Medicine, Faculty of
Medicine, Department of
DSpace
UBCV
Cheong, Alexander Ryan
Master of Science - MSc
University of British Columbia
Introduction: Assessment of head shape is a common reason for referrals to pediatric neurosurgery clinics. To streamline patient assessments, we investigated whether craniofacial practitioners can accurately screen for surgically actionable craniosynostosis by using standardized screening photographs provided by parents. Methods: Parents of children referred to the neurosurgery clinic at BC Children’s Hospital for assessment of a suspected abnormal head shape prospectively submitted a series of standardized photographs which were blindly evaluated by a panel of 7 independent raters, made up of 3 neurosurgeons, 2 plastic surgeons, a pediatrician, and an occupational therapist, both with experience running a head shape clinic. Each rater indicated their likely diagnosis (presence or absence of potentially surgically actionable craniosynostosis) and their level of confidence in that diagnosis. All children were subsequently evaluated in person by an experienced pediatric neurosurgeon with or without the additional consultation of a plastic surgeon. The diagnosis made at the time of in-person evaluation was used as the gold standard. Results: Of 74 children evaluated, 24 (32.4%) had craniosynostosis diagnosed during an in-person assessment. Fleiss-kappa, a measure of assessing agreement among raters, amongst all 7 raters was 0.76 (0.69, 0.82), indicating substantial agreement related to the diagnosis of craniosynostosis based on photographic assessment. Individual raters' diagnostic performance based on photographic evaluation (sensitivity range 0.86-1.0; specificity range 0.77-0.90) compared favourably with the performance of the "majority rule" photographic diagnosis of all 7 raters combined [sensitivity=1.0 (0.88, 1.0); specificity=0.88 (0.76, 0.95)], or the 3 neurosurgeons [sensitivity=1.0 (0.85, 1.0); specificity=0.88 (0.76, 0.95)]. Conclusion: Based on the evaluation of standardized photographs, experienced craniofacial practitioners were able to accurately identify infants with craniosynostosis who may require surgical intervention as well as those whose head shape abnormality would not require surgery. Individual trained raters appear to perform as well as group consensus. Photographic pre-screening may be useful for discriminating between craniosynostosis and plagiocephaly, the two most common etiologies of an abnormal head shape. Implementation of this tool may help reduce wait times and prevent unnecessary travel for patient families, especially those that live in remote communities.
Determining the Accuracy of Screening for Surgically Actionable Craniosynostosis Through the Assessment of Caregiver Provided Photographs by Alexander Ryan Cheong B.Sc., Simon Fraser University, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2021 © Alexander Ryan Cheong, 2021 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: Determining the Accuracy of Identifying Surgically Actionable Craniosynostosis Through the Assessment of Caregiver Provided Photographs submitted by Alexander Cheong in partial fulfillment of the requirements for the degree of Master of Science in Experimental Medicine Examining Committee: Ash Singhal, Department of Surgery, UBC Co-supervisor Patrick McDonald, Department of Surgery, UBC Co-supervisor Erik Skarsgard, Department of Surgery, UBC Supervisory Committee Member Andrew MacNeily, Department of Urologic Sciences, UBC Additional Examiner iii Abstract Introduction: Assessment of head shape is a common reason for referrals to pediatric neurosurgery clinics. To streamline patient assessments, we investigated whether craniofacial practitioners can accurately screen for surgically actionable craniosynostosis by using standardized screening photographs provided by parents. Methods: Parents of children referred to the neurosurgery clinic at BC Children’s Hospital for assessment of a suspected abnormal head shape prospectively submitted a series of standardized photographs which were blindly evaluated by a panel of 7 independent raters, made up of 3 neurosurgeons, 2 plastic surgeons, a pediatrician, and an occupational therapist, both with experience running a head shape clinic. Each rater indicated their likely diagnosis (presence or absence of potentially surgically actionable craniosynostosis) and their level of confidence in that diagnosis. All children were subsequently evaluated in person by an experienced pediatric neurosurgeon with or without the additional consultation of a plastic surgeon. The diagnosis made at the time of in-person evaluation was used as the gold standard. Results: Of 74 children evaluated, 24 (32.4%) had craniosynostosis diagnosed during an in-person assessment. Fleiss-kappa, a measure of assessing agreement among raters, amongst all 7 raters was 0.76 (0.69, 0.82), indicating substantial agreement related to the diagnosis of craniosynostosis based on photographic assessment. Individual raters' diagnostic performance based on photographic evaluation (sensitivity range 0.86-1.0; specificity range 0.77-0.90) iv compared favourably with the performance of the "majority rule" photographic diagnosis of all 7 raters combined [sensitivity=1.0 (0.88, 1.0); specificity=0.88 (0.76, 0.95)], or the 3 neurosurgeons [sensitivity=1.0 (0.85, 1.0); specificity=0.88 (0.76, 0.95)]. Conclusion: Based on the evaluation of standardized photographs, experienced craniofacial practitioners were able to accurately identify infants with craniosynostosis who may require surgical intervention as well as those whose head shape abnormality would not require surgery. Individual trained raters appear to perform as well as group consensus. Photographic pre-screening may be useful for discriminating between craniosynostosis and plagiocephaly, the two most common etiologies of an abnormal head shape. Implementation of this tool may help reduce wait times and prevent unnecessary travel for patient families, especially those that live in remote communities. v Lay Summary One of the more common reasons an infant is referred to a pediatric neurosurgery clinic is for an odd shaped head, with plagiocephaly and craniosynostosis being the most likely cause – the former only requiring repositioning of the infants head while lying down and the latter typically requiring surgical correction. To improve patient care, we wanted to see if we could diagnose a potentially serious head shape problem in an infant by looking at parent provided photographs. Hospital staff were asked to diagnose the infant’s head shape problem by only looking at the provided photos. Their diagnosis was compared to the in-person clinic visit diagnosis to determine accuracy. The results show trained hospital staff can accurately diagnose irregular head shape cause by looking at parent-provided photos. Making this a standardized part of patient care could potentially help prevent unnecessary travel for families living far away and reduce parental anxiety. vi Preface The study was conducted by Alexander Cheong, under the supervision of Dr. Ash Singhal, and Dr. Patrick McDonald, with input from the thesis committee member Dr. Erik Skarsgard. The research was designed by Dr. Ash Singhal, Dr. Patrick McDonald, and Alexander Cheong. Dr. Mandeep Tamber provided guidance and input on the statistical methods utilized in this study. All steps of the study were completed under the guidance and supervision of my research supervisory committee. The abstract of this study was presented at the 49th Annual Meeting of the AANS/CNS Section on Pediatric Neurological Surgery as a panel