal and coronal planes is essential to consistent measurement.  Following image orientation, the appropriate slice on which the airway boundaries are identified is chosen.  The second step of the process requires the landmarks defining the boundaries of the airway to be then identified.  Either of these initial steps is subject to some level of variability and operator error and should be accounted for when assessing method error.  Indeed, in their study of CBCT software accuracy for airway analysis Weissheimer et al.112 used a predefined and orientated airway segment in order to “eliminate variability introduced by using different imaging software programs to define the oropharyngeal airway”. The final step in airway measurement typically is to then choose the sensitivity threshold value at which the software program will differentiate soft tissue from air within the patient’s anatomy. This value is selected on a sliding scale and it allows for the software to distinguish between soft tissue and airway by their radiodensities at the level of each voxel.  The examiner does this by increasing the threshold value along the scale until the entire airway is shaded in by the software.  It should be noted that the same threshold sensitivity value cannot be assigned to all patient scans as you can under- or over-fill the airway, thereby risking under- or overestimating the airway volume.121  It is the authors’ experience that this last step of choosing a threshold value is the most subjective and prone to effecting measurement accuracy and reliability. This has been also been discussed by others.89,112  The search strategy for this review was designed to include all studies that reported the method error or reliability of airway measurement as part of the study protocol. However three studies investigated reliability of CBCT in airway measurement as the specific aim of the study. The first of these studies was conducted by Guijarro-Martinez and Swennen94, who assessed 35 18  non-syndromic patients between 23-35 years of age.  Two examiners assessed the patient scans twice separated 4 weeks apart.  They found that airway volume had excellent reliability, with an intra-examiner reliability of 0.981-0.999 and inter-examiner reliability of 0.986-0.998.  Furthermore they found that minimum cross-sectional area had good-to-excellent reliability, with an intra-examiner reliability of 0.780-0.937 and an inter-examiner reliability of 0.839-0.876.  Intra-examiner reliability varied depending on the specific part of the airway being assessed and the educational background of the examiner.  Some limitations of this study are that the total airway volume was not assessed, only two examiners were used, image orientation was not specified to be performed by the examiners, and manual selection of the sensitivity threshold value was not indicated to have been used in the final assessment.   The second study was conducted by De Souza et al.87, who assessed 60 non-syndromic patients with a mean age of 17.86 years.  Two examiners assessed the patient scans twice separated by a two week interval.  They found that total airway volume had excellent reliability, with an intra-examiner reliability of 0.99 and an inter-examiner reliability of 0.95.  Nasopharyngeal minimum cross-sectional area had good-to-excellent reliability, with an intra-examiner reliability of 0.93-0.98 and an inter-examiner reliability of 0.88.  Oropharyngeal minimum cross-sectional area had excellent reliability, with an intra-examiner reliability of 0.98-0.99 and inter-examiner reliability of 0.98.  One limitation of this study is that the authors did not assess the reliability of each section of the upper airway in regards to volume.  Also, the hypopharynx was not assessed at all on its own for reliability of volume or minimum cross-sectional area assessment.  Furthermore there was no mention in the study as to whether or not image orientation and selection of the sensitivity threshold values was conducted manually.  Lastly, only two examiners were used and their educational backgrounds or experience levels with the process were not provided.  The third study was conducted by Mattos et al.105, who assessed 12 non-syndromic patients of unspecified age.  Three examiners assessed the patient scans twice separated two weeks apart.  They found that airway volume had excellent reliability, with an intra-examiner reliability of 0.987-0.995 and an inter-examiner reliability of 0.992.  Minimum cross-sectional area had moderate to excellent reliability, with an intra-examiner reliability of 0.869-0.999 and an inter-examiner reliability of 0.696-0.988.  Intra-examiner reliability depended on the specific location of the upper airway assessed and on the educational background of the examiners.  Inter-examiner reliability depended on the specific location of the upper airway assessed.  One limitation of this study is that the authors did not assess the reliability of each section of the upper airway in regards to volume.  Furthermore, image orientation and sensitivity threshold value selection was not conducted by the examiners.  2.4.1 Limitations of the Available Evidence  In order to truly assess the reliability of CBCT as a tool to quantitatively measure the airway, the entire procedure of image processing from image orientation, to segmentation of the airway and the selection of threshold value must be evaluated as all three steps are fraught with 19  subjectivity on the part of the examiner. However, the results of this systematic review have demonstrated that the reliability and method error reported in the included studies have only assessed the examiners’ ability to reliably segment the airway.  None of the studies have allowed for the examiners to orient the image or select the sensitivity threshold value manually despite this being essential to the process.  Therefore, even though the studies indicate moderate to excellent reliability, two-thirds of the airway measurement protocol have been largely unexamined in the included studies.   Furthermore, the majority of the studies limited their assessment to intra-examiner reliability and did not consider inter-examiner reliability.  Inter-examiner reliability is just as important as intra-examiner reliability as diagnostic consistency is not only essential within one professional, but amongst professionals as well. There is a wide range of healthcare professionals that would assess the airway of patients with CBCT, and operator experience has been previously shown to influence airway measurement reliability.122  Often a team of professionals spanning different disciplines form a sleep team treating affected patients.  It is also important for reliability amongst healthcare professionals with different backgrounds and training and this is something not readily addressed in the current literature.   For the above reasons, combined with the fact that many studies do not assess the upper pharyngeal airway in its entirety, the reliability of CBCT to assess the upper airway has not been adequately established.  Further studies taking all sources of variability into account are still required to truly determine how reliably CBCT scans of patients can assess volume and minimum cross-sectional area of the upper pharyngeal airway.  2.4.2 Clinical Implications  It is important to note that ALARA principles and SedentexCT guidelines condemn the indiscriminate use of CBCT, stating that its use should be reserved for selected orthodontic cases where conventional radiography cannot provide necessary diagnostic information.123 Therefore, not only should radiation exposure be kept to a minimum, but the use of CBCT examinations for any particular orthodontic patient should be justified.  The CBCT assessment of airway has become commonplace in many areas of orthodontic research, with anatomical linear and volumetric measurements being used to assess the effect of various orthodontic and surgical treatments.  This is despite the fact that a validated and optimized CBCT protocol for airway imaging remains elusive.78  The first step toward this goal would be to determine CBCT’s reliability for upper airway assessment.  Although the current literature suggests that there is moderate to excellent reliability, careful examination of the limitations of the current evidence implies that this question is still unanswered.  Future research should be directed at improving the quality of evidence by addressing both intra-examiner and inter-examiner reliability, while using ICC to describe the variation in measurement.78  Furthermore, reliability should be assessed for both volume and minimum cross-sectional not only for the total upper pharyngeal airway but also for its component 20  sections; the nasopharynx, oropharynx, and hypopharynx.  The anatomical boundaries for each section of the upper pharyngeal airway should also be clearly defined and standardized.  Having many examiners conducting such an assessment would be beneficial, along with assessing if and how reliability changes depending on the examiners’ educational background and clinical experience.  There was not sufficient data in the high quality studies to compare reliability between pediatric and adult patients, but such a study could be beneficial.  Lastly, a meaningful study will allow the examiners to manually perform all steps actually required for assessing the upper pharyngeal airway including image orientation, landmark identification, and selection of the threshold sensitivity for the DICOM file.    2.5 Conclusions  Based on the current and limited evidence, upper pharyngeal airway assessment with CBCT demonstrated moderate to excellent intra- and inter-examiner reliability for volume and minimum cross-sectional area.  However caution is warranted in interpreting these findings as CBCT reliability has only been examined under controlled conditions, which artificially restricts potential sources of variability.  Furthermore, airway volume demonstrated greater intra- and inter-examiner reliability than did minimum cross-sectional area.  