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Texting and connecting in patients with dysautonomia of adolescence : a novel approach between patients… Galvin, Claire Rebecca 2020

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Texting and Connecting in Patients with Dysautonomia of Adolescence: A Novel Approach to Communication Between Patients and their Health Care Providers  by Claire Rebecca Galvin BSc (Honours), The University of Toronto, 2017  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) August 2020 © Claire Rebecca Galvin, 2020     ii The following individuals certify that they have read and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis/dissertation entitled:  Texting and Connecting in Patients with Dysautonomia of Adolescence: A Novel Approach to Communication Between Patients and their Health Care Providers  submitted by Claire Rebecca Galvin in partial fulfillment of the requirements for the degree of Master of Science in Experimental Medicine  Examining Committee: Dr. Kathryn R. Armstrong, Department of Pediatrics, The University of British Columbia Supervisor  Dr. Shubhayan Sanatani, Department of Pediatrics, The University of British Columbia Supervisor  Dr. James E. Potts, Department of Pediatrics, The University of British Columbia Supervisory Committee Member   Dr. Penny L. Sneddon, Department of Pediatrics, The University of British Columbia Supervisory Committee Member   Dr. Kristin M. Houghton, Department of Pediatrics, The University of British Columbia     External Examiner   iii Abstract Rationale: Clinical digital messaging (CDM) (text messaging) improves communication and engagement between adolescent patients and their health care providers (HCP). Dysautonomia of Adolescence (DAOA) is a condition which results in transient dysfunction of the autonomic nervous system (ANS). Many adolescents who are affected withdraw from school, sport, recreational activities; experience social isolation; and have significant mental health challenges. Quality of life (QoL) is severely affected, symptoms are difficult to predict and control. Ongoing support by HCP is needed to support management of symptoms. We sought to implement CDM to support DAOA patients and evaluate patient engagement, satisfaction, QoL and symptom burden.  Methods: A single-centre, 12-month intervention study was performed. CDM was supported by WelTel Inc. Participants received an automated weekly check-in text message asking “How are you?”. Responses were triaged by HCP. QoL and symptom data were collected at three 6-month intervals: T0 baseline, T1 CDM enrollment and T2 post-CDM intervention. Non-parametric Friedman tests were used to determine differences over time. Participant engagement with the CDM platform was assessed through response rate and number of care conversations (>2 text messages between participant and HCP). Participant satisfaction was assessed using surveys administered at T1 and T2.  Frequency counts (%) were performed for categorical variables and a univariate analysis performed on continuous variables. Tests were two-sided and a p<0.05 was considered statistically significant.    iv Results: There was an 80% recruitment rate. Twenty-six participants completed the study. Median (IQR) age of participants was 16.8 (15.7-17.4). Duration of CDM intervention was 33 weeks (26.8-37.3). A total of 896 automated weekly check-in messages were sent, resulting in 206 care conversations. Ninety-five percent of participants found CDM useful. There was no change in total QoL, number of frequent or occasional symptoms (p=0.260, 0.260 and 0.790, respectively).   Conclusion: Twenty-three percent of all messages received from DAOA patients required care conversations. Participants were receptive to and satisfied with the CDM platform.  Total QoL and symptom burden remained unchanged over the study period. CDM facilitated ongoing management of care in participants. Use of CDM technology may teach adolescents to advocate for themselves and become active participants in their own healthcare.   v Lay Summary Teenagers use text messages to connect with their friends and family routinely. Health care providers (HCP) can use texting to communicate better with their teenage patients. Dysautonomia of Adolescence (DAOA) is a condition affecting teens that can cause a variety of symptoms. Teens with DAOA have symptoms that include chest and stomach pain, dizziness and many others. Teens are unable to go to school, play sports, or spend time with friends. We know teens with DAOA need a lot of support from HCP to help manage their condition and wanted to know whether a weekly text message would help them. We found by texting our teenage patients weekly, we increased feelings of connection to HCP, helped them manage symptoms and produced feelings of support. We found that almost one-quarter of messages received from teenage patients needed support from HCP which was able to be provided by text message.        vi Preface Ms. Claire Galvin was responsible for literature review, study design, ethical approval, participant consent/assent, data collection and analysis, result interpretation, writing and revising of manuscripts. As primary supervisor, Dr. Kathryn Armstrong oversaw and provided guidance for all aspects of work related to this master’s thesis and was responsible for concept formation. Dr. Shubhayan Sanatani, co-supervisor gave guidance, assisted with study design, result interpretation and revision of the manuscripts for all chapters of this work. Dr. James Potts, committee member and Ms. Astrid De Souza gave guidance and assisted with study design, data analysis, result interpretation and revising of the manuscripts for all chapters of this work. Dr. Penny Sneddon, committee member, gave guidance, assisted with study design, result interpretation and revision of the manuscripts for all chapters of this work. Mr. Hajir Adl Golchin assisted with data collection, data analysis and co-writing of a manuscript comprising Chapter 3 of this work.  This thesis work took place at BC Children’s Hospital (BCCH), Vancouver, British Columbia, Canada. All data has been collected from patients presenting at the Dysautonomia Clinic in the Children’s Heart Centre at BCCH. Chapters 3 and 4 were undertaken as quality assurance/quality improvement projects. Ethical approval for Chapters 2 and 5 was received from the Children’s and Women’s Research Ethics Board at the University of British Columbia (certificate H14-00627 and H18-02193). Chapters 2, 3, 4 and 5 are currently being written as manuscripts for submission for publication.       vii Table of Contents  Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi List of Tables ..................................................................................................................................x List of Figures .............................................................................................................................. xii List of Abbreviations ................................................................................................................. xiii Acknowledgements .................................................................................................................... xiv Dedication .....................................................................................................................................xv Chapter 1: Introduction ........................................................................................................... 1 1.1 The Autonomic Nervous System ............................................................................ 1 1.2 Dysautonomia ......................................................................................................... 2 1.3 Dysautonomia of Adolescence ............................................................................... 3 1.4 Diagnosis of DAOA ................................................................................................ 4 1.5 Treatment ................................................................................................................ 5 1.6 Difficulties in Treatment ......................................................................................... 9 1.7 Mobile Communication ........................................................................................ 10 1.8 Summary ............................................................................................................... 11 1.9 Research Questions ............................................................................................... 12 Chapter 2: Follow-up to exercise and the multidisciplinary holistic approach to adolescent dysautonomia ........................................................................................................ 14 2.1 Introduction ........................................................................................................... 14 2.2 Methods................................................................................................................. 15  viii 2.3 Results ................................................................................................................... 16 2.4 Discussion, Limitations and Conclusion............................................................... 20 Chapter 3: Characterizing adolescent dysautonomia patients using a multi-disciplinary clinical approach ................................................................................................ 22 3.1 Introduction ........................................................................................................... 22 3.2 Methods................................................................................................................. 24 3.3 Results ................................................................................................................... 25 3.4 Discussion ............................................................................................................. 35 3.5 Limitations ............................................................................................................ 38 3.6 Conclusion ............................................................................................................ 38 Chapter 4: Mental Health Challenges in Adolescents with Dysautonomia ....................... 39 4.1 Introduction ........................................................................................................... 39 4.2 Methods................................................................................................................. 40 4.3 Results ................................................................................................................... 41 4.4 Discussion ............................................................................................................. 42 4.5 Limitations ............................................................................................................ 44 4.6 Conclusion ............................................................................................................ 45 Chapter 5: Texting and Connecting in Patients with Dysautonomia of Adolescence: A Novel Approach to Communication Between Patients and their Health Care Providers .................................................................................................................................. 46 5.1 Introduction ........................................................................................................... 46 5.2 Methods................................................................................................................. 47 5.3 Results ................................................................................................................... 57  ix 5.4 Discussion ............................................................................................................. 75 5.5 Limitations ............................................................................................................ 78 5.6 Conclusion ............................................................................................................ 79 Chapter 6: Conclusions .......................................................................................................... 81 6.1 Summary of Chapters ........................................................................................... 81 6.2 Overall Summary .................................................................................................. 84 6.3 Future Directions .................................................................................................. 84 6.4 Clinical Significance ............................................................................................. 85 References .....................................................................................................................................87 Appendices ....................................................................................................................................97   x List of Tables Table 1.1. Examples of commonly experienced DAOA symptoms………………….4 Table 2.1 Participant symptom burden……………………..