presentation. I had written the abstract which was reviewed and revised by Dr. Ash Singhal, Dr. Patrick McDonald, and Dr. Mandeep Tamber who were listed as co-authors on this abstract. Ethics approval for this study was granted by the University of British Columbia Children’s and Women’s Research Ethics Board (H18-03670). vii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ................................................................................................................................ v Preface ........................................................................................................................................... vi Table of Contents ........................................................................................................................ vii List of Tables ................................................................................................................................ ix List of Figures ................................................................................................................................ x List of Abbreviations ................................................................................................................... xi Acknowledgements ..................................................................................................................... xii Chapter 1: Introduction ........................................................................................................... 1 1.1 Neurosurgical Referral .................................................................................................... 1 1.2 Positional Plagiocephaly .................................................................................................. 1 1.2.1 Etiology ...................................................................................................................... 2 1.2.2 Management and Treatment ................................................................................... 2 1.3 Craniosynostosis .............................................................................................................. 3 1.3.1 Classification ............................................................................................................. 3 1.3.2 Management and Treatment ................................................................................... 5 1.4 Management of Referrals ............................................................................................... 6 1.4.1 Current Practice........................................................................................................ 6 1.4.2 Alternative Screening Methods ............................................................................... 6 1.4.3 Impact of a New Screening Method ........................................................................ 8 1.5 Objective and Hypothesis ............................................................................................... 8 Chapter 2: Materials and Methods........................................................................................ 10 2.1 Ethics Approval ............................................................................................................. 10 2.2 Patient Enrollment ........................................................................................................ 10 2.3 Photo Evaluation............................................................................................................ 11 2.4 Sample Size ..................................................................................................................... 12 viii 2.5 Data Collection ............................................................................................................... 13 2.6 Statistical Analysis ......................................................................................................... 13 Chapter 3: Results ................................................................................................................... 15 3.1 Patient Demographic ..................................................................................................... 15 3.2 Fleiss Kappa ................................................................................................................... 17 3.3 Diagnostic Performance ................................................................................................ 17 3.3.1 Group Diagnostic Performance ............................................................................. 17 3.3.1.1 Diagnostic Performance of All raters ............................................................. 17 3.3.1.2 Diagnostic Performance of Craniofacial Surgeons ....................................... 18 3.3.1.3 Diagnostic Performance of Neurosurgeons.................................................... 18 3.3.2 Individual Diagnostic Performance....................................................................... 18 3.3.3 Rater’s Confidence Level ....................................................................................... 20 Chapter 4: Discussion ............................................................................................................. 21 4.1 Virtual Medicine ............................................................................................................ 21 4.2 Diagnostic Performance ................................................................................................ 22 4.2.1 Group Diagnostic Performance ............................................................................. 22 4.2.2 Individual Diagnostic Performance....................................................................... 23 4.3 Research Implementation ............................................................................................. 24 Chapter 5: Conclusion ............................................................................................................ 25 5.1 Alternative Screening Method ...................................................................................... 25 5.2 Strengths and Limitations............................................................................................. 25 5.3 Future Research ............................................................................................................. 27 Bibliography ................................................................................................................................ 28 Appendix: Craniofacial Screening Questionnaire ................................................................... 32 ix List of Tables Table 1. K Value Interpretation .................................................................................................... 13 Table 2. Group and individual diagnostic performance. .............................................................. 19 x List of Figures Figure 1. Example of caregiver provided photographs. Each set contained a photo of the patient’s head from the front, right, left, back, and top. Consent to use these photos in this thesis and any subsequent manuscript was granted by the caregiver. .................................................... 11 Figure 2. Heat map of geographical distribution of study patients with corresponding list of cities. ............................................................................................................................................. 16 Figure 3. Self-Reported Confidence in Screened Diagnosis ........................................................ 