However, limitations of the current evidence suggest that more research needs to be conducted to adequately determine the reliability of upper pharyngeal airway assessment using dental CBCT.  2.6 Conflict of Interest  There was no conflict of interest present for conducting this systematic review.            21  Chapter 3: Reliability of upper pharyngeal airway assessment using dental CBCT  3.1 Introduction Dental radiography was revolutionized when cone beam computed tomography (CBCT) became readily available in the late 1990’s. Since then its interest has rapidly increased in dental research and clinical practice among general dentists and specialists alike.6 The field of orthodontics is no exception and the relatively recent and increased awareness in obstructive sleep apnea (OSA) in children and adults has driven the assessment of the upper pharyngeal airway using CBCT to the forefront of academic and clinical interest.  More specifically, the ability to perform a three-dimensional evaluation of the upper airway coupled with the lower radiation dose compared to medical CT imaging makes CBCT a potentially attractive tool for the assessment of airway anatomy in OSA patients.16 Before CBCT is employed to quantitatively assess the airway, it is crucial that we establish its reliability as a measurement tool.  While the quantitative assessment of the airway is semi-automated with contemporary software programs, the operator must initially process the DICOM file through several steps including image orientation and selection of threshold sensitivity before measurements are made. These steps have the potential to introduce a level of subjectivity and negatively affect reliability of the airway analysis.  A recent systematic review on the subject has highlighted the significant methodological limitations of the current literature.75  Most significantly, the reliability and method error reported in the literature have only assessed the examiners’ ability to reliably segment and trace the upper pharyngeal airway.  None of the available studies allowed for the manual orientation of the CBCT images and selection of slice and threshold sensitivity by the examiners in the study protocols.  Furthermore, there is not a single study that assesses the upper airway in its entirety or evaluates both inter-examiner and intra-examiner reliability.75   Therefore, this suggests that reliability of upper pharyngeal airway assessment using CBCT has not been adequately established.    The purpose of this study was to determine the intra-examiner and inter-examiner reliability of the complete process of volumetric and cross-sectional area assessments of the upper airway using CBCT.  3.2 Material and Methods The sample size was determined following the recommendations of Walter et al124 for reliability studies.  The parameters included ρO = 0.5 (minimum acceptable level of reliability), ρ1 = 0.9 (expected level of reliability), α = 0.05, β = 0.2 (implying a power test of 80%).105  For this study it was decided that n = 2 (intra-examiner) and n = 6 (inter-examiner).  Considering these factors, it was determined that a sample of CBCT images from a minimum of 9 patients would be sufficient.   22   The initial de-identified DICOM files of 10 adult patients treated at a university based orthodontic clinic were randomly selected from the orthodontic records database of previously treated patients.  Patients younger than 18 years of age, or with clefts, craniofacial syndromes, detectable airway pathology, or those with previous orthognathic or craniofacial surgery were excluded from selection.  This study adheres with the Health Information Protection Act (HIPA), and was accepted by the Research Ethics Board at the University of British Columbia (H12-00951).    The CBCT scans were taken by one operator using the same I-CAT tomograph (Imaging Sciences International, Hatfield, Pa).  The patients were positioned ensuring that the Frankfort horizontal plane was parallel to the floor.  They were instructed to occlude in maximum intercuspation with their tongue touching the palate, and were refrained from swallowing during the scanning period.  Five of the scans were taken using the fast scan protocol and five scans were taken using the slow scan protocol.  The slow scan protocol included 13 X 17 field of view, 0.3 mm voxel size, 17.8 second scan time, 120 kVp tube voltage, and 37.1 mA tube current.  The fast scan protocol included 13 X 17 field of view, 0.4 mm voxel size, 8.9 second scan time, 120 kVp tube voltage, and 18.5 mA tube current.  Images were saved in DICOM files which were uploaded into Dolphin Imaging software (version 11.5; Dolphin Imaging and Management Systems, Chats- worth, Calif) to obtain the primary reconstructed images and the 3D reconstructions.   An oral and maxillofacial radiologist, an academic orthodontist, an academic orthodontists with additional study in airway and sleep apnea, a private practice orthodontist, a senior orthodontic resident, and a junior orthodontic resident were orientated, trained, and calibrated as examiners for upper pharyngeal airway analysis using CBCT images not included in the study.  The calibration protocol included an explanation of the 3D measurement tools in the Dolphin Imaging software and a demonstration of the measurements to be made for this study.  A video and manual were also provided to train the examiners in manual scan orientation, slice selection, landmark identification, and threshold sensitivity selection for upper pharyngeal airway analysis.    Once calibration was complete, the examiners proceeded with the airway analysis protocol for each of the ten sample patients.  This began with the examiners independently and manually orienting the patient 3D image in the coronal, sagittal and transverse planes (Figures 3.1-3.3).  Then they selected the slice in the mid sagittal plane to be traced, and proceeded to trace the upper pharyngeal airway.  The threshold sensitivity value for the software to discriminate soft tissue from air space was then manually selected and adjusted so that the software completely fills in the airway space, without under or over-filling (Figures 3.4-3.6).  After all required parameters were set, the software processed the measurements of the airway.  The selected threshold sensitivity value, minimum cross-sectional area, total upper airway volume, nasopharyngeal airway volume, oropharyngeal airway volume, and hypopharyngeal airway volume were then recorded.  This process was then repeated with the same scans in reverse order with a 4-week interval between assessment periods.  The examiners did not have access to their previous assessments at the second analysis period, and the scans were randomly 23  analyzed to allow for a blinded assessment.  The total upper pharyngeal airway and its components can be seen in Figures 3.7-3.11 and the corresponding landmarks in Table 3.1.  The determination of the minimum cross-sectional area can be seen in Figure 3.12.                                24  Figure 3.1 Orientation of the axial plane using the lower border of the orbit landmarks         25  Figure 3.2 Orientation of the coronal plane using the Frankfort Horizontal Plane (porion to orbitale)       26  Figure 3.3 Orientation of the midsagittal plane using the upper incisive foramen to opisthion        27  Figure 3.4 Correct sensitivity thresholding where the upper pharyngeal airway is completely filled with no “fingers” projecting out from the airway        28  Figure 3.5 Incorrect sensitivity thresholding where the upper pharyngeal airway is under-filled       29  Figure 3.6 Incorrect sensitivity thresholding where the upper pharyngeal airway is over-filled to the point where “fingers” can be seen projecting out of the airway       30  Figure 3.7 Anatomic boundaries of the upper pharyngeal airway including its comprising regions       31  Figure 3.8 Nasopharyngeal airway volume         32  Figure 3.9 Oropharyngeal airway volume         33  Figure 3.10 Hypopharyngeal airway volume         34  Figure 3.11 Total upper pharyngeal airway volume         35  Figure 3.12 Minimum cross-sectional area of the upper pharyngeal airway        36  Table 3.1 Definitions of the anatomic boundaries for each region of the upper pharyngeal airway  Anterior boundary Posterior boundary Superior boundary Inferior boundary Total Airway Line extending from Sella to the posterior nasal spine (PNS) to the tip of the epiglottis to the base of the epiglottis and entrance to the esophagus Line extending from Sella to the superior pharyngeal wall to the inferior pharyngeal wall  Sella point Line extending from the base of the epiglottis and entrance to the esophagus to the posterior inferior pharyngeal wall Nasopharynx Line extending from Sella to the posterior nasal spine (PNS) Line extending from Sella to the posterior pharyngeal wall Sella point Line extending from the posterior nasal spine (PNS) to the posterior superior pharyngeal wall  Oropharynx Line extending from the posterior nasal spine (PNS) to the tip of the epiglottis  Line extending from the posterior superior pharyngeal wall to the posterior middle pharyngeal wall Line extending from the posterior nasal spine (PNS) to the posterior superior pharyngeal wall Line extending from the tip of the epiglottis to the posterior middle pharyngeal wall Hypopharynx Line extending from the tip of the epiglottis to the base of the epiglottis and entrance to the esophagus Line extending from the posterior middle pharyngeal wall to the posterior inferior pharyngeal wall Line extending from the tip of the epiglottis to the posterior middle pharyngeal wall Line extending from the base of the epiglottis and entrance of the esophagus to the posterior inferior pharyngeal wall       37  Intra-examiner and inter-examiner reliability was calculated using ICC for the measurements obtained by each examiner at both assessment periods.  Using SPSS version 24 (SPSS Inc, Chicago, IL), ICC values along with 95% confidence interval were also used to assess inter- examiner reliability by comparing their first and second assessments.  Reliability was ranked according to the ICC value and considered excellent when it was above 0.9, good when it was between 0.75 and 0.9, moderate when it was between 0.5 and 0.75, and poor when it was below 0.5.105  In addition, examiner variation was calculated as the absolute value of the difference between the two recordings made for each parameter.  