……………………….17 Table 3.1 Patient demographics………………………………..……………………27 Table 3.2 Source of referrals to Dysautonomia Clinic…………………..….……….27 Table 3.3 Medication usage by DAOA patients…………………………………….31 Table 3.4 Initial self-report and parent-proxy PedsQLTM…………….……………..32 Table 3.5 Initial and follow-up self-report PedsQLTM……………………..………..32 Table 3.6 Initial and follow-up parent proxy PedsQLTM…………………..………..33 Table 3.7 Pearson correlation coefficients between self-report and parent-proxy….33 Table 3.8 Patient exercise stress test……………………………………….………..35 Table 4.1 Mental health challenges of the DAOA cohort…..…………….….……..42 Table 5.1 Summary of data collection over study period…………………….……..55 Table 5.2 Participant responses to weekly CDM check-in……………………...…..60 Table 5.3 Median (IQR) symptoms reported by participants ……………..…….….65  Table 5.4 Neurologic symptoms reported …………………………………..……....65 Table 5.5 Cardiac symptoms reported…………………………………….………...66 Table 5.6 Gastrointestinal symptoms reported…………………………………..…..66 Table 5.7 Skin symptoms reported……………………..………..…………………..67 Table 5.8 Joint/Muscle symptoms reported……………………………………..…..67 Table 5.9 Energy/Activity symptoms reported…………………….………………..68 Table 5.10 Comparison between participants with and without a mental health challenge self-report PedsQLTM…………………...…………………………………71  xi Table 5.11 Comparison between participants with and without a mental health challenge parent-proxy PedsQLTM……………………………..…………………….73 Table 5.12 Pearson correlation coefficient between self-report and  parent-proxy report…………………………………………………………………..74  xii List of Figures Figure 2.1 Self-report and parent-proxy PedsQLTM across physical, psychosocial and total domains…………………………………………………………………………19 Figure 3.1 Dysautonomia Clinic referrals …………………………………………..26 Figure 3.2 Types of school DAOA patients attend…………...……………………..29 Figure 5.1 Initial views on CDM influence ……………………..………………….59 Figure 5.2 Future CDM check-in frequency………………………...………………61 Figure 5.3 Participant responses to CDM intervention………………...……………62 Figure 5.4 Most frequent symptom complaints by participants over the    study period………………………………………………………………………….64 Figure 5.5 Self-report PedsQLTM for physical, emotional, social, school, psychological and total function …………………………………...………………..70 Figure 5.6 Parent-proxy PedsQLTM for physical, emotional, social, school, psychological and total function………………………………..……………………71   xiii List of Abbreviations ANS  Autonomic Nervous System BC  British Columbia BCCH  British Columbia Children’s Hospital CDM  Clinical Digital Messaging DAOA  Dysautonomia of Adolescence  HCP  Health Care Provider HIV  Human Immunodeficiency Viruses IQR  Interquartile Range mHealth Mobile Health OI  Orthostatic Intolerance PedsQLTM Pediatric Quality of Life Inventory POTS  Postural Orthostatic Tachycardia Syndrome PSNS  Parasympathetic Nervous System QoL  Quality of Life  SNS  Sympathetic Nervous System   xiv Acknowledgements I would like to express my sincerest gratitude to my supervisor, Dr. Kathryn Armstrong for her guidance and support throughout my degree. I am incredibly thankful for the opportunity she has given me to work on this project. I am so grateful for her mentorship throughout my degree and have felt constantly supported by her every step of the way. I want to thank her for creating a learning environment in which I felt encouraged and valued. I would like to thank Dr. Shubhayan Sanatani for the opportunities he has given me throughout my degree, for his guidance, advice and feedback.  I would like to thank Dr. Jim Potts for his mentorship, advice and time. He has taught me many valuable skills as a researcher and was always willing to go above and beyond to help me accomplish my goals. I would like to thank Astrid De Souza for her endless support, encouragement and mentorship. She has taught me so much throughout my degree and I cannot thank her enough for all of her guidance, edits, advice and for always pushing me to succeed. I would like to thank Dr. Penny Sneddon for her feedback, encouragement and guidance. I appreciate the time she has spent with me and her willingness to teach.  I would like to thank the members of the Cardiology research team and fellow Master’s students for their support and friendship. Lastly, I would like to thank Dania Kallas for her never-ending encouragement, positivity and friendship.  xv Dedication This work is dedicated to my parents and my brother.   To my parents, thank-you for your unwavering support and unconditional love. I would not be where I am without you, your work ethic constantly inspires me to be better and I cannot thank-you enough for all that you have done for me.   To my brother Sean, thank-you for always being somebody I can look up to and depend on. I am so proud of all that you have accomplished, you motivate me to succeed. Thank-you for your endless support and for all the laughs along the way.  In addition, I would like to dedicate this work to the adolescents and families that participated in this research and made this thesis possible. Thank-you for your enthusiasm for research and willingness to share your experiences with me, I truly appreciate all that you have taught me.         1 Chapter 1: Introduction  1.1 The Autonomic Nervous System The autonomic nervous system (ANS) controls automatic functions of the body that lead to a stable internal environment and the maintenance of homeostasis. The ANS functions without explicit cognitive attention or voluntary control.1 The two main divisions of the ANS are the parasympathetic nervous system (PSNS) and the sympathetic nervous system (SNS). The PSNS is known as the “rest and digest” system, the role of which is to store and conserve energy.1 It is a cholinergic system, with its primary neurotransmitter being acetylcholine and it promotes basic resting functions of the human body such as the digestion and absorption of nutrients from food.2,3 The cranial-sacral neural outflow of the PSNS consists of oculomotor (cranial nerve III), facial (cranial nerve VII), glossopharyngeal (cranial nerve IX), vagus (cranial nerve X) nerves as well as S2, S3 and S4 sacral spinal nerves which arise from the spinal cord.2 Effector organs of this cranio-sacral outflow include, but are not limited to, the eyes, heart, blood vessels, lungs, stomach, liver, pancreas, bladder and skin.2 Examples of parasympathetic responses include a decrease in heart rate, pupil constriction and relaxation of stomach sphincters.1 In contrast, the SNS mediates the “fight or flight” response of the body and is responsible for the body’s reaction to stressful, harmful or painful stimuli. The SNS is an adrenergic system, with norepinephrine being its primary neurotransmitter.2,3 Activation of this system results in the increased flow of oxygenated and nutrient-rich blood to skeletal muscles.1 The thoracic-lumbar neural outflow of the SNS division consists of the first thoracic to the third lumbar spinal nerves.2 Effector organs of the thoracic-lumbar outflow include, but are not limited to, the eyes, heart, blood vessels, lungs, stomach,  2 intestines, bladder, skin, pancreas and liver.2 SNS responses include elevated heart rate, increased blood pressure, pupil dilation and constriction of arterioles of the skin.2  1.1.1 Collaboration of the ANS Divisions In order for the body to function properly, the parasympathetic and sympathetic systems must work collaboratively to maintain homeostasis. Both systems work together on an effector organ or tissue so that the body’s internal environment remains stable.   1.1.2 ANS Dysfunction  The parasympathetic system sets the metabolic threshold for the sympathetic response. For example, when a SNS response is needed, PSNS activity will decrease which not only increases the likelihood of a sympathetic response but also lowers the amount of the sympathetic response needed.3 In individuals with autonomic dysfunction this does not occur. The PSNS may set a higher metabolic threshold than what is needed, thus increasing the sympathetic response.3 ANS dysfunction can be extremely debilitating as it affects major organ systems in the body through the cranial-sacral outflow and the thoracic-lumbar outflow meaning that multiple organ systems may be affected simultaneously.2 An increased sympathetic response results in symptoms that are commonly seen in conditions such as dysautonomia.   1.2 Dysautonomia The exaggerated response of the ANS results in numerous symptoms which include dizziness, heart palpitations, “brain fog”, muscle/joint pain, gastrointestinal pain, nausea and  3 fatigue which can impact activities of daily living and reduce participation in regular physical activity. Multiple forms of dysautonomia exist, some of which are acquired throughout one’s lifetime while others are present from birth. The focus of this research will be on Dysautonomia of Adolescence (DAOA), a form that is acquired during the adolescent growth and development period.  1.3 Dysautonomia of Adolescence In adolescents there is a high prevalence of ANS dysfunction, estimated to occur in 1 in 3 individuals.4,5 DAOA is a broad term used by our institution to encompass this ANS dysfunction as well as other conditions such as chronic fatigue, orthostatic intolerance (OI), postural orthostatic tachycardia syndrome (POTS), syncope, pre-syncope, fibromyalgia and concussions, all of which have overlapping clinical features of autonomic dysfunction. It is common for adolescents to present with symptoms that encompass multiple conditions attributed to ANS dysfunction, as a result the diagnosis of DAOA is used. The exact mechanism of DAOA is unknown but is believed to be triggered by hormonal changes, illness, genetics, environment, social stressors and trauma (such as concussions) during the adolescent growth and development period.6 Although DAOA is transient, symptoms may be severe and last throughout the adolescent growth period. Typical symptoms experienced by adolescents can be found in Table 1.1. Symptoms often have debilitating effects on those living with this condition as symptoms may persist for years.     4 Table 1.1. Examples of commonly experienced DAOA symptoms. Symptom Categories  Common Examples Cardiac Fast heartbeat, slow heartbeat, low blood pressure, chest pain  Neurologic Headaches, dizziness, brain fog, poor concentration  Gastrointestinal Nausea, constipation, vomiting, intestinal pain  Skin Hot flashes, heat/cold intolerance, cold extremities  Joints/Muscle Feeling of weakness, pain/aches in joints, pain/aches in muscles Energy/Fatigue Fatigue, sleep disturbance, exercise intolerance  1.4 Diagnosis of DAOA Similar to overlapping conditions of chronic fatigue syndrome and fibromyalgia, there is no diagnostic laboratory test to confirm the diagnosis of DAOA.7-9 Our institution confirms diagnosis on the basis of (i) no underlying pathological disease to account for symptoms; (ii) symptoms affecting at least 2 or more organ systems; and (iii) significant interference with the activities of daily living including poor school attendance and withdrawal from sports participation.10 Diagnosis of this condition is difficult and typically occurs years after symptom onset due to the unfamiliarity with the condition, fear of missing more ominous conditions, and process of conducting multiple investigation for the ANS dysfunction.11  Previous literature reports that it takes a median of 2 years from symptom onset for an individual to be diagnosed with ANS dysfunction.11 Many patients undergo numerous and invasive investigations while they search for a diagnosis to explain their symptom complexes while receiving different diagnoses and medicinal treatments, only to find their condition  5 unimproved or worsened.12-14 Adolescents with dysautonomia and their families grow increasingly frustrated at the lack of understanding of their condition, with many individuals affected by autonomic dysfunction seeing multiple specialists before a diagnosis is made.15 Unfortunately, symptom duration without treatment has been shown to be associated with a decrease in symptom-free rate meaning that the longer adolescents did not receive treatment, the worse their prognosis became.16 With regard to symptom presentation for a DAOA diagnosis, symptoms are separated into 6 categories; neurologic, cardiac, gastrointestinal, skin, joints/muscles and energy/activity. The separation of symptoms into categories help to determine an adolescent’s overall symptom burden as well as the areas which adolescents rate the most troublesome. With regard to interference of daily living, not surprisingly, adolescents affected by DAOA report a low QoL. Many adolescents with DAOA do not attend school on a routine basis, they no longer participate in sports or exercise and they do not regularly engage socially with their peers. Adolescents are limited in the activities they can do and may not keep up with their same-age peers which may lead to a sense of isolation. 10,17,18  All of these factors, as well as the effect on activities of daily living, play a role the diagnosis of DAOA.   1.5 Treatment In alignment with best practices in the management of DAOA, a multidisciplinary team is essential for successful management of this condition.12,15 In our centre, the multidisplinary team is comprised of a pediatric cardiologist, exercise physiologist, nurse clinician, and clinical psychologist. Treatment for DAOA is mainly focused on lifestyle recommendations.  