20 xi List of Abbreviations BCCH: British Columbia Children’s Hospital CT: Computerized Tomography ICP: Increased Intracranial Pressure MRI: Magnetic Resonance Imaging NPV: Negative Predictive Value OT: Occupational Therapist PPV: Positive Predictive Value SIDS: Sudden Infant Death Syndrome UBC: University of British Columbia xii Acknowledgements I would like to express my gratitude to my thesis supervisors, Dr. Ash Singhal and Dr. Patrick McDonald. This thesis would not have been possible without their enthusiastic engagement and invaluable feedback. I would also like to thank my thesis committee member, Dr. Erik Skarsgard who had provided me with insightful suggestions and comments which greatly helped my research. Additionally, I would especially like to thank Dr. Mandeep Tamber, who not only provided me with critical feedback, but also assisted with the development of the study design and statistical analysis. Thank you to all participating healthcare staff members who were involved: Dr. Douglas Courtemanche, Dr. Erika Henkelman, Patricia Mortenson, and Dr. David Smith. Without your participation, this project would not have been possible. A special thank you to Helen McGregor, who was vital in the patient enrollment process. Most of all, thank you to my parents, friends, and colleagues, who have always been there to support me throughout this journey. 1 Chapter 1: Introduction 1.1 Neurosurgical Referral Craniofacial abnormalities such as positional plagiocephaly or craniosynostosis are one of the most common reasons primary care providers refer a child to a pediatric neurosurgeon (1-3). Although both positional plagiocephaly and craniosynostosis are characterized by abnormal changes to the cranial head shape and may appear similar, management of the two conditions is vastly different and must be carefully differentiated – positional plagiocephaly does not usually require surgical intervention whereas craniosynostosis often does (4-6). In recent years, the number of abnormal head shape referrals to pediatric neurosurgery clinics have increased significantly creating longer wait times and creating more stress for families anxious to see a pediatric neurosurgeon (1, 2, 7). 1.2 Positional Plagiocephaly Positional plagiocephaly is a condition characterized by the asymmetrical flattening of the posterior skull, facial asymmetry, ear misalignment, and or asymmetrical eye sockets (orbits) (4, 8, 9). Since the introduction of the "Back to Sleep Campaign" in 1992 by the American Academy of Pediatrics to reduce sudden infant death syndrome (SIDS), the incidence of positional plagiocephaly has increased drastically from 3 in 10,000 live births to 28.8 in 10,000 live births (10-15). This campaign encouraged parents to position their infant in a supine (on their back) or side position instead of a prone position (on their front) while they sleep. The significant increase of referrals to neurosurgery for abnormal head shapes has been widely considered to be associated with the increase in infants sleeping on their backs, causing chronic pressure effects on their malleable skull (4, 9, 10, 12-14, 16). However, some have argued the prevalence of positional plagiocephaly among the general population has remained the same and the incidence 2 could be explained by primary care providers being more aware of this condition (2, 17). Nevertheless, there has been an overall increase in referrals to pediatric neurosurgery to properly diagnose abnormal head shape. 1.2.1 Etiology The cause of positional plagiocephaly is likely multifactorial. When an infant is born, their skull is soft and malleable, allowing their head to exit the narrow birth canal. As a result, it is not unusual for a newborn to have an abnormal head shape immediately after birth. This deformation usually resolves on its own. However, if the infant consistently maintains the same position, this may lead to more chronic pressure and further flattening of one part of the skull leading to positional plagiocephaly (18, 19). Infants with torticollis (tilting of the head due to the shortening of the neck muscle on one side) may have a more difficult time changing the position of their head, which may lead to the development of positional plagiocephaly (4, 8, 20). Another possible cause of positional plagiocephaly can be due to a multiple pregnancy; multiple fetuses in the intrauterine space can prevent the fetus from changing position which may lead to chronic pressure on one side of the head causing plagiocephaly (2, 4, 8). 1.2.2 Management and Treatment Positional plagiocephaly is primarily considered a minor or cosmetic issue and can usually be managed without surgery. The strategy of repositioning is the most common and conservative method which involves changing the head position frequently during sleeping and promotes increased supervised prone or upright time while awake (1, 4, 12, 20). Infants with torticollis may require physiotherapy to improve the range of motion of the infant’s neck to prevent the child from preferring one position and allowing for repositioning to be more effective (17, 18, 21). Orthotic helmet therapy is another form of management that is usually recommended for 3 infants with moderate to severe positional plagiocephaly (18, 22). The helmet fits tightly around the protruding portion of the head and has an empty space around the flat portion of the skull. As the infant’s head grows, the empty space allows for more growth while limiting the protruding portion, thereby shaping the skull to be more symmetrical (4, 12, 18, 22). However, several studies, including a randomized control trial in 2014 suggested skull asymmetry or deformity naturally corrects itself without any formal intervention and the specific indications for helmet orthotics remains controversial (10, 13, 23). 1.3 Craniosynostosis Craniosynostosis is a condition where one or more cranial sutures are prematurely fused through ossification, causing changes to growth patterns and the shape of the skull (24). These cranial sutures are normally made up of cartilaginous tissue, which allows for the infant’s skull to be more malleable in order to fit through the birth canal, and allows for the skull to expand while the infant brain grows (24). Craniosynostosis is not as common as positional plagiocephaly, with an incidence estimated to be 1 in 2500 live births (5, 7, 25). The majority of craniosynostosis cases occur spontaneously with only a small percentage being familial or attributed to a syndrome (5, 24). 1.3.1 Classification The classification of craniosynostosis is based on the involved suture(s) – the main cranial sutures being sagittal, metopic, coronals, and lambdoids (5, 26). The most common variation of craniosynostosis is sagittal synostosis which accounts for 40 to 45% of all cases with a prevalence of 2 to 3.2 per 10,000 live births. This type of craniosynostosis has a male predominance with a ratio of 2.5 to 4:1 (26, 27). Sagittal synostosis results in an elongated 4 (anterior-posterior) narrowed head with a “bossing” or prominence of the forehead and occiput. This head shape is called scaphocephaly (5). Metopic synostosis is the second most common form of craniosynostosis, accounting for roughly 19% to 28% of cases with a prevalence of 0.9 to 2.3 per 10,000 live births. Similar to sagittal synostosis, metopic synostosis also has a male predominance of 1.8 to 2.8:1 (26). Infants with metopic synostosis often have a triangular head shape with a pointed and narrowed forehead, which is referred to as trigonocephaly (5). There are some infants that have a ridge along the metopic suture, but with no trigonocephaly – this metopic ridge is distinct from metopic craniosynostosis and usually does not require surgical