Median examiner variation along with quartiles 1 and 3, as well as the mean examiner variation as a percentage of the mean values were calculated for each parameter.  Furthermore, the method error using Dahlberg's formula was calculated using the examiner with the highest ICC for each parameter.  3.3 Results Intra-examiner and inter-examiner reliabilities estimated by ICC for each parameter are shown in Table II for all 10 scans.  The selection of threshold sensitivity value showed poor intra-examiner (mean ICC 0.473) and poor inter-examiner (ICC 0.100; CI 0.000-0.380) reliability.  Minimum cross-sectional area showed moderate intra-examiner (mean ICC 0.591) and poor inter-examiner (ICC 0.223; CI 0.029-0.581) reliability.  Total airway volume showed good (mean ICC 0.819) and poor inter-examiner (ICC 0.175; CI 0.000-0.533) reliability.  Nasopharyngeal airway volume showed good intra-examiner (mean ICC 0.777) and poor inter-examiner (ICC 0.350; CI 0.124-0.690) reliability.  Oropharyngeal airway volume showed excellent intra-examiner (mean ICC 0.976) and excellent inter-examiner (ICC 0.945; CI 0.849-0.985) reliability.   Lastly, hypopharyngeal airway volume showed moderate intra-examiner (mean ICC 0.747) and moderate inter-examiner (ICC 0.550; CI 0.297-0.822) reliability.   However it should be noted that intra-examiner reliability varied greatly with education and experience level as seen in the difference between the minimum and maximum ICC for each parameter.  Intra-examiner reliability for threshold sensitivity value ranged from 0.260-0.741, minimum cross-sectional area from 0.000-0.983, total airway volume from 0.160-0.992, nasopharyngeal airway volume from 0.279-0.979, oropharyngeal airway volume from 0.930-0.996, and hypopharyngeal airway volume from 0.679-0.811.  The more educated and experienced examiners generally showed considerably higher intra-examiner reliability.  Inter-examiner reliability also greatly increased with more educated and experienced examiners for most parameters as seen in Table 3.2.   Tables 3.3 and 3.4 highlight the differences in intra-examiner and inter-examiner reliabilities between the fast and slow scan protocols respectively.  The slow scan protocol demonstrated generally a higher intra-examiner reliability than the fast scan protocol.  However, the differences between the two protocols was relatively minor for intra-examiner reliability compared to inter-examiner reliability.  The slow scan protocol displayed considerably higher inter-examiner reliability compared to the fast scan protocol. 38  The median examiner variation is shown in Table 3.5 along with first and third quartiles.  To further represent the observer error in our study we also calculated the mean examiner variation as a percentage of the mean values obtained in each parameter, also shown in Table 3.5.  Table 3.5 also includes the method error using Dahlberg's formula which was calculated using the examiner with the highest ICC for each parameter.  The examiner with the highest ICC was used to provide the best case scenario.  Also shown in Table 3.5 is the range of measured values for each parameter.  Threshold value ranged from 44-82, minimum cross-sectional area from 67.90-1960.30 mm2, total upper airway volume from 17433.70-217481.90 mm3, nasopharyngeal airway volume from 3216.50-17922.60 mm3, oropharyngeal airway volume from 6985.20-40242.30 mm3, and hypopharyngeal airway volume from 1949.80-11835.00 mm3.  The raw data can be found in Tables A.4-A.9.  The volumetric and cross-sectional data from this study is relatively consistent with the previous literature.94                    40  Table 3.2 ICC values for intra-examiner and inter-examiner reliability for all scans  Intra-Examiner Reliability Inter-Examiner Reliability Op A Op B Op C Op D Op E Op F Mean ICC Ops A,B,C,D,E,F 95% CI Ops A,B,C,D Ops E,F Threshold Value 0.358 0.690 0.260 0.533 0.254 0.741 0.473 0.100 0.000, 0.380 0.501 0.059 Minimum Cross-Sectional Area 0.928 0.983 0.818 0.898 0.124 0.000 0.591 0.223 0.029, 0.581 0.868 0.116 Total Airway Volume 0.992 0.987 0.967 0.991 0.160 0.819 0.819 0.175 0.000, 0.533 0.956 0.107 Nasopharyngeal Airway Volume 0.954 0.979 0.874 0.976 0.602 0.279 0.777 0.350 0.124, 0.690 0.827 0.228 Oropharyngeal Airway Volume 0.996 0.993 0.983 0.965 0.988 0.930 0.976 0.945 0.849, 0.985 0.985 0.950 Hypopharyngeal Airway Volume 0.810 0.811 0.729 0.747 0.706 0.679 0.747 0.550 0.297, 0.822 0.517 0.663  Op A = Oral and maxillofacial radiologist Op B = Academic orthodontists with additional study in airway and sleep apnea Op C = Private practice orthodontist Op D = Academic orthodontist Op E = Senior orthodontic resident Op F = Junior orthodontic resident     41  Table 3.3 ICC values for intra-examiner and inter-examiner reliability for the fast scan protocol  Intra-Examiner Reliability Inter-Examiner Reliability Op A Op B Op C Op D Op E Op F Mean ICC Ops A,B,C,D,E,F 95% CI Ops A,B,C,D Ops E,F Threshold Value 0.000 0.703 0.531 0.000 0.000 0.897 0.245 0.000 0.000, 0.156 0.459 0.000 Minimum Cross-Sectional Area 0.873 0.996 0.956 0.988 0.104 0.114 0.672 0.152 0.000, 0.732 0.986 0.106 Total Airway Volume 0.983 0.979 0.958 0.984 0.167 0.767 0.806 0.142 0.000, 0.727 0.924 0.127 Nasopharyngeal Airway Volume 0.925 0.989 0.929 0.921 0.862 0.386 0.835 0.187 0.000, 0.754 0.798 0.202 Oropharyngeal Airway Volume 0.993 0.98 0.951 0.985 0.962 0.922 0.966 0.908 0.712, 0.988 0.974 0.905 Hypopharyngeal Airway Volume 0.598 0.495 0.846 0.939 0.461 0.674 0.669 0.489 0.145, 0.903 0.421 0.645  Op A = Oral and maxillofacial radiologist Op B = Academic orthodontists with additional study in airway and sleep apnea Op C = Private practice orthodontist Op D = Academic orthodontist Op E = Senior orthodontic resident Op F = Junior orthodontic resident     42  Table 3.4 ICC values for intra-examiner and inter-examiner reliability for the slow scan protocol  Intra-Examiner Reliability Inter-Examiner Reliability Op A Op B Op C Op D Op E Op F Mean ICC Ops A,B,C,D,E,F 95% CI Ops A,B,C,D Ops E,F Threshold Value 0.609 0.653 0.000 0.748 0.673 0.620 0.516 0.291 0.045, 0.809 0.551 0.150 Minimum Cross-Sectional Area 0.946 0.980 0.763 0.872 0.994 0.000 0.704 0.824 0.552, 0.976 0.831 0.849 Total Airway Volume 0.996 0.991 0.975 0.996 0.996 0.859 0.969 0.917 0.739, 0.990 0.976 0.870 Nasopharyngeal Airway Volume 0.974 0.953 0.765 0.991 0.444 0.038 0.694 0.652 0.311, 0.945 0.814 0.500 Oropharyngeal Airway Volume 0.996 0.997 0.993 0.965 0.995 0.936 0.980 0.958 0.852, 0.995 0.988 0.963 Hypopharyngeal Airway Volume 0.966 0.902 0.540 0.531 0.936 0.764 0.773 0.678 0.314, 0.950 0.721 0.619  Op A = Oral and maxillofacial radiologist Op B = Academic orthodontists with additional study in airway and sleep apnea Op C = Private practice orthodontist Op D = Academic orthodontist Op E = Senior orthodontic resident Op F = Junior orthodontic resident    43  Table 3.5 Examiner variance for all parameters  N/A = Not applicable               Units Mean value Range of data Median observer variance Q1 Q3 Mean observer variance as percent of the mean value (%) Method Error Using Dahlberg's formula Threshold N/A 58.30 44-82 2 1 4 5.34 2.46 Minimum Cross-Sectional Area mm2 260.10 67.90-1960.30 12.10 6.10 61.15 27.23 15.56 Total Airway Volume mm3 31277.80 17433.70- 217481.90 1100.55 429.28  2635.08  15.09 784.20 Nasopharyngeal Airway Volume mm3 6159.90  3216.50- 17922.60 416.00 193.22  785.02  12.86 225.16 Oropharyngeal Airway Volume mm3 18213.40  6985.20- 40242.30 730.00  248.30  1335.52  6.24 542.44 Hypopharyngeal Airway Volume mm3 5972.90  1949.80- 11835.00 710.15  277.20  1427.60  17.81 730.58 44  3.4 Discussion The recent systematic review of the literature on this area of research revealed that there were significant methodological limitations in previous assessments of upper airway anatomy using CBCT imaging.75  More specifically, none of the available studies allowed for the manual orientation, mid-sagittal plane slice selection of the CBCT images and selection of threshold sensitivity by the examiners in the study protocols, despite the fact that these steps are fraught with subjectivity and have the potential to affect reliability.  This is the first study to determine the reliability of upper airway assessment using CBCT which considers the above limitations, combined with examiner experience/qualifications and fast versus slow scan protocols.  Overall, the oropharynx is the only region of the upper pharyngeal airway to exhibit excellent intra-examiner and inter-examiner reliability.  This was independent of examiner education and experience, and selected threshold sensitivity value.  This is consistent with previous studies by El et al.89, and Guijarro-Martinez et al.94 showing that the oropharynx was the region with the highest reliability.  Potential explanations can include that the nasopharynx and hypopharynx are either more sensitive to threshold selection which in itself has poor reliability, or that landmark identification for these regions are more challenging.  Alsufyani et al.78 provides another possible explanation in that the shape of the oropharynx three-dimensionally is essentially similar to that of a tube, being completely hollow.  This allows for relatively straight-forward segmentation and processing by the imaging software.  However, the anatomy of the nasopharynx is more complicated due to the narrow and tortuous pathways of the eustachian tubes and choanae.  The same can be said about the hypopharynx due to the presence of the epiglottis.  This combined with potentially noisy CBCT images results in an extremely challenging segmentation process, owing to difficulties encountered in defining the boundaries and grey level thresholding.  They further conclude that studies which only focus on the oropharyngeal airway will likely over-represent the reliability of the evaluated tools.78     Selection of threshold sensitivity value for the airway displayed poor intra-examiner and poor inter-examiner reliability.  