6 Since all organ systems are affected through the efferent pathways of the ANS, specific treatments targeting specific organs do not relieve symptoms.  Pharmacological treatments for conditions such as those with ANS dysfunction overlap and are difficult to prescribe to DAOA patients because of the variety of symptoms they experience. As mentioned earlier, DAOA encompasses many conditions associated with ANS dysfunction such that a treatment for one area of concern may not be suitable for another. This may cause a larger symptom burden than previously experienced.19 In previous literature there have been mixed findings on whether medications for symptom relief are helpful in conditions with ANS dysfunction such as DAOA.12,20 Reports vary in that although some patients benefit from the use of medications, there are other patients who do not benefit and experience side effects from the medications that exaggerate symptoms. For adolescents, the average number of medications that failed to provide symptom relief is reported to be 3.1.18 Therefore, a holistic approach to symptom management is essential. Specific recommendations include drinking 3-4L of fluid per day, increasing salt intake to ½ teaspoon per day, participating in lower-body strength training activity,10 and supporting the adolescent’s mental health.   1.5.1 Fluid and Salt An increase in fluid and salt intake for adolescents with dysautonomia is essential for symptom management. The population of DAOA is primarily young females, many with recent menarche. The rationale for this approach of increased fluid and salt is that the consumption of fluid and salt will increase blood plasma volume as volume dysregulation is  7 common among patients and may underlie some of the symptoms of DAOA such as dizziness and syncope.21-23 Previous research has suggested drinking between 1.5-3 litres of fluid per day as part of  any treatment recommendation.21,24,25 Improved fluid balance may increase venous return to the heart which helps mediate symptoms associated with postural changes and OI.12 The addition of salt into their diet resolves some of the symptoms experienced by patients with DAOA. Previous research has shown that the addition of salt is effective in reducing syncopal episodes in children with recurrent syncope and there were no reported adverse reactions to increased salt intake, unlike other pharmacological measures used to aid symptom management.26 Thus, one of the first strategies adolescents can adopt in treatment is to track their daily fluid and salt intake to ensure they are meeting these recommendations and mediation other symptoms such as exercise intolerance due to vasodilation, orthostatic intolerance and dizziness.   1.5.2 Exercise Exercise is a key element in the management of DAOA symptoms. Commonly, symptoms of DAOA occur after or during exercise which makes it difficult for adolescents to engage in regular physical activities.12 Although difficult for adolescents to participate in physical activity, previous studies have reported that long-term exercise training in patients with symptoms of DAOA resulted in increased blood volume, total hemoglobin mass, red blood cell volume and improvement in patient QoL after training.27 Particularly, strength training, even in the short-term, improved exercise performance in patients with POTS.28 In a study conducted by the DAOA research group at British Columbia Children’s Hospital (BCCH), they found a significant improvement in QoL of DAOA patients following an 8-week lower  8 body strength training program.10 Exercises included both isometric and isotonic movements such as squats, step-ups, planks and forward lunges.10 Adolescents reported a reduction in their symptoms following the 8-week program.10 Therefore, strength training may increase exercise tolerance and allow adolescents to engage in physical activities they were previously unable to as a result of high symptom burden.   1.5.3 Mental Health In order to provide better care for individuals affected by DAOA it is important to address their overall well-being as opposed to an isolated treatment of their physical symptoms. Psychological support for DAOA patients such as behaviour strategies and cognitive-behaviour therapy may be helpful in the management of symptoms.12 The consequences of symptoms on mental health is vast. Adolescents with chronic pain report emotional distress, anxiety, depression and disability.29 Those affected by symptoms of DAOA have been shown to have a lower subjective QoL, depressive symptoms and increased anxiety.30 In a meta-analysis conducted in 2010 of adolescents with chronic physical illness (including illnesses such as cancer, chronic fatigue syndrome, cystic fibrosis, sickle cell disease, among others) those with chronic fatigue syndrome ranked highest in depressive symptoms.31 It has been shown that patients with symptoms similar to DAOA experience low feelings of control, higher activity restrictions, low energy and are at high-risk for suicide as compared to the general population.32,33 It is important to understand that although transient, DAOA can severely impact an adolescent’s mental health. Thus, the support of adolescent’s mental health as they journey through their diagnosis is essential.    9 1.6 Difficulties in Treatment As noted above, DAOA treatment is mainly focused on lifestyle changes for the adolescent to aid in symptom management. Therefore, the adolescent patient must become an active participant in their own healthcare. Making lifestyle changes is challenging and it can be difficult for adolescents to follow the advice of their health care team, especially when they are so debilitated by their symptoms. Management of symptoms through a stable, consistent routine is necessary, but fluctuations in symptom severity or the development of new symptoms make it difficult to adhere to prescribed lifestyle changes. Furthermore, it may increase the difficulty of treatment adherence if the adolescent is experiencing a formidable mental health burden without support.   Previously, it has been noted that adolescents’ QoL increases after multidisciplinary treatment at a specialized pediatric Dysautonomia Clinic, yet they still function at a lower QoL than their healthy peers.10 This suggests that although the multidisciplinary approach of the Dysautonomia Clinic results in a modest improvement in QoL, more must be done to support these patients; new strategies must be implemented to positively impact QoL. The chronic daily nature of DAOA along with long wait times in between clinical appointments may be an area of improvement that will better support patients.  Ongoing support through increased communication from health care providers (HCP) may benefit these complex patients. An effective means of communication with the adolescent patient is needed. Typically, patient caregivers communicate with the nurse clinician by email or phone and there is little, if any, communication between adolescent patients and their HCP.    10 1.7 Mobile Communication The implementation of a communication tool that allows adolescent patients to access their HCP in-between clinical appointments may have a positive impact on QoL. Increased communication between adolescent patients and their HCP may lead to better management of DAOA and allow patients to seek out assistance should they need it, which may give them more ownership of their health. Anecdotally, DAOA patients report being high achievers/performers and now are unable to participate or no longer function at their previous levels. Ownership over their health may provide them with a sense of control previously lost due to their condition. Mobile health (mHealth) technology, specifically Clinical Digital Messaging (CDM) (text messaging) communication platforms, are an age-appropriate tool that promote two-way communication between the patient and their HCP and may be a valuable clinical resource for communicating with adolescents who send between 30-100 text messages per day.34,35 MHealth initiatives have previously been used for issues such as health monitoring and patient-HCP communication which have been shown to be effective in adolescents with chronic health issues. 36,37 CDM has tremendous potential as a method of health care engagement and has been shown to foster self-efficacy which is crucial for adolescent populations.35, 38,39 Furthermore, improvements in QoL have been reported after use of a CDM intervention.40 The use of a CDM platform in the care of DAOA patients will allow adolescents to access their HCP using an easy and accessible communication tool, one that the adolescent already uses and has access to. The use of CDM tools has had positive outcomes in behavioral interventions and may serve as a reminder for patients to adhere to treatment programs or interventions. 37,41    11 1.7.1 WelTel WelTel Incorporated (Vancouver, British Columbia, Canada) is a digital health messaging platform used to promote two-way interaction between patients and their HCPs. The basis of the digital platform is simple: patients receive a weekly text message that asks “How are you?”. Responses are then triaged to HCP who contact the patient if a problem is reported. Previous research has demonstrated that using WelTel technology to communicate with multi-drug resistant Human Immunodeficiency Viruses (HIV) patients in Kenya resulted in increased engagement, treatment adherence and improved health outcomes for HIV patients.42 In addition, patients reported that they felt supported in their healthcare.42 In British Columbia (BC) this digital health platform has been adopted by adult HIV clinics to improve patient engagement and medication adherence.43 Patients describe that using the platform made them feel less isolated, more supported and had feelings of  acknowledgement.43 This tool has been shown to be beneficial in connecting with patients and may be useful in adult populations with chronic health conditions. Currently, it is unknown how this innovative technology will impact DAOA patients.  1.8 Summary Based on the previous literature of mHealth technology and WelTel, the implementation of digital messaging for DAOA patients may close the gaps in support for this group leading to an improvement in the support of patients as well as in their QoL. We recognize that advances have to be made in the care of patients with DAOA as their QoL is below that reported for healthy, acutely ill, or chronically ill children.44 As a result, a CDM platform using WelTel will be used to facilitate communication between adolescents and their HCP.  12 Weekly text messages will serve to open a line of communication to the DAOA patient. Frequent communication directly with adolescents will allow for more personalized care and overall support.   Chapters 2-4 of this thesis will form the basis of our understanding of the DAOA condition in our patient cohort. In Chapter 2, we aim to determine the sustainability of QoL improvements following treatment in the Dysautonomia Clinic in a small subset of discharged patients. In Chapter 3, we retrospectively review clinical charts of patients in the Dysautonomia Clinic to gain insight into DAOA patient characteristics, as well as the multidisciplinary approach used in their care. In Chapter 4, we will review the mental health challenges that affect DAOA patients. With this background information in mind, we have developed three research questions in Chapter 5 to assess the feasibility and outcomes of using CDM to communicate with patients being followed in the Dysautonomia Clinic at BCCH.   1.9 Research Questions 1.    How feasible and acceptable is the use of a CDM platform (WelTel) to communicate with patients followed in the Dysautonomia Clinic? i. To determine whether the CDM platform messages were sent and received by participants ii. To determine participant enrollment iii. To determine participant satisfaction with the CDM platform.  iv. To determine the level of engagement of participants.   13 2.    Does the use of a CDM communication platform reduce symptom burden and improve QoL in patients with DAOA? i. To determine whether there is a reduction in the symptom burden (using the Symptom Burden Questionnaire) of study participants after 6 months of CDM intervention. ii. To determine whether there is a significant difference in PRE and POST QoL (using the PedsQLTM Questionnaire 44-46) in study participants after 6 months of CDM intervention.  3.     What is the scope of the mental health challenges in the study participants? i. To review the mental health challenges of DAOA participants  ii. To determine if mental health challenges have a significant impact on QoL scores among the participants  14 Chapter 2: Follow-up to exercise and the multidisciplinary holistic approach to adolescent dysautonomia  2.1 Introduction Dysautonomia describes an imbalance within the autonomic nervous system that commonly manifests in conditions such as orthostatic intolerance, vasovagal syncope and postural orthostatic tachycardia syndrome (POTS).47 Approximately one-third of adolescents experience autonomic dysfunction.4 Dysautonomia of Adolescence (DAOA) is a broad term used to describe a transient autonomic disorder that starts around the onset of puberty.  