correction (5, 26, 28). The next most common form of craniosynostosis is unicoronal synostosis with 12% to 24% of nonsyndromic cases and has a prevalence of 0.7 in 10,000 live births. This form of craniosynostosis affects females more than males with a ratio of 1.6 to 3.6:1 (26). Unicoronal synostosis causes anterior plagiocephaly resulting in a flattening of the forehead ipsilateral (same side) to the affected suture. The prematurely fused coronal suture also results in displacement of the ear, orbit, and nasal root creating a trapezoidal head shape. Bicoronal synostosis is another form of coronal synostosis that affects the coronal sutures on both sides accounting for roughly 3% of nonsyndromic cases and most syndromic cases with a prevalence of 0.5 per 10,000 live births (5, 26). Unilateral lambdoid synostosis is much rarer, accounting for only 2% of cases affecting 0.1 per 10,000 live births. This form of synostosis causes flattening of the ipsilateral occiput and forehead leading to a trapezoidal head shape. Although this head shape is referred to as posterior plagiocephaly, it is distinct from positional plagiocephaly and must be carefully differentiated as the treatment for both conditions is vastly different (5, 26, 29). 5 Multiple suture craniosynostosis are most commonly associated with syndromes. Crouzon syndrome, Apert syndrome, Pfeiffer syndrome, Saethre-Chotzen syndrome, Carpenter Syndrome, Muenke Syndrome, and Antley-Bixler syndrome are all examples of syndromes that are characterized by the fusion of both coronal sutures (bicoronal), often in combination with other sutures, as well as other obvious craniofacial deformities and complex multisystem issues(24, 26). The incidence of syndromic craniosynostosis has been estimated to be roughly 12% to 31% of all cases(30). Although it is much rarer, approximately 5% of non-syndromic craniosynostosis cases involve multiple sutures (31). 1.3.2 Management and Treatment Unlike positional plagiocephaly, craniosynostosis often does require surgical intervention, usually for cosmetic reasons. Earlier treatment is associated with fewer complications and more treatment options (5, 6, 24, 32) and as such, prompt referral and assessment is critical. If left untreated, craniosynostosis can result in worsened cranial deformity, cranial growth restriction, psychosocial issues from the child's peer interactions, developmental delay, and, in some rare cases, increased intracranial pressure (ICP) (5, 7, 26, 33, 34). There are 4 surgical methods for the treatment of craniosynostosis: Open cranial vault reconstruction, minimally invasive strip craniectomy with post-operative molding helmet, minimally invasive strip craniectomy with spring implantation, and cranial distraction (5). Open cranial vault reconstruction is an operation usually performed on patients after 6 months of age to decrease any surgical risk. This is usually a lengthy procedure that involves removing and reshaping bones, has a higher likelihood of requiring a blood transfusion, and prolonged hospital stays (5, 27). Both minimally invasive strip craniectomy procedures utilize an endoscope to open the closed suture. It is usually recommended to patients around 3-4 months of age as it relies on the malleability of the infant’s 6 skull to expand and remodel (27, 35, 36). Endoscopic minimally invasive strip craniectomy typically has reduced complications, less blood loss and hence lower transfusion rates, shorter hospital stays, and shorter operative times (37). Cranial distractors are another device used to treat craniosynostosis. This device is implanted in a bone cut and the device is expanded every day at a rate of 1 mm by turning a screw, which separates the two bones apart slowly. This slow expansion allows for distraction osteogenesis (generation of new bone) to fill in the gap afterwards. After a few months, the distractors are removed (5, 27). The most optimal surgical technique is most often decided by the patient’s age of presentation, in addition to surgeon and family preference (27, 35). 1.4 Management of Referrals 1.4.1 Current Practice Diagnosis of either craniosynostosis or positional plagiocephaly is primarily made based on the child's history and a physical examination of the head. In select patients, radiographic imaging such as x-ray or computerized tomography (CT) is also required. When a primary care provider is concerned the child may have craniosynostosis, they would then refer the child to a specialty clinic for confirmation and surgical management where indicated (38). 1.4.2 Alternative Screening Methods With the significant increase in referrals for abnormal head shape to pediatric neurosurgery or craniofacial clinics, some hospital programs have sought alternatives to having each patient evaluated by a neurosurgeon or craniofacial plastic surgeon. A program at Oregon Health & Science University established a plagiocephaly screening clinic which consisted of pediatric nurse practitioners who were trained to differentiate positional plagiocephaly from craniosynostosis patients. Over the 7-year period, they had found that the nurse practitioners had 7 accurately screened over half of the referred patients without the aid of a surgeon and did not overlook any craniosynostosis cases (39). Similarly, BC Children’s Hospital (BCCH) has established a Plagiocephaly Clinic that is run independently of neurosurgery by an occupational therapist and a pediatrician – both had received training by a pediatric neurosurgeon on differentiating plagiocephaly from craniosynostosis. A retrospective chart review of all of the patients managed by the BCCH Plagiocephaly Clinic from 2008 to 2014 demonstrated a 100% sensitivity and 99% specificity when identifying craniosynostosis and referring those patients to a pediatric neurosurgeon (20). Both programs demonstrated the safety and efficacy of having non-surgeon healthcare professionals screen referred patients. The current literature is sparse when looking at alternative screening methods for differentiating positional plagiocephaly from craniosynostosis and differentiating head shapes within the range of normal and craniosynostosis. Only a few studies have looked at using photography or video to accurately measure or screen for cranial deformities. In 2010, Schaaf et al. had used digital photographs, taken by the investigators in a controlled environment, to reliably quantify cranial deformities by measuring cephalic indexes and cranial vault asymmetry using software called Quick Ceph® (40). In a 2017 study, Barbero-Garcia et al. used a slow-motion video taken with a smart phone in the clinic by the researchers, creating a 3D image to accurately measure and evaluate cranial deformations (41). Although both studies had measurements that were very similar to clinical measurements and were effective at quantifying craniofacial abnormalities, they still required the patients to visit the hospital (40, 41). A recent published study in 2021 by Bookland et al. looked at evaluating a novel diagnostic software system to identify craniosynostosis retrospectively using their database of patient photos. Results of the study showed the software had an accuracy of 93.3%, with a sensitivity of 92% and a specificity of 8 94.3%. With the pilot data, it was suggested this was a viable substitute for optical scanner or CT based craniometrics to screen for craniosynostosis. However, it is important to note the patient photos were collected by practitioners in clinic and may not be indicative of real-world scenarios. Additionally, the dataset lacked pictures for less common subtypes of craniosynostosis including bicoronal, lambdoid, and multisuture synostosis making the software only viable for the commonly occurring synostoses (42). Proposing a prospective screening tool study that takes advantage of the near ubiquity of handheld cellphone cameras that parents already possess would provide real world evidence that can potentially be implemented in any health care center. 