Previously, Alves et al.121 conducted a study to determine the optimal threshold value on Dolphin Imaging software to measure airway volume.  They reported that a threshold value of 73 was most accurate, and that values of 70, 71, 72, 74, and 75 had no statistically significant differences in measurement outcomes.  This study however was conducted using airway replicas of only the oropharynx made of silicone to determine the optimal threshold value, which can likely over-estimate the reliability as previously stated by Alsufyani.78  Furthermore it is clear from the current study and others85,91 that threshold values for segmenting the airway in silicone models may have little applicability to the values required in scans of actual patients. It is interesting to note that selection of the threshold sensitivity value showed poor reliability even amongst the educated and experienced examiners, but their intra-examiner reliability in the other parameters was still relatively high.  This could mean that threshold selection may not have a major effect on reliability, but maybe threshold selection combined with the manual orientation and mid-sagittal plane slice selection all play minor roles that when 45  combined can have a more significant effect on reliability, especially with less experienced examiners. The slow scan protocol generally displayed higher reliability than the fast scan protocol, however this trend was much more pronounced for inter-examiner reliability than for intra-examiner reliability.  This could be explained in that the increased scan time, decreased voxel size, and increased tube current provided for greater resolution in the CBCT image.78  However increasing scan time is not always desirable.  Firstly the slow scan protocol comes at an associated cost with an increased radiation dosage, with the slow scan protocol having an effective dose of 127.3 µSv whereas the fast scan protocol has an effective dose of only 64.7 µSv.7  A further limitation is if the scan time is too long then the patient can undergo multiple breathing cycles.  This can result in some motion artifact which can affect the resolution of the airway boundaries.78 The protocol of this study mimics the upper airway assessment process as would be performed in a clinical setting.  Random human error is inevitably introduced with each manual step, thereby affecting reliability.  Perhaps the most noteworthy finding from this study is that the intra-examiner and inter-examiner reliability for all parameters were lower than previously reported in the literature.75  This can be due to the fact that in this study the examiners had to perform each step of the assessment process manually, whereas the previous studies essentially only assessed the ability of the examiners to reliably trace the upper pharyngeal airway.  Between manual orientation, mid-sagittal plane slice selection, and selection of the threshold sensitivity value, these are all steps in the assessment process that introduce an element of subjectivity and are therefore burdened with potential to introduce error.  To demonstrate the magnitude of this error, inter-observer error was presented as the median observer error along with the first and third quartiles for each parameter as seen in previous studies.125,126  The mean inter-observer difference as a percentage of the average values obtained in each parameter was also provided.  Indeed, in CBCT studies which report changes in airway anatomy less than the values of mean percentage error presented in Table V (6% for oropharynx, 27% for minimal cross sectional area), this may in fact be due to measurement error rather than treatment effect. It is clear from this study that education and experience level of the examiner has a significant effect on both intra-examiner and inter-examiner reliability.  The findings are positive in that the examiners which demonstrated the greatest reliability are those who would be readily assessing the upper pharyngeal airway of patients in the clinical setting.  However, the reliability displayed by the residents was significantly poorer.  This is important because it is not uncommon for orthodontic residents to be the examiners in CBCT research as they are readily available in academic institutions.92,112,114 Overall, the results of the present study raise questions towards the value of quantitative assessments of the upper airway using CBCT imaging when using this common measurement protocol. While excellent reliability in the oropharyngeal region was found, the inter-examiner reliability of measurements of both volume of the nasopharynx and overall minimal cross sectional area was poor. As shown in Table 3.5, inter-observer differences can range upwards of 27% of the measured value, which should be taken in to consideration when changes in airway 46  dimensions are being assessed. This has direct implications for associations with sleep disordered breathing as minimum cross-sectional area is a crucial measure of flow limitation and airway collapsibility,127 and the nasopharynx is the most common area of obstruction with children with obstructive sleep apnea.128       A limitation of this study was that there could have been a greater number of scans for both the fast and slow scan protocols to allow for a more substantial assessment of reliability between these two imaging protocols.  This can be difficult as more time would be required by the examiners, but this would be an important area of future research as the current literature does not address the topic of optimizing scan protocols to increase reliability while reducing the radiation dose to the patient.  A further limitation of this study is that only one examiner of each level of experience or training were included, and that the sample was comprised of only adult patients.  A future study with multiple examiners of each experience level and the inclusion of pediatric patients would provide a better understanding of how reliability is effected by these factors.  Furthermore, the assessments of the CBCT scans were not performed on a greyscale monitor, and a future study which does would improve the available evidence.  What is clear from the findings of this study is that in any future research assessing the upper airway using CBCT and reporting reliability, examiners must perform all steps in the assessment process manually as clinicians would in a clinical setting and this should be reported.  Furthermore, any studies measuring changes in airway volume and/or minimum cross-sectional area should also report whether the differences found are above the range of errors introduced by the measurement protocols.  3.5 Conclusions This is the first study to evaluate the reliability of upper pharyngeal airway assessment using CBCT where the examiners performed each step of the analysis manually, as would be conducted in a clinical setting.  Selection of the threshold sensitivity value generally had poor reliability.  Reliability improved with examiner experience, though was generally low for the hypopharynx and nasopharynx volumes and overall minimal cross sectional area.  The oropharyngeal airway volume was the only parameter found to have generalized excellent intra-examiner and inter-examiner reliability.        47  Chapter 4: Should Dental CBCT Be Used Today For Quantitative Assessments of the Upper Pharyngeal Airway: Final Thoughts   This is the first study to evaluate the reliability of upper pharyngeal airway assessment using dental CBCT where the examiners performed each step of the analysis manually.  Selection of the threshold sensitivity value generally had poor reliability.  Reliability greatly improved with education and experience level of the examiner.  Volumetric assessments demonstrated greater reliability than did minimum cross-sectional area, with oropharyngeal airway volume being the only parameter to have generalized excellent intra-examiner and inter-examiner reliability.  The slow scan protocol generally showed greater reliability with a greater effect on inter-examiner reliability.  However further research is necessary to make more definitive assertions about the effect of scan protocol on reliability.  Even once reliability is adequately established, this is not sufficient evidence to support the use of CBCT by clinicians to assess a patient’s upper airway to diagnose OSA.  Validity of CBCT to determine the true volumetric and cross-sectional area measurements of a patient’s airway must then be evaluated, and this is fraught with confounding factors.   The primary confounding factor for CBCT studies assessing airway is head, body, and jaw position at the time of scan acquisition as they can have a large influence on the upper airway dimension.  A non-randomized controlled trial study by Ono et al.129 studied how changes in head/body position induce changes in upper-airway dimensions specifically related to three positions, supine, supine with the head rotated and lateral recumbent.  They demonstrated a significant increase in volume in the retro-glossal region of oropharynx when subjects rotated their head to the left in the supine position and when changing from the supine to the lateral recumbent position.  Another non-randomized controlled trial study by Pirilä-Parkkinen et al.130 compared the pharyngeal airway size in different cranio-cervical postures in children with sleep-disordered breathing (SDB) and asymptomatic control children who were age and gender matched.  The upper airway in both groups were evaluated in neutral, extension, and flexion head positions.  The hypopharyngeal airway in the SDB group increased by head extension compared to natural head position, and this increase was higher for the SDB group than in the asymptomatic group.  An additional non-randomized controlled trial study by Zhang et al.131 investigated the effect of head and body positions on the oropharynx caliber in normal subjects when their jaw was protruded by using magnetic resonance imaging.  Four different jaw, head and body positions were assessed: jaw protrusion, supine with jaw protrusion, supine-head rotation with jaw protrusion and lateral decubitus with jaw protrusion.  The subjects in this study displayed no sign of breathing-related disorders.   