DAOA encompasses symptoms such as syncope, “brain fog”, palpitations, fatigue, gastrointestinal pain, musculoskeletal issues and nausea. The complexity of symptoms that arise from DAOA in conjunction with normal investigations makes diagnosis difficult, with many patients seeing multiple specialists before diagnosis.10 Patients with DAOA may be so debilitated by their symptoms that they are unable to attend school, withdraw from sports and recreational activities, leading to social isolation12 and a poor quality of life (QoL).10   Our institution confirms a DAOA diagnosis when adolescents experience a significant impairment in their QoL, with the presence of at least two symptoms in categories of cardiac, neurologic, musculoskeletal, gastrointestinal, or low energy/fatigue with no underlying pathological disease to account for their symptom complex. Patient management by a multidisciplinary team includes advice about increasing fluid intake to between 3-4 L per day with the addition of ½ teaspoon of salt to the diet. An 8-week lower body exercise program is recommended to all patients in order to introduce exercise into their routines as many withdraw from exercise after symptom onset. The exercise program has been described by  15 Armstrong et al.10 The multidisciplinary team includes a pediatric cardiologist, clinical exercise physiologist, clinical psychologist and nurse clinician.   Previously, we evaluated the QoL in a patient cohort before and after the unsupervised at-home strength training program and showed a significant improvement in QoL.10 However, there is a lack of research looking at the sustainability of the associated changes in QoL of DAOA patients. Therefore, we sought to determine the QoL of DAOA patients after a minimum of two years following participation in the strength training and multidisciplinary clinical program.   2.2 Methods All participants (n=17) in the original 8-week lower body strength training program were eligible for inclusion. We contacted all participants via mail and phone call. Participants were asked to complete the Pediatric Quality of Life Inventory (PedsQLTM) questionnaire and its parent-proxy report.44 Baseline QoL scores completed prior to the 8-week program (T0) and scores obtained immediately after completion of the program (T1) were compared to present QoL scores (T2). This study was approved by the University of British Columbia Children’s and Women’s Health Centre’s Research Ethics Board (certificate H14-00627).  Participant data from our cohort’s initial 8-week exercise program study was used for baseline (T0) and post 8-week exercise program (T1) PedsQLTM scores. Medians and interquartile ranges are reported. Non-parametric Friedman tests were performed to determine differences at the three time points (T0, T1, T2). If significance was found, post-hoc  16 Wilcoxon Signed-Rank tests were used to compare differences between paired time points. A Mann-Whitney U test was performed to determine pairwise differences between self-report and parent-proxy PedsQLTM scores. Pearson correlation coefficients were also performed to determine association between self-report and parent-proxy PedsQLTM scores. All tests were two-sided. A p<0.05 was used to determine statistical significance. Statistical analyses were performed using IBM SPSS Statistical Software (IBM Corporation, Armonk, NY).  2.3 Results Seven of the original 17 participants completed both the PedsQLTM and parent-proxy report. All respondents were female with a median age of 19.0 (18.0-21.0) years. Table 2.1 shows the participants’ symptom burden at initial evaluation/after the 8-week training program (T0/T1) and at least two years after participation (T2). The median number of symptoms experienced by participants at T0/T1 was 4 and at T2 participants experienced a median of 5 symptoms spanning throughout different organ systems.            17 Table 2.1. Participants’ most frequent and severe symptoms.    The PedsQLTM questionnaire assesses QoL across 3 different domains (Total, Physical and Psychosocial) and were compared across the 3 time points (T0, T1, T2). T2 scores were collected a median of 3.3 years (2.5-3.9) after completion of the 8-week strength training program (T1). QoL in these participants remained stable, although did show an upward trend over the 3 time points (T0, T1, T2) across all domains as shown in Figure 2.1A: Total (p=0.200), Physical (p=0.180) and Psychosocial (p=0.223). Similarly, parents also reported that their child’s QoL remained stable over time in the Total (p=0.115) and Physical (p=0.163) domains, but reported a significant improvement in the Psychosocial domain (p=0.028) post-hoc and determined the difference to lie between T0 and T1. Figure 2.1A and B show participant and parent QoL scores in each domain over the study period. There was  18 no significant difference between participant and parent scores across all time points in all domains (Figure 2.2).                       19                           Figure 2.1. Box plot A shows participant self-report QoL scores across domains. Box plot B shows parent proxy QoL scores across domains, p=0.028 between T0 and T1 in the Psychosocial domain.   20 2.4 Discussion, Limitations and Conclusion This report shows that for our participants QoL remains stable over time. Despite small improvement in median QoL score in all domains for our participants, DAOA patients have a QoL remain below the average for healthy, chronically ill or acutely ill children.44 Despite the premise that the symptoms of DAOA resolve as patients finish their pubertal growth spurt, many patients report that their symptom burden does not change with the removal of some symptoms and the addition of others, but they are able to cope with their symptoms more effectively over time with less functional impairment. These changes are something we commonly see in practice and may be a contributor to QoL scores as patients continually have to learn to manage the development of new symptoms which may impact them in a negative way.   Our study was limited by its small sample size. All eligible participants were mailed questionnaires and contacted via phone call. All participants agreed to be part of the study but ten of the original study participants did not return questionnaires. We acknowledge this is an inherent problem with longitudinal studies as we cannot comment on the health status of non-responders which may be different from the study participants. Unfortunately, we cannot make any references to QoL in the greater DAOA population given our small sample size.   Our report illustrates that QoL remains low in this subset of DAOA patients.  This work highlights the need for a holistic multidisciplinary team approach to the management of DAOA as shown by participants overall symptom burden. Finding new ways to support our  21 patients including more support for the patient’s mental health may be needed to address their low QoL. Ongoing work to support these adolescents as they transition from a pediatric to an adult health care setting is vital to aid these patients in become functioning members of society.    22 Chapter 3: Characterizing adolescent dysautonomia patients using a multi-disciplinary clinical approach  3.1 Introduction  Approximately one-third of children will experience a transient imbalance or dysregulation of their Autonomic Nervous System (ANS) leading to symptoms such as syncope, presyncope and palpations.4 Persistent dysregulation of the ANS during pubertal years is termed dysautonomia of adolescence (DAOA). DAOA is a broad term used to encompass ANS dysfunction as well as other conditions such as chronic fatigue, orthostatic intolerance, postural orthostatic tachycardia syndrome (POTS) and fibromyalgia, all of which have overlapping clinical features of autonomic dysfunction. Currently, the characteristics of the DAOA population are unknown.   The etiology of DAOA is unknown but is believed to be triggered by hormonal changes, illness, stress and trauma during the adolescent growth and development period. Typical symptoms include syncope, pre-syncope, palpitations, muscle/joint pain, fatigue, gastrointestinal pain and nausea. Although, transient symptoms may be severe and last throughout adolescent growth period. Diagnosis is difficult, many patients undergo extensive investigations, receive multiple diagnoses and treatments, only to find their condition unimproved.12   The effect of DAOA has widespread consequences affecting daily activities such that many withdraw from school, sports, recreational activities and experience a loss of social interaction with their peers.12 The withdrawal from regular activities poses significant  23 interference on adolescent quality of life (QoL).10,17,18 Patients with DAOA have reported lower subjective QoL, depressive symptoms and increased anxiety.30 Furthermore, adolescents that experience symptoms associated with DAOA report emotional distress, anxiety, depression and disability (i.e. the perceived difficulty in performing regular activities such as school, home and social activities).29   Treatment for DAOA is focused around a multidisciplinary approach, specifically a holistic approach to symptom management and the inclusion of well-being supports.10,12,15 A key element in symptom management is the addition of exercise into treatment recommendations along with lifestyle changes. Previous research has reported that long-term exercise training in patients with DAOA symptoms have resulted in increased blood volume and improvement in QoL.27 Additionally, lifestyle changes such as an increase in fluid and salt intake aim to minimize symptoms such as recurrent dizziness and syncope in DAOA patients.12,21   A multidisciplinary pediatric Dysautonomia Clinic was established at British Columbia Children’s Hospital (BCCH) in January 2017 to provide treatment and support for this patient population. Health care providers on the multidisciplinary team include a pediatric cardiologist, nurse clinician, clinical exercise physiologist and a clinical psychologist.  Specific recommendations from the Clinic include the addition of a ½ teaspoon of salt into the diet which can be added throughout the adolescents’ daily meals, as well as the inclusion of 3-4 liters of fluid per day. Adolescents are recommended to participate in a lower body strength training program composed of three sets of squats, squat holds, forward lunges,  24 plank, gluteal bridge and step ups, five days per week. All patients are offered an opportunity to speak with a clinical psychologist.   The aim of this study was to conduct a two-year retrospective review and describe the clinical presentation, symptom burden, QoL and exercise capacity of the cohort of adolescent patients attending the multidisciplinary Dysautonomia Clinic.  3.2 Methods This was a retrospective chart review of patients referred to the BCCH Dysautonomia Clinic who had a clinical appointment between January 1, 2017 and December 31, 2018. Inclusion criteria were those who were referred and had a clinical appointment during this period who met the criteria for a diagnosis of DAOA: (i) no other medical condition to account for symptoms; (ii) symptoms affecting at least two or more organ systems; and (iii) significant interference with the activities of daily living including poor school attendance and withdrawal from sports participation.10 Exclusion criteria were patients who did not meet the criteria for a DAOA diagnosis. Healthy institutional cohorts were used for comparison.48    Demographics and clinical characteristics were extracted from clinical charts and entered into a Research Electronic Data Capture (REDCap) electronic database hosted at the BCCH Research Institute.49,50 REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing: (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to  25 common statistical packages; and (4) procedures for data integration and interoperability with external sources. Demographic data included age, sex, weight, height, body mass index (BMI), Body surface area (BSA), school attendance and exercise habits. Clinical data including medical history, symptom burden, QoL (using the Pediatric Quality of Life Inventory, PedsQLTM)44 and exercise stress test results were recorded. Patients were assessed at their first clinical visit and subsequent follow-up visits at 6-month intervals. The exercise stress test was performed according to an institutional protocol.48  Frequency tables were generated for all categorical variables with the number (%) reported. A univariate analysis was used for all continuous variables with medians and interquartile ranges (IQRs) reported.  PedsQLTM scores between initial visit and first follow-up visit of our DAOA patients were compared. A Mann-Whitney U test was performed to determine group differences. All tests were two-sided and a p<0.05 was considered statistically significant. All statistical analyses were performed using SPSS version 22.0 software (IBM Corporation, Armonk, NY, USA).  