1.4.3 Impact of a New Screening Method As the only tertiary care center in the province, BCCH receives patients from all over BC and the Yukon – many of whom must travel long-distances, costing families time and money. To better serve these rural and remote communities, some clinics have utilized telemedicine, or virtual health – the delivery of health care services remotely using communication technologies, eliminating the need for patient travel (43). A study done at BCCH in 2019 found virtual health visits had helped families avoid travelling an average of 705 km and had an average estimated direct cost avoidance of $585 per patient family (44). Implementation of a remote screening method for abnormal head shape referrals would potentially help families avoid unnecessary travel, reduce costs and potentially reduce consultation wait times. Although there is a mixed socioeconomic family referral population at BCCH, those of lower socioeconomic status would benefit most from the implementation of this tool. 1.5 Objective and Hypothesis The goal of this study was to develop and assess a new screening method for patients referred to pediatric neurosurgery to help families avoid unnecessary travel, especially those that live far 9 from a neurosurgical center. The objectives of the study were to investigate the accuracy of the participating craniofacial practitioners as a group and as individuals, in addition to the assessment of the strength of agreement among the practitioners. Our hypothesis was that craniofacial practitioners can accurately screen for surgically actionable craniosynostosis by using a series of standardized photos taken by the patient’s caregiver(s). Surgically actionable craniosynostosis was defined as the clinical or radiographical diagnosis of craniosynostosis where surgical correction is offered. The absence of surgically actionable craniosynostosis was defined as a diagnosis where the management or treatment did not involve surgery. We undertook to test this hypothesis prospectively, in a real-world setting, keeping the safety of study participants in mind. 10 Chapter 2: Materials and Methods 2.1 Ethics Approval The study’s ethics was approved by the UBC Children’s and Women’s Research Ethics Board (H18-03670). 2.2 Patient Enrollment In this prospective evaluation study, patients referred to the pediatric neurosurgery clinic at BCCH for an abnormal head shape who met the study inclusion criteria were contacted by the neurosurgery research coordinator to be offered participation in the study. Inclusion criteria were defined as any patients referred to pediatric neurosurgery for abnormal head/skull shape or suspected craniosynostosis. Patients were excluded if they had a magnetic resonance imaging (MRI), or computerized tomography (CT) scan at the time of referral as that would provide a definitive diagnosis and screening patient photographs would not be necessary. Once informed consent was obtained, the patient’s caregiver(s) was provided with instructions and examples of how to take the standardized photographs of their child and were instructed to send the photos to the research coordinator via email as seen in Figure 1. The caregiver(s) was asked to take the photos in a well-lit environment against a plain neutral color background. If the patient had a lot of hair, the caregiver(s) was asked to wet the child’s hair prior to taking the photo to help discern the actual shape of the head. 11 Figure 1. Example of caregiver provided photographs. Each set contained a photo of the patient’s head from the front, right, left, back, and top. Consent to use these photos in this thesis and any subsequent manuscript was granted by the caregiver. 2.3 Photo Evaluation A team of craniofacial practitioners who regularly saw abnormal head shape referrals were enlisted to take part in this study. This team was comprised of 1 pediatrician and 1 occupational therapist (who ran the BCCH plagiocephaly clinic and thus had significant experience evaluation head shape), 2 craniofacial plastic surgeons (who are a part of the BCCH craniofacial plastics program), and all 3 pediatric neurosurgeons at BCCH. Each set of photos was compiled with the de-identified patient’s referral documents, and was presented with a screening survey questionnaire, either in person with an iPad, or online via the UBC Qualtrics survey platform (See Appendix A for survey questionnaire). Each team member was asked to blindly evaluate (rate) the photos and documents and to provide their diagnosis. The rater’s diagnosis was grouped into 1 of the 3 following categories: presence of surgically actionable craniosynostosis, absence of surgically actionable craniosynostosis, and cannot determine diagnosis. The patients were then evaluated in clinic as per standard of care by their attending pediatric neurosurgeon or attending pediatric neurosurgeon accompanied by a craniofacial plastic surgeon. This in-person evaluation was used as the gold standard for the diagnosis. If a team member saw the patient in 12 clinic prior to screening the patient’s study photos, the rater’s assessment for that patient would not be included in their diagnostic performance analysis. Results of the screening questionnaire were then compared with the clinic results to determine each rater’s diagnostic accuracy. 2.4 Sample Size The sample size was calculated by using Cohen’s kappa statistical test of interrater reliability (45). We first assume the outcome, the results of the screening tool to be binary (yes, they did require surgery; no, they did not require surgery) and compare that with the clinical results (yes, they did require surgery; no, they did not require surgery). We then defined the following variables and used the equation below: 𝑁𝑁 = 4 �(1− 𝜅𝜅)𝑊𝑊2� �(1− 𝜅𝜅)(1− 2𝜅𝜅) + 𝜅𝜅(2− 𝜅𝜅)2𝜋𝜋(1− 𝜋𝜋)�1. 962 With the assumption of kappa (K)=0.9 as the chosen strength of agreement (see Table 1 below), W=0.2 as the maximum distance between the lower confidence limit and upper confidence limit, π=0.5 as provided by the pediatric neurosurgeons as their rough estimate of the prevalence of craniosynostosis in the BCCH pediatric neurosurgery referral clinic population, our calculated sample size (N) was 72 referred patients. 13 Table 1. K Value Interpretation Value of K Strength of agreement 0 – 0.2 Slight 0.21 – 0.4 Fair 0.41 – 0.6 Moderate 0.61 – 0.8 Substantial 0.81 – 1.0 Almost Perfect 2.5 Data Collection Patient’s age, sex, date of referral, date of clinic visit, city the patient resides in, and clinic diagnosis were collected. The data was extracted from each patient’s electronic and paper medical chart. Each rater provided their diagnosis and treatment recommendations based on the photos and referral notes. Additionally, raters indicated their self-confidence level with the screened diagnosis in the survey questionnaire on a Likert scale from 1 to 10, 1 being not confident and 10 being extremely confident. 