They found that jaw protrusion increased the volume of oropharynx at the level of the retro-palatal- and the retro-glossal regions compared with non-protruded positions.   48  Moreover, according to a systematic review on the effect of head and tongue posture on pharyngeal airway dimensions and morphology conducted by Gurani et al.132, altered head, body and jaw position, respectively had a significant effect on the upper airway dimensions and volume at the time of image acquisition.  The oropharyngeal airway and specifically the retro-palatal and retro-glossal regions of the oropharynx, were the most affected portions of the upper airway when evaluated in respect to head rotation, head extension, jaw protrusion and altered body position.  Both volume and cross-sectional area showed an increase when evaluated in respect to head extension, head rotation, altered body position, and jaw protrusion.  However, they stated that only limited and poor quality evidence was available since no validated method existed with regard to the position of head, jaw or body at the time of image acquisition.  Therefore they concluded that higher levels of evidence was needed and future studies require a standardized method of head and tongue posture during image acquisition.  A study by Guijarro-Martinez and Swennen94 states that other confounding factors for upper airway analysis with CBCT include respiratory phase and tongue posture during image acquisition, as they can qualitatively and quantitatively affect the size and shape of the oropharyngeal airway.  To control these variables, it is suggested that the patient should be instructed to avoid swallowing and any other movement during the CBCT scan, breathe gently, and maintain the mandible in a reproducible position, either maximum intercuspation or centric relation.94  As scanning technology improves and scan acquisition time decreases it will become much easier to control these variables.  In order to quantify the effect of patient body positioning during CBCT airway examination, Camacho et al.133 conducted a retrospective study describing how total volume and cross-sectional area measurements change in OSA patients associated with a supine versus an upright position.  They found that the airway was smaller when patients were in a supine compared with an upright position.  Not only was a decrease seen in total airway volume but also a decrease in cross-sectional area was observed at the levels of the posterior nasal spine, uvula tip, retrolingual and tongue base.  Minimum cross-sectional area of the overall airway was also decreased in the supine position compared to the upright position. Total airway volume decreased by 32.6% and cross-sectional area measurements decreased between 32.3% and 75.9% when patients were in a supine position.  They concluded that the airway of OSA patients was significantly smaller when they were in a supine compared with an upright position.  This can be problematic because in a clinical setting, CBCT assessments of the airway are generally taken with the patient in the upright position, potentially providing a false impression of the patient’s airway dimensions while sleeping.  As the scans used in our study came from a bank of scans from UMN, it is unknown whether or not the above confounding factors were considered at the time of image acquisition.  However, as the scans were selected at random for the assessment of examiner reliability, these confounding factors do not play a significant role in this study.  The body mass index of the patients included in this study was not recorded by UMN and it is currently unknown how high levels of obesity as is often found in OSA patients may affect the reliability of measurements.  However it will be imperative for future validity studies to take the above factors into account 49  when establishing protocol and methodology.  Unless the described issues are accounted for in future studies, quantitative assessments of patients’ upper pharyngeal airway volume and minimum cross-sectional area using dental CBCT may indeed be meaningless.  There is a trend in orthodontics to use quantitative data of patients’ airways pre and post-treatment to determine the effects of a particular intervention on the airway dimensions.  Not only does this study indicate that these conclusions should not be made by clinicians based on dental CBCT imaging, but this also begs the question as to whether or not the airway volume and/or minimum cross-sectional area can be directly related to an individual’s susceptibility to OSA.  A group of studies, one by Barrera and another by Cheng, used MRI to determine how the airways of OSA versus healthy patients respectively behave.134,135  What the combination of studies found was that in healthy patients, especially those with increased BMI, increased age, and smaller airways, they physiologically compensated for these anatomical risk factors for airway collapse by actively dilating their airways during inspiration via increased activity of the genioglossus muscle.  In patients with OSA, this compensation did not occur.  Therefore, quantitative airway dimensions may not play as significant role in the development of OSA compared to how the patients physiologically compensate for their anatomical risk factors. Ultimately the static dimensions of the airway as measured in an upright and awake patient in a CBCT scan may have little to no correlation with how the airway functions during sleep in any particular patient.   4.1 Conclusion In conclusion, our data on reliability and the associated confounding factors with establishing validity of upper pharyngeal airway assessment suggests that CBCT might be reserved as a qualitative tool to evaluate the airway rather than a quantitative one.  What is clear from this research is that further studies are required before CBCT can be advocated valid and reliable comparisons in upper airway dimensions either between patients or within an individual at different points in time.           50  Bibliography 1.  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J Physiol. 2014;592(21):4763-4774. doi:10.1113/jphysiol.2014.279240.                   61  Appendix A  Table A.1 Characters of the included studies in the systematic review (N=42) Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Alves et al.79 Reliability sample yes 12 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.0 NP             Total Airway Volume >0.98       Original sample no 8-10 years old                           Minimum cross-sectional area 0.91               Non-syndromic               62  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Alves et al.80 Reliability sample yes 16 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.0 NP             Total Airway Volume >0.98       Original sample no 8-10 years old                           Minimum cross-sectional area 0.91                     Non-syndromic               63  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Bandiera et al.81 Only Asthmatic group 52 No asthma NP Upper airway   ICC Dolphin Imaging® software, version 11.5 NP             Total Airway Volume 0.99         Asthma group mean 14.85 years old Control mean 16.65 years old                         Nasopharyngeal minimum cross-sectional area 0.99         Asthmatic                                   Oropharyngeal minimum cross-sectional area 0.98     64  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Brunetto et al.82 No 20 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.5 NP             Upper segment volume 0.941         18-30 years old                           Lower segment volume 0.934         Non-syndromic                           Total upper airway volume 0.948                                          Minimum cross-sectional area 0.902     65  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Burkhard et al.83 Yes 11 NP Automatic Upper airway   Dahlberg formula OsiriX®, Mimics® and BrainLab® NP             Airway Diameter Inter-observer 98.9%         19-44 years old (mean 26 years old)         Inter-program 94.2%                             Non-syndromic       Total Airway Volume Inter-observer 99.2%                            Inter-program 96.1%     66  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Celikoglu et al.84 Reliability sample yes 10 Non –syndromic NP Upper airway   ICC Mimics 15.01 NP             Total Airway Volume >0.977         Surgical group mean age 14.1 years old Mean age 13.4 years old                         Nasopharyngeal airway volume >0.977         Bilateral cleft lip and palate                                 Oropharyngeal airway volume >0.977     67  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Chang et al.85 No 14 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.0 60 units             Cross-sectional area 0.853         9-16 years old (mean 12.9 years old)                                                   Non-syndromic               68  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Cheung and Oberoi86 Reliability sample yes 7 Matched non-syndromic NP Upper airway   Pearson correlation coefficient and Lin concordance CB Works 3.0 NP             Total Airway Volume 0.99 and 0.99       Original sample no Mean age 10.6 years old                           Minimum cross-sectional area 0.99 and 0.99                   Unilateral and bilateral cleft lip and palate              69  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               De Souza et al.87 No 60 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.5 NP             Total airway volume Intra  researcher 1: 0.99         Mean 17.86 years old         Intra researcher 2: 0.99                   Inter 0.95         Non-syndromic                           Nasopharyngeal minimum cross-sectional area Intra  researcher 1: 0.98                   Intra researcher 2: 0.93                   Inter 0.88                          70  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               De Souza et al.87            Oropharyngeal minimum cross-sectional area Intra  researcher 1: 0.99     Continued              Intra  researcher 2: 0.98                   Inter 0.98     