3.3 Results  3.3.1 Demographics There were 118 referrals to the Dysautonomia Clinic between January 1, 2017 and December 31, 2018. During this time period there were a total of 159 clinical visits, 139 exercise tests and exercise prescription consultations and 59 patients were referred to the Dysautonomia Clinical psychologist on the team, based on chart review and assessment by the multidisciplinary team. A total of 93/118 referrals (79%) met DAOA diagnostic criteria and  26 of those diagnosed patients, 43/93 (46%) had follow-up appointments during the study period. Figure 3.1 shows the breakdown of referrals to the Clinic. Patients were discharged once there was an improvement in their overall functioning reported by the adolescent and their caregivers and/or they reached age 18 years which is the age to transition from pediatric to adult care. Patient demographics are summarized in Table 3.1. The source of patient referrals to the Dysautonomia Clinic is presented in Table 3.2.   Figure 3.1. Flowchart illustrating referrals to the Dysautonomia Clinic. *Thirteen patients were referred to the Clinic who may have previously met diagnostic criteria but did not require DAOA services as symptoms subsided before appointment.         Referrals(n=118)Did not meet diagnostic criteria(n=6)Met diagnostic crtieria (n=93)Current patients(n=56)Discharged (n=37)Did not require DAOA services*(n=13)No show at initial appointment(n=6) 27 Table 3.1. Patient demographics. The number (%) or median (IQR) are reported. Demographics N = 93 Sex (female) 60 (65%) Age (years) 15.7 (14.2-16.7) Height (cm) 168.0 (159-175) Weight (kg) 58.4 (51.7-65.9) BSA (m2) 1.65 (1.53-1.80) BMI (kg/m2) 20.3 (18.2-22.7) Time to diagnoses (months) 24 (12-48) cm=centimeters; kg=kilograms; m=meters  Table 3.2. Source of patient referrals to the Dysautonomia Clinic.  Referring Service N = 93 General Pediatrics 49 (53%) Neurology 10 (11%) Family Medicine 10 (11%) Biochemical Diseases 7 (8%) Rheumatology 5 (5%) Endocrinology 4 (4%) Cardiology 4 (4%) Gastroenterology 3 (3%) Urology 1 (1%)  28  3.3.2 School Activity  The types of school attended by the cohort of DAOA patients are found in Figure 3.2. For DAOA patients who did attend a regular stream school, 50% report missing some school days, including 19% who report missing a total of 1-2 months of school, 6% who report missing between 3-6 months and 7% who report missing more than 6 months of school since symptom onset.         29  Figure 3.2. Flowchart illustrating the types of schooling reported by the cohort of DAOA patients.  Total Patients(n=93)Regular Stream School(n=72)Missing School 1-3 Days/Week(n=26)Missing School 4-5 Days/Week(n=10)Home School(n=9)Online(n=5)Alternative (n=3)Missing School 4-5 Days/Week(n=1)Mixture (Regular and Online) (n=1)Does not Attend School (n=1)Not Reported(n=2) 30 3.3.3 Symptom Burden Of the 93 DAOA patients studied, 95% had cardiac symptoms, 94% had neurological symptoms, 82% had gastrointestinal symptoms, 71% had fatigue, 65% had skin issues and 39% had joint/muscle complaints. Time to diagnosis was a median of 2.0 years (1.0-4.0). The two most common aggravating factors were physical activity (46%) and position change (34%), followed by heat (22%), stress/anxiety (20%), prolonged sitting/standing (18%), eating (8%) and light/noise (7%). Concussion or infection was self-reported as the reason for symptom onset in a total of 33% of patients. Incidentally, a diagnosis of Ehlers-Danlos Syndrome was reported in 1 patient.   At the initial visit, 94% of the patients did not meet the fluid intake recommendations of 3-4L daily and 91% of the patients did not meet the salt intake recommendations of ½ teaspoon daily. Fifty-six percent reported trying different medications for symptom relief without any improvements. The most common medications used by the DAOA patients are summarized in Table 3.3.                  31 Table 3.3. Medications and supplements commonly used by the cohort of DAOA patients. General Medication Classification Example of Medication Number of Adolescents Anti-Nausea & Vomiting 5-HT3 antagonist, PPI, antihistamine 26 (28%) Anti-Constipation PEG, Bisacodyl, Prucalopride 7 (8%) Anti-Diarrhea  Imodium, Probiotics 5 (5%) Anti-Hypertension  Beta-blockers, CCBs, Antiadrenergic agents 5 (5%) Pain relief  NSAIDs, Gabapentin, Pregabalin 16 (17%) Anti-Headache Triptans 6 (6%) Sleep Medication Melatonin  11 (12%) Antidepressant/Anxiety  SSRI, TCA, Benzodiazepine 24 (26%) Antipsychotic Atypical Antipsychotics 4 (4%) Attention deficient hyperactivity disorder Medication Methylphenidate, Lisdexamfetamine, Dextroamphetamine 10 (11%) Multivitamin/ Supplements Vitamins, Iron, Omega, Magnesium, Zinc, Coenzyme Q10, Folic Acid 26 (28%) 5-HT3=5-hydroxytryptamine; CCBs=Calcium channel blockers; NSAIDs=Nonsteroidal anti-inflammatory agents; PEG=Polyethylene glycol; PPI=Proton-Pump Inhibitors; SSRI=Selective serotonin reuptake inhibitors; TCA=Tricyclic antidepressants  3.3.4 Quality of Life Seventy-eight of 93 patients (84%) completed the PedsQLTM questionnaire at their initial clinical visit and 74/93 parents/guardians (80%) completed the parent-proxy PedsQLTM.  32 Median and IQR domain scores for Physical, Psychosocial and Total QoL for initial visit are found in Table 3.4.   Table 3.4. Initial Dysautonomia Clinic visits PedsQLTM scores.  PedsQLTM Domain QoL Initial Patient Scores (n=78) QoL Initial Parent-Proxy Scores (n=74) Physical 43.8 (28.1-62.5)  37.5 (20.3-60.9)  Psychosocial  58.3 (47.9-66.7)  53.3 (43.3-61.7)  Total 52.7 (41.3-64.4)  47.8 (35.9-59.2)  Forty-three patients had a follow-up appointment during the period of chart review. Thirty-three patients (77%) completed both the initial and follow-up PedsQLTM questionnaires. There was no significant difference between initial and follow-up appointment QoL scores (Table 3.5).  Table 3.5. Median and IQR scores of initial and first follow-up PedsQLTM questionnaires.  PedsQLTM Domain QoL Initial Patient Scores (n=33) QoL Follow-up Patient Score (n=33)  Physical 43.8 (26.6-59.4) 46.89(32.8-67.2) p=0.271 Psychosocial  60.0 (50.0-66.7) 60.0 (47.5-71.7) p=0.596 Total 54.4 (41.8-64.8) 57.1 (43.5-71.2) p=0.277   33 Parent-proxy scores of those who completed both initial and follow-up questionnaires (n=32) are found in Table 3.6. There was a significant difference in all domains between initial and follow-up parent-proxy scores (all p<0.05). Initial and follow-up self-report and parent-proxy scores were significantly associated for all domains, found in Table 3.7.  Table 3.6. Median and IQR scores of initial and follow-up Parent-proxy PedsQLTM questionnaires. PedsQLTM Domain QoL Initial Parent-Proxy Scores (n=32) QoL Follow-up Parent-Proxy Score (n=32)  Physical 34.4 (18.8-59.4) 42.2 (29.7-68.8) p=0.019* Psychosocial  53.3 (43.3-62.9) 58.0 (43.3-68.3) p=0.046* Total 45.7 (35.9-60.9) 53.8 (43.8-70.1) p=0.017*   Table 3.7. Pearson correlation coefficients between self-report and parent-proxy (n=32)   PedsQLTM Domain Pearson Correlation Significance Initial Physical r=0.86 p<0.001* Psychosocial r=0.76 p<0.001 Total r=0.86 p<0.001 Follow-up Physical r=0.84 p<0.001 Psychosocial r=0.74 p<0.001 Total r=0.84 p<0.001  34 3.3.5 Exercise  Eighty-three of the 93 patients (89%) completed an exercise test on initial visit; the results are summarized in Table 3.8. Reasons for non-participation in an exercise stress test include patient refusal, scheduling issues or for patient safety concerns. On initial visit, treadmill time was lower in DAOA patients compared to a previously-published healthy institutional cohort [9.8 minutes (8.0-12.0) vs 15.3 minutes (13.8-16.8); p<0.001].48 At the initial exercise test, 17 patients (20%) did not attain a peak heart rate of >90% predicted. A peak heart rate greater than 195 bpm (maximal test) was achieved in half of the patients. Thirty-five of 93 patients (38%) completed the exercise stress test at both initial and follow-up appointments. The treadmill time remained unchanged [9.7 minutes (8.0-11.2) vs 10.5 minutes (8.0-13.0); p>0.05] at the time of discharge (n=35).               35 Table 3.8. Exercise stress test results. Median (IQR) are reported.  Stress Test Results N = 83 Supine Heart Rate (bpm) 72 (64-82) Supine Systolic BP (mmHg) 110 (104-118) Supine Diastolic BP (mmHg) 68 (60-78) Standing Heart Rate (bpm) 94 (82-105) Standing Systolic BP (mmHg) 110 (101-118) Standing Diastolic BP (mmHg) 70 (63-80) Duration of Exercise (s) 586 (479-720) Peak Heart Rate (bpm) 196 (187-200) Max Systolic BP (mmHg) 160 (142-172) Max Diastolic BP (mmHg) 70 (60-80) bpm=beats per minute; BP=Blood pressure; mmHg=millimeters of Mercury; s=seconds.  3.3.6 Psychology Of the 59 psychology referrals, 28 (47%) were referred but were not seen by psychology during the data collection period or had accessed other supports during this time.  Thirty-one were seen by our clinical psychologist (53%), with 24 of 31 (77%) requiring long-term supports either through the Dysautonomia Clinic or in the community.     3.4 Discussion To our knowledge, this is the first study to use a multi-disciplinary approach to describe a DAOA cohort using QoL, symptom burden and exercise capacity of patients at initial  36 presentation and following treatment. Over half of the referrals made to the Dysautonomia  Clinic came from general pediatrics, with other referrals from Family Medicine and specialty clinics such as Neurology, Biochemical Diseases, Rheumatology, Cardiology, Gastroenterology and Endocrinology. This illustrates the variety of symptoms experienced by our DAOA patients as we have a diversity of referring specialties. Symptom onset by self-report was a median of 2.0 years (1.0-4.0) before diagnosis. Other studies suggest that long diagnostic journeys as well as patients seeing multiple specialists can leave patients frustrated with the lack of understanding of their condition. 14,15 Previous literature surrounding orthostatic intolerance conditions similar to DAOA found that delay in diagnosis was a risk factor for prolongation of symptoms.16 Consequently, the diagnostic delay in conditions such as DAOA may have large consequences in how adolescents are affected by their symptoms which may contribute to their QoL. Patients may then be unwilling to accept their diagnosis once given as they may feel they need to continue to search for an organic cause.14 Previous literature suggests medication may contribute to uncomfortable side effects which may worsen symptom complexes.15 In our review, we found 56% of patients reported trying different medications for symptom relief yet symptom burden reports remain high suggesting that medication may not help elevate some symptoms patients experience with this condition in agreement with previous literature.   Using the PedsQLTM as a measure of well-being, we found that DAOA patients self-report a QoL that is low. The low QoL is consistent with other studies of patients with conditions similar to DAOA such as POTS who also report low QoL, specifically in the physical and mental health domains.30 Factors contributing to low QoL may be due to a feeling of lack of  37 control, poor sleep patterns, limitations on activities, pain and diagnostic delays.16,33 In our cohort, it is important to note that there was no significant difference between the self-report QoL scores at initial and follow-up visit. Interestingly, parent-proxy reports show a significant difference in all domains from initial to follow-up visit. Although the multidisciplinary approach of the Dysautonomia Clinic results in a modest improvement in parent-proxy ratings of QoL, we must look for other ways to provide support for patients to further improve outcomes. Although patients have the opportunity to see a clinical psychologist through the Dysautonomia Clinic, mental health of our DAOA patients have not been studied. Previous research in fields such as chronic pain, POTS and fibromyalgia has provided evidence to suggest that factors such as anxiety, depression, negative coping strategies and suicidal ideation are present within these patient cohorts.29-33 Future studies surrounding the mental health of DAOA patients may provide better insight into the QoL of this patient population.   While the majority of adolescent patients attended regular school, 50% reported missing school in some capacity due to their symptoms. The self-reported high symptom burden of our patients may be a factor in patients’ removal from typical adolescent activities such as school attendance. Adolescents unable to attend school may miss out on social interaction as well as experience social isolation which may be a contributing factor to QoL scores.   At the initial visit, peak heart rate was only achieved in half of the patient cohort which reflects that DAOA patients were unable to push themselves to their maximal exercise capacity. Results showed that at their follow-up visit, exercise time for adolescent patients  38 was not significantly different from the initial visit. Poor exercise tolerance has been described in the literature for overlapping conditions such as POTS, chronic fatigue syndrome and fibromyalgia.51 Long periods of inactivity may play a role in the poor exercise capacity of the DAOA patients. Continuing to work towards improving the ability to exercise in these patients may also have positive effects on their QoL.   3.5 Limitations There are a few limitations to this study. Firstly, this was a retrospective clinical review of our patient cohort, thus, many factors were not controlled and were limited by the information recorded in the patients’ clinical charts. In addition, some patients did not complete their initial and/or follow-up questionnaires leading to a smaller sample size. Furthermore, we do not know whether patients adhered to our treatment recommendations; thus, we cannot make causal inferences as to the effects of our multi-disciplinary approach to treatment.   