2.6 Statistical Analysis Interrater reliability was calculated using Fleiss Kappa statistical measure to assess the strength of agreement between all 7 raters (46). The group diagnostic performance based on the “the majority rule” of all 7 raters combined, the 5 pediatric neurosurgeons and plastic surgeons at BCCH that specialize in reshaping the skulls of patients (craniofacial surgeons) combined, and the 3 neurosurgeons combined was determined using a 2x2 contingency table to calculate sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and accuracy (47). Positive predictive values (PPV) and negative predictive values (NPV) were also calculated 14 using the disease prevalence based on the study population. If a rater had indicated “cannot determine diagnosis”, their rating would be excluded from the analysis. Furthermore, if a tie had occurred among raters, that patient’s diagnosis was not included in the analysis as a clear diagnostic consensus was not determined. Individual diagnostic performance was also calculated in the same fashion and was compared to the majority rule performance. Statistical analysis was performed using IBM SPSS statistical package version 27. 15 Chapter 3: Results 3.1 Patient Demographic Between May 2019 to December 2020, 74 out of the 104 (71%) eligible referred patients were enrolled into the study. Three patients were excluded from participating – 1 patients had CT scan confirming plagiocephaly and another patient had a CT scan confirming unicoronal craniosynostosis. The other patient was excluded as the patient changed providers and the new pediatrician recommended a neurosurgery appointment was no longer necessary. Out of the 30 non-enrolled eligible study participants, 16 declined participation, 5 did not respond with pictures after being provided with the study information, 4 did not respond to any form of communication, 4 were missed by the study coordinator, and 1 had troubles understanding English and ultimately did not participate. Of the 74 enrolled patients, 48 were male and 26 patients were female, with a mean age of 6.6 months at the time of referral. The average time from date of referral to clinic visit was 38.9 days. Enrolled patients lived an average of 297 km away from BCCH, with 37 out of 74 patients (50%) living outside of Metro Vancouver. The locations of where each patient travelled from are detailed in Figure 2. Of the 74 patients that were enrolled, 24 (32.43%) were diagnosed with surgically actionable craniosynostosis – 12 patients diagnosed with sagittal craniosynostosis (2:1 males to female ratio), 4 patients with coronal craniosynostosis (1:1 male to female ratio), and 8 patients with metopic craniosynostosis (7:1 male to female ratio). Of the 50 patients whose diagnosis was not surgically actionable, 15 had positional plagiocephaly, 11 had a mild metopic ridge, 21 had nothing clinically significant, 1 had Loeys-Dietz syndrome (with no fused sutures), and 2 had other non-surgical diagnoses. 16 Figure 2. Heat map of geographical distribution of study patients with corresponding list of cities. 17 3.2 Fleiss Kappa The strength of agreement among all raters was determined by using the statistical measure Fleiss Kappa (48). The interrater reliability between all raters was found to have a kappa of 0.76 (0.69, 0.82), which is interpreted as substantial agreement amongst all raters related to the diagnosis of surgically actionable craniosynostosis based on the photo assessment (Table 1). Similar results were seen when looking at the interrater reliability of the 5 participating craniofacial surgeons with a kappa of 0.77 (0.69, 0.86) indicating substantial agreement. The 3 neurosurgeons had a higher kappa of 0.82 (0.68, 0.96) denoting almost perfect agreement. 3.3 Diagnostic Performance To assess the diagnostic performance of the photo screening test, we first looked at the performance of all 7 raters together. By grouping individual rater’s diagnosis for each patient, we were able to determine each patient’s screened diagnosis using a majority rule decision. Anecdotally, although not measured, participants took approximately 1-2 minutes to review the set of photos before coming to a diagnostic conclusion. 3.3.1 Group Diagnostic Performance 3.3.1.1 Diagnostic Performance of All raters Together, the 7 raters had a total of 24 true positives, 6 false positives, 44 true negatives, and 0 false negatives. A false negative is a patient who has the disease (surgically actionable craniosynostosis) but was misdiagnosed as not having the disease based on the screening tool. A false positive is a patient that didn’t have the disease, but was diagnosed as having the disease based on the screening tool (50). The group had a sensitivity of 1.00 (0.88, 1.00), a specificity of 0.88 (0.76, 0.95), positive likelihood ratio of 8.33 (3.93, 17.65), and a negative likelihood ratio of 0. Based on the disease prevalence in this study population (32.43%), the PPV was 0.80 (0.65, 18 0.89) and the NPV was 1.00. Overall, all raters together screening patients on a majority rule decision had an accuracy of 0.92 (0.83, 0.97) (Table 2). 3.3.1.2 Diagnostic Performance of Craniofacial Surgeons Similarly, when looking at the diagnostic performance of the 5 craniofacial surgeons grouped together, there were 24 true positives, 4 false positives, 44 true negatives, and 0 false negatives. This resulted in a sensitivity of 1.00 (0.86, 1.00), a specificity of 0.92 (0.80, 0.98), positive likelihood ratio of 12.00 (4.70, 30.67, and a negative likelihood ratio of 0. The PPV of the craniofacial surgeons was 0.85 (0.69, 0.94), the NPV was 1.00, with the overall accuracy being 0.94 (0.86, 0.98) (Table 2). 3.3.1.3 Diagnostic Performance of Neurosurgeons We looked at the diagnostic performance of the 3 pediatric neurosurgeons grouped together in the same fashion. They had 23 true positives, 6 false positives, 44 true negatives, and 0 false negatives. The group’s sensitivity and specificity were 1.00 (0.85, 1.00) and 0.88 (0.76, 0.95) respectively, with a positive likelihood ratio of 8.33 (3.93, 17.65) and a negative likelihood ratio of 0. The neurosurgeons had a PPV of 0.80 (0.65, 0.89), NPV of 1.0, and an overall accuracy of 0.92 (0.83, 0.97) (Table 2). 3.3.2 Individual Diagnostic Performance Individual rater’s diagnostic performance of the photo screening test compared favourably to the “majority rule” grouped raters with sensitivity ranging from 0.86 to 1.0, specificity ranging from 0.77 to 0.90, PPV ranging from 0.65 to 0.82, NPV ranging from 0.92 to 1.0, and overall accuracy ranging from 0.81 to 0.94. Table 2 (below) provides detailed results of individual’s diagnostic performance. 19 Table 2. Group and individual diagnostic performance. Group Performance Sensitivity Specificity PPV NPV Accuracy All Raters 1.00 (0.88, 1.00) 0.88 (0.76, 0.95) 0.80 (0.65, 0.89) 1.00 0.92 (0.83, 0.97) Craniofacial Surgeons 1.00 (0.86, 1.00) 0.92 (0.80, 0.98) 0.85 (0.69, 0.94) 1.00 0.94 (0.86, 0.98) Neurosurgeons 1.00 (0.85, 1.00) 0.88 (0.76, 0.95) 0.80 (0.65, 0.89) 1.00 0.92 (0.83, 0.97) Individual Performance Rater 1 0.96 (0.78, 1.00) 0.84 (0.70, 0.93) 0.74 (0.60, 0.84) 0.98 (0.84, 1.00) 0.88 (0.78, 0.94) Rater 2 1.00 (0.83, 1.00) 0.90 (0.77, 0.97) 0.82 (0.67, 0.91) 1.00 0.94 (0.84, 0.98) Rater 3 1.00 (0.85, 1.00) 0.83 (0.69, 0.92) 0.73 (0.60, 0.84) 1.00 0.88 (0.78, 0.95) Rater 4 0.96 (0.78, 1.00) 0.88 (0.74, 0.96) 0.79 (0.62, 0.90) 0.98 (0.86, 1.00) 0.90 (0.80, 0.96) Rater 5 1.00 (0.84, 1.00) 0.88 (0.76, 0.95) 0.80 (0.65, 0.89) 1.00 0.92 (0.83, 0.97) Rater 6 0.90 (0.70, 0.99) 0.77 (0.62, 0.88) 0.65 (0.52, 0.76) 0.94 (0.82, 0.98) 0.81 (0.70, 0.90) Rater 7 0.86 (0.64, 0.97) 0.83 (0.69, 0.92) 0.70 (0.56, 0.82) 0.92 (0.81, 0.97) 0.84 (0.73, 0.92) 20 3.3.3 Rater’s Confidence Level Raters had an overall self-reported average confidence level of 7.62 out of 10, with raters having a minimum confidence level of 2 and maximum level of 10. Individual average confidence levels ranged from 6.84 to 8.01. The self-reported confidence level for screened diagnosis that were true