Di Carlo et al.88 Reliability sample yes 7 NP NP Upper airway   ICC Mimics 15.0 NP             Total volume 0.9       Original sample no 13-43 years old                           Lower nasopharynx volume 0.9         Non-syndromic                           Velopharynx volume 0.7                                     Oropharynx volume 0.9     71  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               El and Palomo89 Yes 30 NP OrthoSegment uses manual segmentation Upper airway   ICC Dolphin Imaging® software, version 11.0 NP             Oropharynx volume Orthosegment: 0.99             Other 3 programs use automatic segmentation     Dolphin 3D: 0.99 InVivoDental version 4.0.70                 InVivoDental: 0.99                   OnDemand3D: 0.99 OnDemand3D version 1.0.1.8407                                   Nasopharynx volume Orthosegment: 0.98 OrthoSegment                 Dolphin 3D: 0.88                   InVivoDental: 0.97     72  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               El and Palomo89   Continued             OnDemand3D: 0.89     Enciso et al.90 Reliability sample yes 20 AHI<10 NP Upper airway   ICC vWorks 5.0 NP             Total volume 0.965       Original sample no Mean age 57.5 years old Mean age 50.8 years old                         Minimum cross-sectional area 0.979                  OSA and snorers AHI>10               73  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Feng et al.91 Reliability sample yes 10 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.0 25, 30, 40, and 50             Nasopharyngeal volume Intra researcher 1: 0.96       Original sample no 9-43 years old         Intra researcher 2: 0.99                   Inter measurement 1: 0.96                   Non-syndromic         Inter measurement 2: 0.97     74  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Glupker et al.92 Reliability sample yes 10 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.5 NP             Nasopharyngeal volume >0.8       Original sample no Mean age 40.3 years old                           Oropharyngeal volume >0.8         Non-syndromic                                     Minimum constricted area >0.8     75  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Grauer et al.93 Reliability sample yes 5 NP Semiautomatic segmentation Upper airway   Mean coefficient of variation InsightSNAP software, version 1.4.0 NP             Total Airway volume 1.90%       Original sample no 17-46 years old                           Superior component NP         Non-syndromic                                      Inferior component NP     76  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Guijarro-Martinez and Swennen94 No 35 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.0 Preliminary assessment of all scans              Nasopharynx minimum cross-sectional area Intra researcher 1: 0.848   using manual thresholding      23-35 years old         Intra researcher 2: 0.937   (range 48-81)               Inter: 0.876         Non-syndromic                           Nasopharyngeal volume Intra researcher 1: 0.981                   Intra researcher 2: 0.992   Average threshold of                Inter: 0.986   preliminary scans was 70  77  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic                Guijarro-Martinez and Swennen94                 and this was the threshold value  Continued            Oropharyngeal minimum cross-sectional area Intra researcher 1: 0.780   that was then used in the study               Intra researcher 2: 0.825                   Inter: 0.837                                     Oropharyngeal volume Intra researcher 1: 0.997                   Intra researcher 2: 0.999                   Inter: 0.998                           78  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Guijarro-Martinez and Swennen94            Hypopharyngeal minimum cross-sectional area Intra researcher 1: 0.904     Continued              Intra researcher 2: 0.936                   Inter: 0.839                                     Hypopharyngeal volume Intra researcher 1: 0.994                   Intra researcher 2: 0.996                          Inter: 0.994     79  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Hart et al.95 No 71 NP NP Upper airway   ICC Invivo5 -1000 and - 604.3 Hounsfield units             Total airway volume All values ranged from 0.77-0.99         Mean age 18.8 years old       Nasopharyngeal volume                   Oropharyngeal volume                      Non-syndromic       Minimum cross-sectional area       80  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Hong et al.96 Reliability sample yes 10 NP NP Upper airway   Mean coefficient of variation InVivoDental -1024 to -300 Hounsfield units             Total airway volume 1.94% for all measurements       Original sample no 18-30 years old (mean age 20.6 years old)       Minimum cross-sectional area         Reliability sample yes                               Non-syndromic               81  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Iannetti et al.97 No 4 NP NP Upper airway Total Airway volume Intra: Wilcoxon signed rank test Dolphin Imaging® software, version 11.0 NP               Z = -0.770, P = 0.441         5-9 years old         Mean difference 11.8 mm3                             Aperts or Crouzon syndromes         Inter: Mann-Whitney test                   4.34                           Mean difference 12.7 mm3     82  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Iwasaki et al.98 Reliability sample yes 10 Non-syndromic not requiring RME Threshold segmentation Upper airway   ICC INTAGE Volume Editor NP             Intraoral airway volume All measurements ranged from 0.965-0.998       Original sample no Mean age 9.96 years old Mean age 9.68 years old     Retropalatal airway volume                   Oropharyngeal airway volume           Non-syndromic requiring RME Age, sex, and dentition matched     Total airway volume                              83  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Jiang et al.99 Reliability sample yes 20 NP NP Upper airway   ICC Mimics 16.01 NP             Total Airway volume >0.98 for all measurements       Original sample no 6-18 years old       Minimum cross-sectional area                                            Non-syndromic               84  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Kim et al.100 Reliability sample yes 10 NP NP Upper airway   Dahlberg formula InVivoDental -1024 to             Total airway volume Varied from 1054.47 to   -300 Hounsfield units   Original sample no 17-48 years old (mean age 30.04 years old)       Nasopharyngeal airway volume 1418.88 mm3 for the volumetric measurements                 Oropharyngeal airway volume                    Non-syndromic       Hypopharyngeal airway volume       85  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Kim et al.101 Reliability sample yes 15 NP NP Upper airway   Dahlberg formula InVivoDental NP             Superior pharyngeal airway volume Varied from 57.36 to 91.37 mm3 for the volumetric measurements       Original sample no Mean age 11.19 years old       Middle pharyngeal airway volume                   Inferior pharyngeal airway volume           Non-syndromic       Total airway volume                                           Minimum cross-sectional area Varied from 11.33 to 36.12 mm2      86  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Kochel et al.102 Reliability sample yes 20 NP NP Upper airway   Dahlberg formula Mimics® Innovation Suite 14.1 NP             Total airway volume 78.0 mm3       Original sample no Mean age 31.8 years old                           Upper pharyngeal airway volume 90.3 mm3         Non-syndromic                          Middle pharyngeal airway volume 125.1 mm3                                     Lower pharyngeal airway volume 66.4 mm3                                  Upper minimum CSA  10.1 mm2     87  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Kochel et al.102            Middle pharyngeal minimum cross-sectional area 3.5 mm2     Continued                               Lower pharyngeal minimum cross-sectional area 2.8 mm2                                               Smallest pharyngeal cross-sectional area 5.2 mm2     88  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Lenza et al.74 Reliability sample yes 5 NP NP Upper airway   Dahlberg formula Mimics® Innovation Suite 12.13 NP             Lower nasopharyngeal airway volume 145.42 mm3       Original sample no Mean age 18 years old                           Upper velopharyngeal airway volume 249.68 mm3         Non-syndromic                           Lower velopharyngeal airway volume 168.32 mm3                                     Upper OAV 283.86 mm3                         89  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Lenza et al.74            Lower Oropharyngeal airway volume 364.43 mm3     Continued                                Total airway volume 475.58 mm3                                     Lower nasopharyngeal minimum cross-sectional area 19.08 mm2                                    Upper velopharygeal minimum cross-sectional area 31.95 mm2                                     Lower VCSA 10.40 mm2                          90  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Lenza et al.74            Upper Oropharyngeal minimum cross-sectional area 19.07 mm2      Continued                               Lower oropharyngeal minimum cross sectional area 14.34 mm2                                              Smallest cross-sectional area 22.93 mm2     91  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Li, L. et al.103 No 60 Normal mandibular length  NP Upper airway   Method error Mimics® Innovation Suite 16.0 NP             Minimum cross-sectional area Varied from 5.76-7.85 mm2         Mean age 11.57 years old Mean age 11.72 years old                                                  Non-syndromic Retrusive mandible Matched for age, sex, and development condition             92  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Li, YM. et al.104 No 29 NP NP Upper airway   r Mimics® Innovation Suite 10.01 NP             Nasopharyngeal airway volume