3.6 Conclusion This study suggests that adolescents with dysautonomia are debilitated by their condition and have lower function than their healthy peers in terms of QoL and exercise capacity, even with a multidisciplinary approach to treatment. It provides us with insight into the diagnostic journey of these patients which may pose a significant barrier to treatment adherence. With low QoL scores, high symptom burden and poor exercise tolerance, we recognize the need for more therapeutic support in DAOA patients in order to promote their physical, emotional and psychological well-being.  39 Chapter 4: Mental Health Challenges in Adolescents with Dysautonomia  4.1 Introduction The World Health Organization (WHO) defines mental health as “a state of well-being in which the individual realizes his or her own abilities, can cope with the normal stresses of life, can work productively and fruitfully and is able to make a contribution to his or her community”.52 In Canada, there is an estimated prevalence of mental illness between 18-20%.53 Specifically in adolescents aged 13-19, mental illness prevalence rates are estimated between 25.9% and 29.1%.53 While over a quarter of adolescents in Canada struggle with mental health, mental health burden may be even more prevalent for adolescents with a chronic health condition such as those with autonomic nervous system (ANS) dysfunctions.   In chronic health conditions, it has been reported that there is a correlation between mental health and ratings of quality of life (QoL).54 Dysautonomia of Adolescence (DAOA) is a condition that results from a dysregulation of the ANS during puberty. DAOA has overlapping clinical features of other conditions such as chronic fatigue, postural orthostatic tachycardia syndrome (POTS), orthostatic intolerance and others.  Symptoms have a significant impact on QoL with many adolescents reporting a poorer QoL compared to other pediatric chronic illness populations.10,55-57 Symptoms affect multiple organ systems in the body, with symptom fluctuations being a common occurrence. DAOA patients report typical symptoms being syncope, palpitations, fatigue, gastrointestinal pain and nausea. Adolescents may experience symptoms associated with DAOA for years as the adolescent growth and development period subsides. Symptoms can be so disruptive many adolescents with this condition no longer attend school, participate in sports and no longer attend recreational  40 activities.12 While high symptom burdens for DAOA patients may be contributing to reports of poor QoL, it is unknown what role mental health has. There is an insufficient amount of research looking at underlying mental health conditions in patients with DAOA that may be contributing to poor QoL.  In this study, we aim to better understand the mental health challenges of adolescents with dysautonomia though a preliminary chart review.   4.2 Methods This was a single-centre retrospective chart review performed for quality improvement/quality assurance purposes. Charts of all patients actively followed in or previously discharged from a tertiary care Dysautonomia Clinic between January 2017-November 2019 were accessed. Charts were reviewed for mental health history. Diagnosed mental health condition was defined as a diagnosis by a psychologist and/or psychiatrist as stated in clinic notes. Undiagnosed mental health challenge was defined as concerns raised by a health care provider within clinic notes, which may have been treated by a mental health professional, but not substantial enough to receive a diagnosis or remains suspected but undiagnosed. Mental health challenges were classified as significant symptoms reported and/or a formal diagnosis of anxiety, depression, attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), eating disorders, somatization, mood disorders, suicidal ideation or self-harm. Frequency tables were generated for all categorical variables.  41 4.3 Results In total, 140 patients with a diagnosis of DAOA were reviewed (94 female, 67%). Median (IQR) age of patients when they received their DAOA diagnosis was 15.5 (14.0-16.2)  Seventy-three patients (52%) were actively followed in the tertiary care centre and 67 patients (48%) were discharged between January 2017 and November 2019. Ninety-two of 140 (66%) had some form of mental health challenge including 21 (15%) with a history of suicidal ideation and/or self-harm. Forty-two (30%) had no mental health concerns and 6 (4%) were unknown.   Of the 92 patients with a mental health challenge, 47 (51%) were diagnosed with a mental health condition prior to formal DAOA diagnosis and 14 (15%) were diagnosed after DAOA diagnosis. It is unknown whether onset of DAOA symptoms occurred prior to mental health diagnosis. Thirty-one of 92 (34%) reported symptoms of a mental health challenge but no confirmed mental health diagnosis. A breakdown of mental health symptoms and diagnoses are shown in Table 4.1.         42 Table 4.1. Mental health challenges among the DAOA cohort  Among the 140 patients, 68 (49%) accessed psychology services either through the Dysautonomia Clinic as part of their standard of care or in the community, 10 (7%) have been referred to other health care services and 29 (21%) did not access services. Psychiatric services were required by 33 patients (24%).  4.4 Discussion To the best of our knowledge, this is the first study to report the mental health challenges of DAOA patients. We found that 65% of our DAOA patients had mental health challenges documented in their clinical chart. The most documented mental health challenge for patients was a combination of anxiety, depression, or other concomitant challenge such as mood disorders, somatization, ADHD, OCD and eating disorders. We also found over a 75% of Mental Health Challenge Diagnosed (n=61) Symptoms Present, No Formal Diagnosis (n=31) Total (n=92) Anxiety 15 (25%) 6 (19%) 21 (23%) Depression 6 (10%) - 6 (7%) Anxiety and/or Depression and/or Concomitant Diagnosis 27 (44%) 8 (26%) 35 (38%)  Other  13 (21%) 14 (45%) 27 (29%)  Unknown - 3 (10%)  3 (3%)  43 patients accessed some form of mental health help through psychology or psychiatry and 15% of the total study cohort experienced suicidal ideation and/or participated in self harm.   The prevalence of mental health challenges in our DAOA cohort is more than double that of the estimated prevalence of mental health illness among Canadian adolescents.53 Our results reiterate similar findings of increased mental health challenges such as depression, low QoL and levels of anxiety in adolescents with similar chronic conditions to DAOA such as chronic pain.29 Furthermore, in cohorts of adolescents with chronic physical illness, those with chronic fatigue syndrome ranked highest in depressive symptoms compared to illnesses such as cancer or sickle cell disease.31 As chronic fatigue syndrome has overlapping clinical features with DAOA, our findings reflect previous research.    In our study cohort, diagnosed anxiety and anxiety with co-dominant diagnoses were the most prevalent conditions. Work by Kellerman et al, report that stability of the adolescent’s prognosis given by physicians was related to significantly lower levels of anxiety.58 Instability in prognosis was defined as changes due to disease, such as an unpredictable disease course. Interestingly, those with a prognosis of less stability in one’s condition can negatively impact levels of anxiety.58 This may be particularly important for our work as the condition of DAOA is not predictable. Patients experience peaks and troughs in symptoms throughout their growth and development years. Fluctuations in symptom severity and the psychological impact that this has on adolescents may be a factor in the diagnosed and undiagnosed anxiety of our patients.     44 Fifteen percent of the study cohort of DAOA patients were reported to have suicidal ideation and/or participated in some form of self-harm. This is consistent with previous literature by Pederson and Brooke who reported a risk of suicide in adults with a diagnosis of POTS, a condition with similar symptoms to DAOA.33 For adolescent age groups in particular, those who experienced depression reported a significantly higher level of suicidal ideation as compared to their peers who had not experienced depression.59 This further illustrates the importance of characterizing the mental health of the DAOA population to minimize the risk of suicide and self-harm through mental health intervention.   4.5 Limitations This study was a clinical chart review. We acknowledge that these are only preliminary results confined by information available in the patient’s clinical record and does not give a full picture of the scope of mental health in this study cohort. We were unable to assess the level of anxiety, depression and other concomitant mental health challenges in this cohort and could only stratify using a “present/not present” approach. It is unclear as to whether a mental health challenge exacerbates symptoms of DAOA or DAOA symptoms negatively impact their mental health as we could not delineate the timing of the symptoms in relation to the timing of the mental health challenges. A future prospective study using validated mental health measures to accurately assess the mental health of DAOA patients would vastly improve our understanding of the implication of this condition on adolescents and their mental well-being. Future studies should also consider the patients’ protective factors such as resilience, self-perception, and social supports. In addition, the number of DAOA patients who have accessed psychology services may be inflated. As part of standard of care, patients  45 are able to access a psychologist through the Dysautonomia Clinic. This may have caused an increase in the number of patients accessing psychology services as it was available to them through standard of care practice in the Dysautonomia Clinic even if no mental health challenges were present.   4.6 Conclusion This single centre retrospective chart review demonstrates the need for mental health interventions and supports for DAOA patients. It highlights the prevalence of mental health challenges in this cohort and encourages us to continue to support these adolescents throughout the peaks and troughs of this condition. We recognize that validated mental health measures are needed and essential to aid in both our understanding and treatment of DAOA patients.   46 Chapter 5: Texting and Connecting in Patients with Dysautonomia of Adolescence: A Novel Approach to Communication Between Patients and their Health Care Providers  5.1 Introduction  The use of mobile health (mHealth) technology has gained increasing utilization as a way to facilitate better health outcomes and provide easier access to care. Access to smartphones that enable the use of this technology is widespread, with 76% of Canadians owning a smartphone.60 In particular, 94% of adolescents and young adults report owning a smartphone.60  Prevalent access to smartphones in the adolescent age group make delivering mHealth to this age demographic readily available. Specifically, the use of text messages for adolescent populations may be valuable to aid in health management as adolescents report sending up to 100 text messages daily.34,61   Text messaging or otherwise known in a healthcare context as clinical digital messaging (CDM) has previously been shown to improve communication between adolescent patients and their health care providers (HCP) and increase patient engagement and adherence to treatment protocols.34,36 Furthermore, text messaging in varied pediatric and adolescent patient populations has been shown to be effective at promoting behaviour change, is quick, has diverse functionality and allows HCP to intervene at more opportune times.62  WelTel, a digital health messaging platform has been established to promote two-way communication between patients and their HCP using CDM technology. Previous research using the WelTel platform has demonstrated success in patient-orientated outcomes such as a  47 significant improvement in treatment adherence as well as HCP and patient satisfaction.42,63-66 The use of WelTel as a means to provide CDM has shown great benefits in adult patient populations; however, it is unknown how the CDM technology will impact an adolescent population.  