positives ranged from 7.13 to 8.72, true negatives ranged from 6.95 to 8.31, false positive ranged from 5.88 to 8.13, and false negative with an average of 7 out of 10. Figure 3. Self-Reported Confidence in Screened Diagnosis 0 38 82648113162101420204060801001201401601801 2 3 4 5 6 7 8 9 10Frequency of Self-Reported Confidence Level21 Chapter 4: Discussion 4.1 Virtual Medicine Providing quality health care to rural communities often presents challenges, as medical subspecialties are usually centralized in urban metropolitan health care centers. In our prospective study, we had found that 50% of the study participants were from outside of Metro Vancouver with families travelling on average 595km to and from BCCH. This illustrates how a Canadian metropolitan hospital provides health care services to such a vast area. To better serve these remote areas, the use of telemedicine or virtual medicine have been employed to deliver timely access to safe and reliable sub-specialty care (44, 49). Over the past few decades, the use of telemedicine, or virtual health has become more widespread as advances in technology have allowed for greater connectivity (50). Health care providers are able provide detailed patient examination through high-definition video calls and even perform surgery using remotely controlled advanced robotics (51, 52). The COVID-19 global pandemic has since necessitated the need for virtual medicine as many hospitals have implemented policies to limit the spread of the virus. By moving consultations to a remote setting, quality care can continue to be delivered in a timely manner while minimizing the risk of exposure to the COVID-19 virus (53). As access to cellular devices has become near ubiquitous, virtual medicine has become even more accessible to the general population. Results of our study looking at prospectively remotely screening for surgically actionable craniosynostosis through photos has shown good validity compared to the gold-standard of in-clinic visits. A diagnostic tool of this design and accuracy can easily be integrated into the standard of care as most patient families would have access to a handheld device with a camera. Having families send photos to be remotely screened could 22 prevent unnecessary travel, which is especially beneficial to patient families of lower socioeconomic status. 4.2 Diagnostic Performance 4.2.1 Group Diagnostic Performance Interrater reliability between all 7 raters was almost identical to that of the 5 craniofacial surgeons with a kappa of 0.76 and 0.77, respectively. This suggests the trained surgeons and non-surgical staff (i.e. pediatrician and occupational therapist) have similar conclusions on clinical signs when assessing the photos and were not due to chance. However, more research is necessary to confirm whether including more non-surgical staff would result in similar interrater reliability, as there was an uneven representation of surgical staff to non-surgical staff. As expected, the 3 neurosurgeons as a group had the highest kappa of 0.82 denoting almost perfect agreement. This is most likely due to their diagnostic methods being similar as all 3 neurosurgeons taking part in this study regularly consult each other on patient cases. Evaluation of standardized photos for craniosynostosis using a majority rule group consensus of all 7 raters demonstrated perfect sensitivity and high specificity. Additionally, both the craniofacial surgeon group diagnosis and the neurosurgeons group diagnosis also had perfect sensitivity as well as high specificity. Meaning, all our tested majority rule groups using this screening tool had no false negatives and very few false positives. It is important from a patient’s perspective that a screening tool for craniosynostosis referral has a high sensitivity. A false negative screen would mislead the patient’s family into thinking they had nothing to worry about, creating false reassurance. This could potentially delay the required surgical treatment the child actually needed for their craniosynostosis, which may result in fewer treatment options, larger surgery, worse cosmetic outcomes, and possibly more complications 23 (6). However, a false positive may not be as impactful. A referred patient being screened as a false positive would result in the patient being seen by the neurosurgeon, which would be the case if a pre-clinic visit screening program never existed. The neurosurgeon can then examine the child in person and reassure the family there actually was nothing surgically actionable and that the child didn’t have craniosynostosis (in the case of a false positive). A possible consequence of a false positive may result in the child having to undergo more diagnostic tests like a plain skull radiograph or a CT scan in order to definitively rule out craniosynostosis (26). The high sensitivity and specificity among the different groups suggests a committee made up of at least 3 or more trained raters would be able to accurately screen for surgically actionable craniosynostosis using caregiver provided photographs. Though a committee of 3 trained raters may sound laborious, based on the anecdotal retrospective review of the time each rater took to review the photos, this might in fact represent 10 minutes a month in time and could potentially save hours of travel time for families. These raters could be made up of trained non-surgical staff who regularly see abnormal head shape referrals like the Plagiocephaly Clinic at BCCH or the Craniofacial disorder clinic at the Oregon Health & Science University (20, 39). To ensure high sensitivity, the group of raters should also include one or more craniofacial surgeons. In an unblinded scenario, having more raters may potentially allow for higher accuracy, increased true positives and decreased false positives (54). If implemented, many patient referrals can be batched and screened together, which could save time for patient families that did not have anything clinically significant and possibly decrease wait times for neurosurgery. 4.2.2 Individual Diagnostic Performance Although performance of individual raters was comparable to the group performance, there were raters who had false negatives when screening for craniosynostosis. Those that do not have 24 surgical training (or who do not see the same volume of surgical referrals) did not perform as well, resulting in lower sensitivity and specificity. This emphasizes the importance of having multiple raters, especially those that have surgical training to form a more accurate consensus as shown in our results. Kurvers et al. demonstrated combining independent decisions of raters using a majority rule increased both sensitivity and specificity, resulting in grouped raters consistently outperforming single raters (55). When looking at the average self-reported confidence levels of the screened diagnosis, we had found there was no significant differences between true positives, true negatives, false positives, and false negatives – self-reported confidence levels did not seem add value to the diagnostic validity. 