Interobserver >0.9 for all measurements         18-35 years old (mean age 23.6 years old)       Oropharyngeal airway volume                   Total airway volume                     Class III skeletal non-syndromic               93  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic               Mattos et al.105 Yes 12 NP NP Upper airway   ICC Dolphin Imaging® software, version 11.5 NP             Palatal plane minimum cross-sectional area Undergrad 0.993         NP         Ortho 0.993                   Radio 0.993         Non-syndromic         Inter 0.988                                     Soft palate level minimum cross-sectional area Undergrad 0.975                   Ortho 0.984                   Radio 0.996                   Inter 0.974                        94  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age                   Syndromic                Mattos et al.105           Tongue level MCSA cross-sectional area Undergrad 0.935                  Ortho 0.974     Continued              Radio 0.987                   Inter 0.960                                    Vallecula level minimum cross-sectional area Undergrad 0.993                   Ortho 0.984                   Radio 0.989                   Inter 0.696                                    Sagittal area Undergrad 0.983                   Ortho 0.979                   Radio 0.985                   Inter 0.977                        95  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Mattos et al.105            Minimum axial area Undergrad 0.999                   Ortho 0.869                   Radio 0.999     Continued              Inter 0.932                                    Total airway volume Undergrad 0.995                   Ortho 0.987                   Radio 0.994                                Inter 0.992     96  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Oh et al.106 No 64 NP NP Upper airway   ICC InVivoDental -1,024 to -300 Hounsfield units             Nasopharyngeal volume and minimum cross-sectional area Ranged from 0.969 to 0.998 for all measurements         8-13 years old (mean age 11.03 years old)                                                 Non-syndromic               97  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Sears et al.107 Reliability sample yes 8 NP NP Upper airway   Pearson correlation CB Works 2.1 NP             Nasopharyngeal volume 0.88       Original sample no Mean age 23.85 years old                           Oropharyngeal volume 0.97         Non-syndromic                          Hypopharyngeal volume 0.79     Starbuck et al.108 Reliability sample yes 10 NP Semiautomatic segmentation Upper airway   ICC Dolphin Imaging® software, version 11.5 NP             Nasal airway volume 0.98       Original sample no 7-18 years old                                       Cleft lip and palate               98  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Stefanovic et al.109 NP 62 Age and gender matched non-extraction group NP Upper airway   ICC Dolphin Imaging® software, version 11.0 NP             Nasopharyngeal volume >0.98 for all measurements         Mean age 12.97 years old Mean age 12.86 years old     Oropharyngeal volume                   Minimum cross-sectional area           Non-syndromic                          extraction group               99  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Valladares-Neto et al.110 Original sample no 13 NP NP Upper airway   Dahlberg formula InVivoDental software (version 5.0) NP             Upper volume −0.41 to 0.56 ml       Reliability sample yes Mean age 35.5 years old                           Lower volume −0.41 to 0.56 ml                         Non-syndromic                       Minimum cross-sectional area −22.30 mm2     100  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Vizzotto et al.111 No NP NP NP Upper airway   ICC Image Tool software version 3.0 NP             Nasopharyngeal axial area 0.81-0.95 for all measurements         Mean age 17.5 years old       Oropharyngeal axial area                                            Non-syndromic               101  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Weissheimer et al.112 No 33 NP Acrylic phantom Upper airway   ICC Mimics 14.12, FT indicated fixed thresholding             Oropharyngeal volume ITK-Snap 0.99 Dolphin Imaging® software, version 11.7,  was used at      7.2-14.5 years old (mean age 10.7 years old)   Semiautomatic segmentation     Mimics 0.99 Ondemand3D version 1.0.9.1451, −1000 to −587 grey levels               OsiriX 0.99 OsiriX version 4.0,       Non-syndromic         Dolphin 3D 0.99 ITK-Snap version 2.2.0                 InVivoDental 0.99                   OnDemand3D 0.94                   Mimics FT 1.00     102  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Weissheimer et al.112              ITK-Snap FT 1.00                   OsiriX FT 1.00     Continued               OnDemand3D FT 1.00     Xu et al.113 No 62 23-27 years old (mean age 25.1 years old) NP Upper airway   Pearson correlation coefficient Mimics 10.01 NP             Total airway volume Intra 0.999         22-27 years old (mean age 25.8 years old) Non-syndromic       Inter 0.999                             Cleft lip and palate       Minimum cross-sectional area Intra 0.997                        Inter 0.992     103  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Yoshihara et al.114 Yes 10 Mean age 10.9-15.4 years old NP Upper airway   Dahlberg formula 3-D Rugle NP             Superior oropharyngeal volume Varied from 62.44 to 101.13 mm3 for volumetric measurements         Mean age 10.6-14.7 years old Non-syndromic     Inferior oropharyngeal volume                   Total airway volume           Cleft lip and palate                                  Minimum cross-sectional area Varied from 3.01 to 5.16 mm2     104  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Zhao et al.115 No 48 8.6–15.8 years old (mean age 12.8 years old) NP Upper airway   ICC Vwork version 5.0 NP             Oropharyngeal airway volume Subjects 0.990         8.9–15.1 years old (mean age 12.8 years old) Age and sex matched     Retropalatal airway volume Controls 0.991                 Retroglossal airway volume                    Non-syndromic requiring RME Non-syndromic not requiring RME     Minimum cross-sectional area       105  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Zheng et al.116 Original sample no 15 NP NP Upper airway   Dahlberg formula CBWorks 2.1 -1024 and             Nasopharyngeal volume Ranged from 91.53–152.82 mm3   -318   Reliability sample yes Mean age 15.65 years old       Oropharyngeal volume for volume measurements   Hounsfield units             Hypopharyngeal           Non-syndromic       Total airway volume                                                 Minimum cross-sectional area Ranged from 9.16 to 33.28 mm2     106  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Aboudara et al.117 Original sample no 10 NP NP Upper airway   Pearson product correlation, 3-D Doctor NP               mean percentage error, and mean absolute error       Reliability sample yes 6-17 years old (mean age 14 years old)       Nasopharyngeal volume >0.9                   1.60%         Non-syndromic         48.7 ± 41.1 mm3                                     Nasopharyngeal area >0.9                   2.00%                     6.7 ± 7.6 mm2     107  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Haskell et al.118 No 26 Non-syndromic OSA patients without appliance NP Upper airway   ICC Dolphin Imaging® software, version 11.0 NP             Total airway volume 0.995 with appliance         NP         0.999 without appliance         Non-syndromic OSA patients with appliance                           Minimum cross-sectional area 0.990 with appliance                       0.995 without appliance     108  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               Iwasaki et al.119 Original sample no 10 Mean age 8.4 years old NP Upper airway   ICC and Dahlberg formula INTAGE Volume Editor –1024 to             Upper airway volume 0.975-0.999   –300   Reliability sample yes Mean age 8.8 years old Non-syndromic class I malocclusion       162.48 mm3                             Non-syndromic class III malocclusion       Nasopharyngeal minimum cross-sectional area 0.975-0.999                   1.37 mm2                                     Oropharyngeal minimum cross-sectional area 0.975-0.999                    1.69 mm2     109  Study Randomized Sample Control  Gold Standard/ Segmentation Airway Measurements Reliability Test Used and Statistics Imaging Software Threshold     Size     Region (ie/ volume, minimum cross-sectional area)     Value(s)     Age               NP, Not Provided.                                 