Dysautonomia of Adolescence (DAOA) is a chronic condition that results from a transient dysfunction of the autonomic nervous system during pubertal growth and development. Treatment is focused on lifestyle changes which can be mediated by HCP from adolescents’ home. Quality of life (QoL) is severely affected in these adolescents. Many withdraw from school, sport, recreational activities, experience social isolation and have significant mental health challenges. Fluctuations in symptom severity or the development of new symptoms is common and requires ongoing support from HCP. Support through CDM may reduce the need for in-person hospital visits as well as provide adolescents with the tools and support necessary to navigate their condition. As previously discussed, CDM has shown great benefits for adolescent and pediatric patient populations while WelTel has established itself as a leader in digital health outreach. Therefore, we sought to implement CDM using the WelTel messaging platform to support DAOA patients and evaluate patient engagement, satisfaction, symptom burden and QoL.   5.2 Methods  5.2.1 Research Questions and Objectives 1.    How feasible and acceptable is the use of a CDM platform (WelTel) to communicate with patients followed in the Dysautonomia Clinic?  48 i. To determine whether the CDM platform messages were sent and received by participants ii. To determine participant enrollment iii.    To determine participant satisfaction with the CDM platform.  iv. To determine the level of engagement of participants.  2.    Does the use of a CDM communication platform reduce symptom burden and improve QoL in patients with DAOA? i. To determine whether there is a reduction in the symptom burden (using the Symptom Burden Questionnaire) of study participants after 6 months of CDM intervention. ii. To determine whether there is a significant difference in PRE and POST QoL (using the PedsQLTM Questionnaire 44-46) in study participants after 6 months of CDM intervention.  3. What is the scope of the mental health challenges in the study participants? i. To retrospectively review the mental health challenges of DAOA patients  ii. To determine if mental health challenges has a significant impact on QoL scores among the population 5.2.2 Hypothesis H10i- Participants will receive <1 automated message per week   H1Ai – Participants will receive 1 automated message per week    49 H10ii- Less than 50% of potential participants approached will consent to participate in the study H1Aii- At least 50% of potential participants approached will consent to participate in the study  H10iii- Less than 80% of participants will be satisfied with the CDM communication platform after a 6-month period. H1Aiii- At least 80% of participants will be satisfied with the CDM communication platform after a 6-month period.   H10iv- Participant response rate will be less than 70%. Three percent of messages will require follow-up from HCP.  H1Aiv- Participant response rate will be at least 70%. Greater than three percent of messages will require follow-up from HCP.  H20i- There will be no change in symptom burden following the implementation of a 6-month CDM communication platform. H2Ai There will be one-point reduction in the frequency of symptoms (i.e. frequent to occasional, occasional to none.) improvement in symptom burden, as measured by the Symptom Burden Questionnaire, following the CDM intervention.  H20ii There will be no change in QoL, as measured by the PedsQLTM Questionnaire, following the implementation of a 6-month CDM communication platform.    50 H2Aii There will be 15% improvement in QoL, as measured by the PedsQLTM Questionnaire, following the CDM Intervention.  H30ii- There will be no difference between QoL scores of participants that have a mental health burden compared to those who do not have a mental health burden. H3Aii-There will be a 15% difference in QoL scores between participants that have a mental health burden compared to those who do not have a mental health burden. Participants with mental health burden will report significantly lower QoL.  5.2.3 Participant Recruitment  Participants were recruited from the Dysautonomia Clinic at BC Children’s Hospital (BCCH). Potential participants were identified by their HCP using the inclusion criteria listed below. Participants were introduced to the study by a member within the participant’s circle of care. Participants were recruited during their regular clinical appointment at the Dysautonomia Clinic by the graduate student (CG).  Ethical approval for this study was obtained from the University of British Columbia and Children’s Women’s Health Centre Clinical Research Ethics Board (Certificate H18-02193).  5.2.4 Participant Inclusion and Exclusion Criteria  5.2.4.1 Inclusion 1. Follow-up patient in the Dysautonomia Clinic at BCCH, defined as a patient who has received at least 6 months of treatment as part of their standard of care  51 2. Between the ages of 12-18 years 3. English-speaking 5.2.4.2 Exclusion 1. No access to a personal mobile device with a designated telephone number 5.2.5 CDM Intervention Every Monday at 12:00pm, participants received a text message to their personal cellular device which asked “How are you?”. Participants responses varied with “Ok”, “Not Ok”, or with any question, comment, or concern they had pertaining to their health and clinical care. Responses were assessed by a study team member and triaged to the appropriate HCP which included the participant’s doctor, nurse, psychologist, or exercise physiologist. Participants were contacted by the appropriate HCP within 48 hours through the CDM communication platform. If no response was received from the participant by Wednesday of that week, participants received an additional message on Wednesday at 12:00pm which asked “Haven’t heard from you yet, how are you?”. Any messages received were triaged to the appropriate HCP. Messages were checked and responded to between 8am-4pm Monday-Friday.   5.2.6 Outcome Measures  5.2.6.1 Symptom burden All DAOA patients completed the Symptom Burden Questionnaire before each of their clinical visits as part of the standard of care for all DAOA patients. This questionnaire is used by the primary physician (KA) to determine symptom severity and the level of debilitation caused by the symptoms. The symptoms are separated into 6 categories; neurologic, cardiac,  52 gastrointestinal, skin, joints/muscles and energy/activity each with subcategories of specific symptoms which are rated on a 5-point scale from 0 (never or almost never have the symptom) to 4 (frequently have it, effect is severe). No symptoms were defined as a symptom eliciting a symptom burden score of 0, occasional symptoms were defined as a symptom eliciting a symptom burden score of 1 or 2 and frequent symptoms were defined as a symptom eliciting a symptom burden score of 3 or 4. As this is part of the DAOA patient’s clinical care, it did not take the participant any additional time to complete the Questionnaire. Symptom burden measurements were taken at baseline (T0), CDM Enrollment (T1) and after the 6-month CDM intervention (T2) (see Appendix A).  5.2.6.2 Self-report and parent-proxy PedsQLTM  All DAOA patients completed the PedsQLTM and its parent-proxy before each of their Dysautonomia Clinic visits as part of their standard of care. Therefore, this did not take any additional time beyond that of standard care. The PedsQLTM is a validated and reliable questionnaire to measure health-related QoL in children and adolescents.44-46 The PedsQLTM is a practical measurement tool with minimal respondent and administrative burden. 67 It is used in other pediatric clinical populations such as those with asthma, cerebral palsy, rheumatology and diabetes, which show good internal consistency and reliability. 55,57,68,69 The PedsQL is free to use, easily understood by parents and children and a good measure for overall QoL.67 Thus, we choose to use the PedsQLTM as our primary tool to assess QoL in our study. The PedsQLTM is a 23-item questionnaire broken up into 4 scales (physical functioning, social functioning, emotional functioning, school functioning) with 3 summary scores as the final output (total score, physical health summary score and psychosocial health summary score). Each item was given a score out of 4, 0 being if the symptom is almost  53 never a problem and 4 being if the symptom is almost always a problem. Each score was then reverse scored and transformed on a scale from 0-100. Scores closer to 100 represented higher health-related QoL. PedsQLTM measurements were taken at baseline (T0), CDM Enrollment (T1) and after the 6-month CDM intervention (T2) (see Appendix B and C).    5.2.6.3 PRE-Survey The PRE-survey was administered to participants after consent and assent had been obtained (T1) and before input of mobile numbers into the WelTel CDM system. All PRE-surveys were administered during the participants’ regular clinical appointment. The PRE-survey asked the participant multiple choice and short answer questions related to their opinions on using a CDM platform as part of their health care (see Appendix D).   5.2.6.4 Participant CDM Data Weekly responses and number of care conversations (>2 text messages between participant and HCP) were recorded as a measure of participant engagement. Participant messages were categorized into the following main themes: no response, OK, symptom concerns, school concerns, exercise questions and advice, coping/mental health support, medication questions, sleep advice and other (including appointment scheduling).    5.2.6.5 POST-Survey The POST-survey was administered to participants after 6 months of using the CDM communication platform (T2), in-person during the participants regularly scheduled clinical appointment or via a REDCap link during the COVID-19 pandemic. The POST-survey asked  54 the participant multiple choice and short answer questions related to the effectiveness, use, outcomes and overall experiences using the CDM communication platform (see Appendix E).   5.2.6.6 Mental Health Status Data collected from participants’ clinical charts included mental health concerns (either diagnosed or undiagnosed), mental health services accessed by patients and diagnoses broken up into categories of anxiety, depression, suicidal ideation, self-harm behaviour, multiple mental health diagnoses, other (including eating disorders, Attention Deficit Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD)). Diagnosed mental health burden was defined as a diagnosis by a psychologist, psychiatrist or if stated in previous clinic notes. Undiagnosed mental health burden was defined as concerns raised by a HCP within clinic notes, which may have been treated by a mental health professional, but not substantial enough to receive a diagnosis or remains suspected but undiagnosed.           55 5.2.7 Data Collection Table 5.1. Summary of data collection at each study visit.  Baseline T0 CDM Enrollment T1 6 Month CDM Intervention T2 Ongoing PedsQLTM Self-Report and Parent-Proxy ✓ ✓ ✓  Symptom Burden Questionnaire ✓ ✓ ✓  PRE-Survey  ✓   POST-Survey   ✓  CDM Data    ✓ Participant Demographics    ✓  5.2.8 Data Storage and Security  5.2.8.1 CDM Storage and Security The WelTel communication platform was specifically designed as an outreach tool for healthcare environments. In keeping with the University of British Columbia (UBC), Children’s and Women’s Health Centre Research Ethics Board requirements, the WelTel communication platform is hosted on a secure UBC server. WelTel personnel are able to access specific text messages from patients or HCPs only if there is a direct problem with sending or receiving messages. Should this occur, permission from the Dysautonomia Clinic must be given to WelTel before any action is taken. All WelTel employees work under strict non-disclosure agreements. Participants on the communication platform do not have access  56 to the personal cell phone numbers of their HCPs. All messages sent and received through the program were from a phone number associated with WelTel.  5.2.8.2 Data Storage Study data were collected and managed using REDCap electronic data capture tools hosted at the BCCH Research Institute.49,50 REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies, providing: (1) an intuitive interface for validated data capture; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for data integration and interoperability with external sources. The data was manually inputted into the database by the graduate student (CG) or REDCap surveys were used to send a link directly to the participant and automatically populated in REDCap with participant responses. Survey and questionnaire data were collected during regular in-person clinic appointments for T0 and T1. T2 data was collected during regular in-person clinic appointments. Anyone who was unable to attend an in-person clinical appointment due to COVID-19 was sent REDCap survey links. CDM data was collected and stored on the WelTel platform.    5.2.9 Statistical Analysis Frequency counts (%) were performed for all categorical variables and a univariate analysis performed on all continuous variables. Medians and interquartile ranges (IQR) are reported. Non- parametric Friedman tests were used to determine differences in QoL scores at the three time points (T0, T1, T2). A Wilcoxon Signed-Rank Test was used to compare responses  57 between paired time points. Pearson correlation coefficients were used to determine the association between self-report and parent-proxy PedsQLTM scores. Non-parametric Mann-Whitney U tests were used to determine differences among QoL scores between those with mental health burden and those with no mental health burden.  