4.3 Research Implementation Implementing a prospective screening process for abnormal head shape referrals in a hospital would help identify those that do not need any intervention and possibly prevent unnecessary travel for patients and their families, which can especially benefit families of lower socioeconomic status. Primary care physicians or parents can send standardized photos of infants suspected of having craniosynostosis to a screening committee for review to see if a consult is required. This would not only save patient’s time and money, but also avoid any stress or anxiety from attending a surgical consultation (56, 57). This reduction in patient referral volume would result in reduced wait times for a neurosurgical appointment for craniofacial disorders as well as other neurosurgical conditions. Screening patients remotely would also prove to be especially helpful during the COVID-19 pandemic since travel restrictions are implemented and many hospitals have limited in-person visits (53). This would allow patient families to safely confirm whether a neurosurgical consultation is required without having to put themselves at risk. 25 Chapter 5: Conclusion 5.1 Alternative Screening Method This prospective study demonstrates craniofacial practitioners can accurately screen for surgically actionable craniosynostosis by evaluating standardized photos taken by the patient’s caregiver. There was substantial agreement among all 7 raters as a group when evaluating surgically actionable craniosynostosis using patient generated photos, meaning their consensus was not due to chance. Similar results were seen when looking at interrater reliability of just the craniofacial surgeons as a group and only the neurosurgeons as a group. Individually trained raters appeared to perform nearly as well as the group consensus, with group diagnostic performance demonstrating perfect sensitivity and specificity when screening for surgically actionable craniosynostosis. Since the photos were provided by the patient families, results provide real-world evidence that a photographic pre-screening tool may prove to be useful, and can help discriminate between craniosynostosis and positional plagiocephaly. Families, especially those living in remote communities would benefit the most, as a screening tool could help prevent unnecessary travel. Implementation of this prospective screening tool could optimize resource utilization and medical management by only seeing patients that require medical intervention. 5.2 Strengths and Limitations The main strength of this study is the ease of implementation and the low-cost nature of the screening tool. Additionally, the screening method is proven to be robust enough to account for photo quality variation as the photos were provided by the caregiver(s). Furthermore, this real world method of utilizing patient family provided photos for screening surgically actionable craniosynostosis is novel and has not been published in the literature. 26 One of the main limitations is that this was a single center study, which may limit the study’s results from being applied to other institutions. It is possible that the referral patient population, hospital protocol, and/or staff training may be unique to BCCH. Another study limitation was the enrollment of families that did not speak English. Follow up reminders with non-English speaking families proved to be a logistical challenge, even with hospital provided translators. Other study limitations could be associated with the socioeconomic and technical challenges when technology is involved. As this study involves the use of a handheld device with a camera, there is the possibility that a referred patient family may not have access to a device capable of taking photos. Furthermore, families of lower socioeconomic background may not be facile in taking pictures, reducing the accuracy of screening patients. Patient families may also lack the technological literacy to send the photos to the research staff. One limitation associated with the study population was the lack of multisuture craniosynostosis patients. Without patients with multisuture craniosynostosis, we are unable to conclude or validate that the screening tool is effective in diagnosing this cohort. It is possible that one of the patient families who had declined participation could have had multisuture craniosynotosis – further enrollment may potentially resolve this limitation. Although the sample size calculations mentioned in the methods indicated the amount of patients recruited was sufficient for a statistical analysis, further enrollment may be needed in order to confirm the confidence interval of false negatives, and determine if the study outcome is a true finding. Lastly, there is the limitation of not knowing the true sensitivity of the gold standard in-clinic visit, as this method has never really been studied. This brings up the question of how high does the sensitivity need to be for a novel diagnostic screening tool, especially when the true sensitivity of the gold standard is largely unknown. It may be possible to address this limitation 27 if every child that is seen in-clinic has a CT scan, but that would increase patient risk by subjecting them to radiation. 5.3 Future Research A possible future study could utilize the pictures gathered from this study with the parents’ consent, as a teaching or assessment tool for neurosurgical residents. Before a resident starts their pediatric neurosurgery residency, they could screen half of the patient photos. Residents would complete their rotation, then are assessed again with the remaining half of the photos to measure improvement. Although there has been a study on machine learning for remotely screening craniosynostosis that has been recently published, their study utilized practitioner obtained pictures from their clinic (42). If enough patient family provided photos were collected, a similar machine learning software could be applied to see if an algorithm is able to identify craniosynostosis at the same level of accuracy as craniofacial practitioners. Training the machine learning algorithm would provide a more realistic scenario. Hundreds of patient photos would need to be obtained to properly train the learning algorithm, making a multi-centre approach ideal. If this software is validated to be as accurate as craniofacial practitioners, it could be developed into a phone or computer application for the use of primary care physicians. 28 Bibliography 1. Maugans TA. The misshapen head. Pediatrics. 2002;110(1 Pt 1):166-7. 2. Bialocerkowski AE, Vladusic SL, Wei Ng C. 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Journal of pediatric surgery. 2020;55(4):590-6. 32 Appendix: Craniofacial Screening Questionnaire Craniofacial Screening Tool Questionnaire - Screening Study Subject ID ____________ Screening Phase Role: Date Screened: _______________ [ ] Neurosurgeon (DD/MMM/YYYY) [ ] Occupational Therapist [ ] Pediatrician [ ] Plastic Surgeon Diagnosis The child most likely has the following: [ ] Positional Plagiocephaly [ ] Craniosynostosis [ ] Sagittal [ ] Coronal [ ] Lambdoid [ ] Metopic [ ] Multisuture [ ] Nothing clinically significant [ ] Cannot determine diagnosis [ ] Other, please specify: ____________________ Do you routinely obtain radiographic imaging? [ ] Yes [ ] No Based on the photos, is radiographic imaging required to diagnose the patient? [ ] Yes [ ] No Based on the photos, this patient… [ ] Needs to be seen in the plagiocephaly clinic [ ] Needs to be seen in a plastic surgery /neurosurgery clinic [ ] Does not need to be seen in a clinic How confident are you with the diagnosis? 1 2 3 4 5 6 7 8 9 10 (Not Confident) (Extremely Confident) Recommendations? ____________________________________________________________________
Thesis/Dissertation
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Experimental Medicine
Vancouver : University of British Columbia Library
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Graduate
Singhal, Ash
McDonald, Patrick
Determining the accuracy of screening for surgically actionable craniosynostosis through the assessment of caregiver provided photographs
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