110  Table A.2 CBCT machine settings of the included studies in the systematic review (N=42) Study CBCT Machine Field of View Tube Current (mA) Tube Potential (kVp) Exposure Time (sec) Resolution/Voxel size (mm) Alves et al.79 i-CAT, Imaging Sciences International 13 × 17 cm 5 120 20 0.4 Alves et al.80 i-CAT, Imaging Sciences International 13 × 17 cm 5 120 20 0.4 Bandiera et al.81 i-CAT, Imaging Sciences International 13 × 23 cm 36.9 120 40 0.4 Brunetto et al.82 i-CAT, Imaging Sciences International 13 × 17 cm 5 120 20 0.4 Burkhard et al.83 KaVo 3D Exam, KaVo Dental GmbH NP NP NP NP NP Celikoglua et al.84 NewTom 5G 13 cm NP NP 14-18 0.3 Chang et al.85 Scanora 3D 14.5 × 13.0 cm NP 125 20 0.35 Cheung and Oberoi86 Hitachi MercuRay, Hitachi Medical Corporation 8 x 8 inch NP NP NP 0.4 De Souza et al.87 i-CAT, Imaging Sciences International 13 × 23 cm 36.9 120 40 0.4 Di Carlo et al.88 NewTom 3G 12 inch NP NP NP 0.36 El and Palomo89 Hitachi CB MercuRay, Hitachi Medical Systems America 12 inch 2 120 9.6 0.377 Enciso et al.90 Newtom QR 3G NP NP 68 NP NP Feng et al.91 3D eXam, KaVo NP varied 5 120 14.7 0.2 Glupker et al.92 NP 13.3 inches NP NP 8.9 0.3 Grauer et al.93 i-CAT, Imaging Sciences International NP NP NP 20-38 0.3 111  Study CBCT Machine Field of View Tube Current (mA) Tube Potential (kVp) Exposure Time (sec) Resolution/Voxel size (mm) Guijarro-Martinez and Swennen94 i-CAT, Imaging Sciences International 17 × 22 cm 48 120 20 0.4 Hart et al.95 Iluma Ultra, IMTEC or 19 × 22 cm 3.8 120 40 0.3 ProMax 3D, Planmeca 17 × 20 cm 14-Jan 90 27 0.2 Hong et al.96 Master 3D, Vatech 20 × 19 cm 3.6 90 15 0.3 Iannetti et al.97 NP NP NP NP NP NP Iwasaki et al.98 CB MercuRay, Hitachi Medical 512 × 512 matrix 15 120 9.6 0.377 Jiang et al.99 Galileos, Sirona   7 85 14 0.15 Kim et al.100 Master 3D, Vatech 19 × 20 cm NP NP NP 0.3 Kim et al.101 Master 3D, Vatech 12 inches NP NP NP 0.3 Kochel et al.102 KaVo 3D eXam®, KaVo Dental 23 × 17 cm 3−8 90−120 8.5 0.4 Lenza et al.74 Newtom QR 3G 12 inches NP NP NP 0.36 Li, L. et al.103 KaVo 3D Exam, KaVo Dental GmbH NP 5 120 8.9 0.3 Li, YM. et al.104 Galileos, Sirona NP 07-May 85 NP NP Mattos et al.105 i-CAT, Imaging Sciences International 13 × 17 cm 5 120 20 0.25 Oh et al.106 Master 3D, Vatech 20 × 19 cm 3.6 90 15 0.3  112         Study CBCT Machine Field of View Tube Current (mA) Tube Potential (kVp) Exposure Time (sec) Resolution/Voxel size (mm) Sears et al.107 Hitachi CB MercuRay, Hitachi Medical Systems America 12 inches 10 100 9.6 NP Starbuck et al.108 i-CAT, Imaging Sciences International 13 cm NP NP 8.9 0.3 or 0.4 Stefanovic et al.109 Hitachi MercuRay, Hitachi Medical Corporation 12 inches 2 120 9.6 0.377 Valladares-Neto et al.110 i-CAT, Imaging Sciences International 12 inches 47.7 120 40 0.4 Vizzotto et al.111 i-CAT, Imaging Sciences International 13 cm 08-Mar 120 NP 0.25 Weissheimer et al.112 i-CAT, Imaging Sciences International NP 8 120 40 0.3 Xu et al.113 3D Accuitomo 170 XYZ slice view tomograph, J Morita Mfg Corp 17 × 12 cm 4.5 85 NP NP Yoshihara et al.114 CB MercuRay, Hitachi Medical 192.5 mm 15 120 9.6 0.377 Zhao et al.115 NewTom 3G NP NP NP 36 NP Zheng et al.116 CB MercuRay, Hitachi Medical NP 10 110 10 NP Aboudara et al.117 NewTom-9000, Quantitative Radiology 9 X 9 cm 15 110 18 0.3 Haskell et al.118 i-CAT, Imaging Sciences International 22 cm NP NP 20 0.4 Iwasaki et al.119 CB MercuRay, Hitachi Medical NP 15 120 9.6 0.377 NP, Not Provided.   113  Table A.3 Examination characteristics of the included studies in the systematic review (N=42) Study Number of Examiners Number of Times Repeated Time Period Between Repeated Measurements Qualifications of Examiners Alves et al.79 1 1 1 week NP Alves et al.80 1 1 1 week NP Bandiera et al.81 1 1 30 days NP Brunetto et al.82 1 1 2 weeks NP Burkhard et al.83 2 0 0 NP Celikoglua et al.84 1 1 2 weeks NP Chang et al.85 1 3 1 week Orthodontist Cheung and Oberoi86 1 1 NP NP De Souza et al.87 2 1 3 weeks NP Di Carlo et al.88 1 1 NP Dentist El and Palomo89 1 1 2 weeks Orthodontist Enciso et al.90 1 1 60 days NP Feng et al.91 2 1 NP NP Glupker et al.92 1 1 2 weeks Orthodontic resident Grauer et al.93 1 3 NP NP Guijarro-Martinez and Swennen94 2 1 4 weeks Oral maxillofacial surgeon (one examiner) Hart et al.95 1 1 NP Dentist Hong et al.96 1 3 NP NP Iannetti et al.97 2 2 NP Dentist and physician Iwasaki et al.98 1 1 1 week Orthodontist Jiang et al.99 1 1 2 weeks NP Kim et al.100 1 1 NP NP Kim et al.101 1 1 2 weeks NP Kochel et al.102 1 1 2 weeks NP 114  Study Number of Examiners Number of Times Repeated Time Period Between Repeated Measurements Qualifications of Examiners Lenza et al.74 2 1 NP Orthodontists Li, L. et al.103 1 1 1 month NP Li, YM. et al.104 2 1 1 week Orthodontists Mattos et al.105   3   1   2 weeks   An undergraduate student,  an orthodontist, and a dental radiologist Oh et al.106 1 2 1 week Orthodontist Sears et al.107 1 1 2 weeks NP Starbuck et al.108 1 1 2 weeks Orthodontist Stefanovic et al.109 1 1 2 weeks NP Valladares-Neto et al.110 1 1 10 days Orthodontist Vizzotto et al.111 1 1 15 days Dental radiologist Weissheimer et al.112 1 1 2 weeks Orthodontic resident Xu et al.113 2 1 1 month NP Yoshihara et al.114 1 1 2 weeks Orthodontic resident Zhao et al.115 1 1 NP Orthodontist Zheng et al.116 1 1 1 week NP Aboudara et al.117 1 1 NP Orthodontist Haskell et al.118 1 2 NP NP Iwasaki et al.119 1 1 1 week NP NP, Not Provided.      115  Table A.4 Raw data for threshold value Scan # 1 2 3 4 5 6 7 8 9 10 A1 45 55 56 55 56 60 55 59 52 44 A2 56 55 55 56 58 61 55 58 53 54 B1 48 54 56 52 60 66 53 60 60 54 B2 50 58 60 57 60 62 59 58 58 54 C1 48 52 51 55 55 55 47 58 56 53 C2 48 56 53 64 60 58 58 55 58 53 D1 55 55 53 56 55 59 50 59 52 50 D2 57 58 56 51 55 55 53 56 51 50 E1 64 62 66 65 64 68 66 66 62 63 E2 64 67 65 67 65 65 66 66 64 62 F1 82 60 56 72 57 67 49 79 55 64 F2 75 63 60 70 60 70 54 66 65 62                   116  Table A.5 Raw data for measured minimum cross-sectional area in mm2 Scan # 1 2 3 4 5 6 7 8 9 10 A1 131.6 160.9 223.3 360.6 285.4 241.0 514.6 119.9 291.7 334.0 A2 139.6 153.5 217.9 269.9 290.5 138.8 484.1 120.3 296.5 355.1 B1 131.2 158.2 218 357.6 293.6 134.2 437.4 126.5 304.1 363.4 B2 135.1 164.5 235.6 354.4 294.8 143.7 499.9 117.5 284.7 359.6 C1 134.1 128.6 204.3 332 283.7 121.3 397.8 120.3 288.5 156.1 C2 134.6 67.9 214.9 363.7 293.8 137.3 464.8 114 301.1 356.5 D1 142.3 156.5 219.8 333.8 283.6 126.7 396.8 121.5 281.2 340 D2 144.4 172.2 232 354.7 280.9 237 500 116 298.3 342.6 E1 149.8 181.5 250.6 378.9 1960.3 245.9 524.9 134.4 336.9 396.6 E2 149.8 189.6 241.5 385.3 309.7 235.7 561 132.6 330 387.6 F1 175.7 84.6 221.5 388.1 288.5 137.8 411.3 166 276.7 442.9 F2 156.5 72.6 93.8 174.3 130 68.8 89.2 134.8 146.8 134.3                   117  Table A.6 Raw data for measured total upper pharyngeal airway volume in mm3 Scan # 1 2 3 4 5 6 7 8 9 10 A1 18142.5 21518.0 26567.3 31449.5 35365.6 20576.0 48384.6 21322.8 27739.6 31061.2 A2 20803.9 21392.8 26475.9 30935.3 35772.6 20184.6 48304.2 21613.3 28788.3 32910.1 B1 17433.7 20253.4 25638.3 27699.9 34712.1 20025.7 45887.2 20594.7 27814.5 34471.9 B2 17870.4 20770.3 23517.2 29463.1 33749.7 20040.1 48609.2 19780.7 29345.7 33167.1 C1 18949.3 19580 23051.4 35840.6 34885.8 22252.7 45739.5 22586.2 31990.2 35415.5 C2 17796.9 19104.4 27112.6 34893.2 38568.5 21496.4 50818 21075.3 30585.8 36175.2 D1 20176.6 20063.4 24741.9 36663.4 36711.6 22701 47964.3 23236 30973.1 34383 D2 20391 21034.7 24461.5 33618.9 36548.8 22340.2 48932 22614.3 29390.4 34852.9 E1 21151.8 18377.4 26401.7 30991.8 217481.9 24961.7 52516.5 24859.6 33116.4 38339.9 E2 21608 21867.9 30758.6 39394.6 41750.4 23305.7 54142.5 25156.8 33130.9 38242.5 F1 33252.9 18328.6 21029.4 29329.8 37555.7 23800 47284.8 34484 31430.8 36325.5 F2 31231.9 21425.5 29630.6 35591 37740.4 25109.4 48732.2 24846.5 35079.1 33699.2            118  Table A.7 Raw data for measured nasopharyngeal airway volume in mm3 Scan # 1 2 3 4 5 6 7 8 9 10 A1 4917.6 6457.7 3996.1 5254.9 7532.8 9063.2 5134.2 6503.7 6647.7 5099.6 A2 5514.0 5790.6 4269.9 5861.2 7693.3 9099.4 5334.2 7078.9 6681.3 4496.2 B1 4232.1 3947.1 3480.6 5867.9 7120.4 7401.6 6046.7 8316.8 6014.9 5177.9 B2 4333.2 4030.1 3737.8 6284.5 7147.1 6889.3 6276.4 8369.8 5352.8 5171.3 C1 4578.5 3692.5 3216.5 5830.4 6801.6 8504.6 5289.8 7498.5 6018.7 4916.6 C2 4860.6 4697.7 3510.8 6374.1 6971.1 9606.6 7084.2 8723.1 6812.8 5283.6 D1 5122.4 4842.1 3349.2 5584.7 6690.4 9850 5775.4 7673 4871.1 3908 D2 5141.9 4000.4 3945.7 5404.9 6958.1 9608.2 5962.7 7487.2 5389.2 4170.7 E1 6051.6 4155.2 4275.2 4738.1 7507.3 9591.4 5949.9 7787.4 5283.6 5525.9 E2 5574.3 4570.6 4226.1 6055.3 7111.6 6472.3 4711.1 6365.7 4501.6 5196.7 F1 17922.6 5870.1 4107.6 5862.1 7863.8 8104.1 6093.1 11767.2 5974.4 7626.2 F2 8573.8 5674.9 6415.3 6852.6 8010.5 7497.7 6708.7 6634.5 6185.5 6157.6            119  Table A.8 Raw data for measured oropharyngeal airway volume in mm3 Scan # 1 2 3 4 5 6 7 8 9 10 A1 9339.0 11019.5 16245.8 20037.2 20871.9 9123.3 35746.4 9454.3 16804.8 20865.2 A2 9231.5 12143.2 16877.8 19769.8 20972.5 9255.7 35031.7 9305.4 16742.3 22756.0 B1 9556.6 13287.3 17046.6 18584.3 21601.1 11108.4 32380.6 7793.2 18484.4 22740.4 B2 9736 13033.8 15185.5 19563.6 22039.7 11062.8 34046.2 7653.1 18685.4 23079.9 C1 9283.4 12588.1 14302.2 19677.9 21494.8 8969.3 33486.4 8834.9 18561.9 23139.3 C2 9140.7 12113.3 17507.9 20423.2 23406.6 9060 35557.5 6985.2 19475.2 23347.1 D1 10048.7 12593.5 15529.6 20378.1 21104.3 8607.6 34362.4 9382.6 18718.4 23823.8 D2 10101 13295.2 14349.3 19231.5 21364.1 8055.6 34652.8 8387.8 12302.2 22933.6 E1 11032.3 13143.1 17579.6 21940.6 23931.8 10440.7 39290.7 11734.5 20749.6 26464.1 E2 11601.7 13813.7 18417.2 22987.2 27276.4 12609.9 40242.3 11967.2 21046.3 25701.5 F1 14988.2 12642.8 17931.8 23823.8 21755.8 11500.1 35360.4 16555.2 19372.1 26140.5 F2 17274.8 12803.9 19143.7 22598.3 24686.8 15793.7 36371.7 11143.1 22288.5 26624.1            120  Table A.9 Raw data for measured hypopharyngeal airway volume in mm3 Scan # 1 2 3 4 5 6 7 8 9 10 A1 3999.0 3877.3 6002.6 6417.6 8300.0 2268.8 7349.8 5649.1 5081.2 5789.0 A2 6087.0 3722.9 5199.4 5234.2 6685.7 2279.1 7826.4 5570.2 6089.5 6022.1 B1 4069.8 3642.6 5615.3 2705.2 6184.1 2027.7 7501.5 4189.3 3987.5 6988.3 B2 3996.9 3655 5395.9 4281 4349.2 1949.8 7831.4 4215.1 5680.9 5651.1 C1 5068.3 3081.6 5694.4 10248.5 7787 4763.1 7869.6 6473.8 6941.5 6773.6 C2 3933.4 2097.7 4511.4 7796.6 6866.2 3401.7 8030.4 5624.7 3684.8 7434.2 D1 4829.4 3551.3 3880.1 11497.7 8184 2339.6 8518 7337.6 6839.1 7590.7 D2 5249.1 3523.7 4572.5 9319.7 8272.2 4655.6 8488.8 6766.9 11835 7298.8 E1 6028.1 2828.2 3517.8 4601.1 7753.9 4975.8 9419.7 7148.1 7131.1 8888.4 E2 5555.9 3828.8 5100.4 9233.4 7948.9 4479.6 8726 7510.7 8167.4 9281.8 F1 3979.2 4673 3382 7265.1 8597.2 3785.8 8758.3 7336.3 7105.6 5398.9 F2 4705.8 3476 6828.4 9957.8 9045.2 4282.7 9299.9 5958.1 6942.3 7850.3            121  Figure A.1 Landmarks used for hard tissue orientation of the CBCT scans Opisthion On the occipital bone, the midpoint on the posterior margin of the foramen magnum Incisive Foramen The opening in the hard palate immediately behind the maxillary incisor teeth Porion The point on the cranium located at the upper margin of each ear canal (external auditory meatus)  Orbitale A point midway between the lowest point on the inferior margin of the two orbits                       122  Figure A.2 Examiner data collection form Scan # 1 2 3 4 5 6 7 8 9 10 Threshold value            Minimum cross-sectional area (mm2)           Total airway volume (mm3)           Nasopharyngeal airway volume (mm3)           Oropharyngeal airway volume (mm3)           Hypopharyngeal airway volume (mm3)               

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