All tests were two-sided and a p<0.05 was considered statistically significant. IBM SPSS Statistical Software (IBM Corporation, Armonk, NY) was used to complete the analyses.  5.3 Results  5.3.1 Demographics From November 2018-December 2019, 44 potential participants were approached for recruitment to this study. Six declined participation citing no interest (n=2), message frequency was too often (n=3) and no access to a personal cell phone (n=1). Thirty-eight DAOA patients were interested in participating, although 3 did not complete consent forms. Thirty-five participants were consented and enrolled on the CDM platform (30 female, 86%). Three participants withdrew from the study before CDM intervention was complete, with the CDM responses reported as unhelpful (n=2) or were not reported (n=1).   Thirty-two participants were eligible to complete T2 of the study, 6 participants did not return their T2 questionnaires and surveys thus were excluded from analysis leaving a total of 26 study participants.   Twenty-six participants completed the study (23 female, 88%) with a median (IQR) age of 16.8 years (15.7-17.4) at CDM enrollment (T1). Eleven participants completed their  58 questionnaires during their regular clinical appointment at the Dysautonomia Clinic. Fifteen participants completed their questionnaires at-home online due to the COVID-19 pandemic as the Dysautonomia Clinic suspended seeing patients in-person during this time. T2 questionnaires were received between May 2019-May 2020 due to the rolling recruitment of this study.    5.3.2 CDM PRE-Survey All participants completed the PRE-survey (n=26). Twenty-five participants (96%) agreed that it would be beneficial for them to be able to text message their HCP. All 26 participants reported that they would respond to a weekly text message from the HCP. Five participants (19%) cited that they could foresee problems with communicating via a text message which included potential changes to phone plan (n=1), or personal issues with texting i.e. forgetting to respond or being busy (n=4). No participants reported having concerns about communicating via text messaging with their HCP. Figure 5.1 shows participants’ initial views on how CDM from the Dysautonomia Clinic could impact them.   59 Figure 5.1. Participants’ (n=26) initial thoughts about the impact of CDM on their health.    5.3.3 CDM Intervention Period The duration of CDM intervention was a median of 33 weeks (26.8-37.3). A total of 896 automated weekly check-in messages were sent to participants. During participant’s CDM period, 25 (96%) participants asked their HCP at least one question. Seventy-one percent of all automated weekly check-in messages received a response from participants. Participant responses were categorized into 11 different text message themes. Number of responses for each theme is found in Table 5.1. Care conversations defined as messages >2 between participant and HCP occurred in 23% of all weekly message check-ins.    60 Table 5.2. Participant responses to weekly check-in. Participant Text Message Themes: Total Responses (n=896) No Response  261 29%) OK  429 (48%) Symptom concerns  118 (13%)  School concerns 14 (2.0%) Exercise questions and advice 23 (3.0%) Coping/Mental Health support 22 (3.0%) Other (incl. appointment scheduling) 9 (1.0%) Medication questions 10 (1.1%) Sleep advice 4 (0.4%) COVID-19 concerns 4 (0.5%) Unknown 2 (0.2%)  5.3.4 CDM POST-Survey All participants completed the POST-survey (n=26). Twenty-five (96%) participants found it useful to be able to text message their health care team. Twenty-two (85%) participants stated that it would be helpful to continue to text message their health care team after study completion. Figure 5.2 shows the frequency of messages participants would prefer in the future. The CDM platform increased 92% of participants’ feelings of connection to their healthcare team (n=24), those that did not have an increase in feelings of connection did not feel a difference (n=2, 8%).   61   Figure 5.2. Participant suggestions on the future frequency of check-in text messages.   Twenty-four (92%) participants felt comfortable reaching out for help from their HCP using CDM. Those that did not feel comfortable stated that they did not feel a connection with their HCP which made it difficult to ask questions, or the participant did not have any questions to ask. Figure 5.3 shows participant responses on how the CDM platform impacted their health care and treatment adherence.   62 Figure 5.3. Participant responses to POST-Survey CDM outcomes.   Two (8%) of the participants had problems sending and receiving messages from the Dysautonomia Clinic. Of the two participants experiencing problems, one did not have service for multiple weeks and the second did not save the Dysautonomia Clinic number which made it difficult to respond to the weekly check-ins.   The majority of participants would recommend the use of CDM to others with a health condition (n=24). Those that would not recommend CDM to others felt that it should only be used if a connection had already been established between the patient and HCP and that time  63 from initial message sent from participant to response from their HCP was too long such that the question/help needed was no longer necessary.   Feelings surrounding positive support from the health care team were stated by 19 of the participants. Participant feedback included “the best thing from this for me was that it made me feel responsible for making sure I am doing what my body needs me to do and it encouraged me to connect with the health care team”; “It was nice to have support from people who understand and can help me with what I'm going through.”; “I think for me receiving a text every week was helpful to remind me to evaluate how my health was doing for that particular week and see what needed to be adapted or worked on“  Remembering to text back was cited as the most frequent obstacle with 9 participants (35%). Other critiques of the CDM platform from participants included feeling comfortable enough to ask questions (15%) and the impersonal feeling of the weekly messages (8%).  5.3.5 Symptom Burden  Complete T0, T1 and T2 symptom burden data was present for 22 participants. Frequency of 48 potential symptoms are reported by each participant. Table 5.3 shows the number of individual symptoms reported as never present, occasionally present and frequently present (median and IQR reported). There was no significant difference between the number of symptoms present at each data collection point.   64 Most frequent symptom complaints at T0, T1 and T2 for greater than 50% of the study cohort in at least one symptom over the study period are shown in Figure 5.4.   Figure 5.4. Most frequent symptom complaints by participants over the study period.   Tables 5.4-5.9 show the percentage of participants experiencing symptoms in each symptom burden category; Neurologic, Cardiac, Gastrointestinal, Skin, Joints/Muscle, Energy/Activity. Please see Appendix F for a comprehensive list of all symptoms experienced by individual participants at T0, T1 and T2  0%10%20%30%40%50%60%70%80%90%Percentage of ParticipantsSymptomsT0T1T2 65 Table 5.3. Frequency of individual symptoms on the symptom burden report (48 potential symptoms). Median number (IQR) are reported. (n=22).  Frequency T0  T1  T2   No Symptoms Present 14.5 (13-24) 18(11-26) 16 (9-24) p=0.554 Occasionally Present  12.5 (8-19) 12.5 (9-17) 14 (9-16) p=0.789 Frequently Present  13.0 (10-26) 14.5 (7-21) 17 (10-23) p=0.258  Table 5.4. Neurologic symptoms frequently experienced by participants (n=22). Neurologic T0 T1 T2 Headaches 12 (55%) 10 (46%) 9 (41%) Syncope 4 (18%) 1 (5%) 5 (23%) Dizziness 17 (77%)  16 (73%) 14 (64%) Vision changes 10 (46%) 6 (27%) 9 (41%) Vertigo 6 (27%) 7 (32%) 5 (23%) Paresthesia 4 (18%) 3 (14%) 8 (36%) Poor memory 7 (32%) 7 (32%) 14 (64%) Brain fog 6 (27%) 15 (68%) 15 (68%) Confusion/Poor concentration 8 (36%) 12 (55%) 12 (55%) Poor physical coordination 3 (13%) 4 (18%) 4 (18%) Slurred speech 1 (5%) 1 (5%) 1 (5%) Learning disabilities 3 (14%) 2 (9%) 1 (5%)  66 Table 5.5. Cardiac symptoms frequently experienced by participants (n=22). Cardiac T0 T1 T2 Fast heartbeat 12 (55%) 10 (46%) 11 (50%) Slow heartbeat 2 (9%) 4 (18%) 1 (5%) High blood pressure - 1 (5%) - Low blood pressure 11 (50%) 9 (41%) 11 (50%) Skipped heartbeat 4 (18%) 1 (5%) 1 (5%) Pounding heartbeat 13 (59%) 10 (46%) 11 (50%) Chest pain/tightness 8 (36%) 9 (41%) 9 (41%)  Table 5.6. Gastrointestinal symptoms frequently experienced by participants (n=22). Gastrointestinal T0 T1 T2 Nausea 13 (59%) 12 (55%) 13 (59%) Vomiting 2 (9%) 2 (9%) 5 (23%) Intestinal/Stomach pain 11 (50%) 9 (41%) 7 (32%) Irritable bowel 8 (36%) 7 (32%) 9 (41%) Constipation 5 (23%) 6 (27%) 8 (36%) Diarrhea 4 (18%) 5 (23%) 7 (32%) Post-meal symptoms 8 (36%) 8 (36%) 8 (36%) Heart burn 5 (23%) 7 (32%) 4 (18%) Bloating 4 (18%) 5 (23%) 8 (36%)   67 Table 5.7. Skin symptoms frequently experienced by participants (n=22). Skin T0 T1 T2 Flushing, hot flashes 8 (36%) 6 (27%) 1 (5%) Paleness of face 12 (55%) 10 (46%) 10 (46%) Blue extremities 4 (18%) 2 (9%) 5 (23%) Pale extremities 7 (32%) 5 (23%) 9 (41%) Cold extremities 9 (41%) 8 (36%) 13 (59%) Swelling of extremities 3 (14%) 4 (18%) 4 (18%) Excessive sweating (clammy) 9 (41%) 7 (32%) 11 (50%) Heat intolerance 9 (41%) 10 (46%) 9 (41%) Cold intolerance 7 (32%) 5 (23%) 6 (27%)  Table 5.8. Joint/Muscle symptoms frequently experienced by participants (n=22). Joints/Muscle T0 T1 T2 Joints/Muscle 9 (41%) 6 (27%) 7 (32%) Pain or aches in joints 8 (36%) 7 (32%) 5 (23%) Pain or aches in muscles 13 (59%) 13 (59%) 12 (54%) Feeling of weakness 3 (14%) 4 (18%) 3 (14%)   68 Table 5.9. Energy/Activity symptoms frequently experienced by participants (n=22). Energy/Activity T0 T1 T2 Fatigue, sluggishness 17 (77%) 18 (82%) 17 (77%) Apathy, lethargy 11 (50%) 9 (41%) 10 (46%) Hyperactivity 2 (9%) 1 (5%) 4 (18%) Sleep disturbance 13 (59%) 13 (59%) 6 (27%) Exercise intolerance (sports/activities) 14 (64%) 10 (46%) 12 (55%) Missing school 12 (55%) 9 (41%) 8 (36%) Not able to see friends 9 (41%) 7 (32%) 6 (27%)  5.3.6 School and Other Activities Twenty-seven percent of participants improved their school attendance from T0 to T2. Fifteen percent of participants were able to secure part-time jobs since T0. Twelve percent were accepted and went to college, another 12% plan to attend college after graduation.   5.3.7 Quality of Life Complete T0, T1 and T2 self-report PedsQLTM data was present for 20 participants. Non-parametric Friedman tests showed no significant difference across the 3 time points for the Physical (p=0.458), Emotional (p=0.666), School (=0.499), Psychological (p=0.059) and Total (p=0.259) functioning scores. There was a significant difference across the 3 time points for Social Functioning scores (p=0.011). Post-Hoc Wilcoxon signed ranks showed a  69 significant difference between T1 and T2 scores (p=0.007). QoL scores decreased from T1 to T2.  Figure 5.5 shows box and whisker plots for self-report PedsQLTM data over time. With the exclusion of T0, complete self-report data is available for 24 participants. QoL scores decreased from T1 to T2. Wilcoxon signed rank sums between T1 and T2 showed a significant difference in Social (p=0.014), Psychosocial (p=0.014) and Total (p=0.042) Functioning.   Complete T0, T1 and T2 parent-proxy PedsQLTM data was present for 18 participants. Non-parametric Friedman tests showed no significant difference across the 3 time points for all Physical (p=0.946), Emotional (p=0.871), Social (p=0.731), School (p=0.724), Psychological  (p=0.901) and Total (p=0.411) Functioning scores. Figure 5.6 shows box and whisker plots for parent-proxy PedsQLTM data over time.     Table 5.10 shows the association between self-report and parent-proxy PedsQLTM scores for each domain (Physical, Emotional, Social, School, Psychological and Total) over time (T0, T1, T2) (n=18)    70   Figure 5.5. Self-report PedsQL scores (n=20), p=0.007 in social functioning between T1 and T2, represented by a star. The error bars represent the minimum and maximum values reported by participants. Outliers are represented by a small circle.      71 Figure 5.6. Parent-proxy PedsQLTM scores (n=18). The error bars represent the minimum and maximum values reported by participants. Outliers are represented by a small black circle.  Table 5.10. Pearson correlation coefficient between self-report and parent-proxy report (n=18). Asterisks (*) indicate significance at the p=0.05 level, (**) indicate significance at the p=0.01 level.  Physical Emotional  Social School Psychological  Total T0 r=0.807** r=0.842** r=0.724** r=0.437 r=0.649** r=0.720** T1 r=0.783** r=0.740** r=0.583* r=0.663** r=0.707** r=0.743** T2 r=0.934** r=0.556* r=0.758** r=0.773** r=0.715** r=0.825**   72 5.3.8 Mental Health Eighteen participants (69%) had reports of a significant mental health challenge and 8 (31%) had no reported symptoms or symptoms not classified as significant. Those with a significant mental health challenge had anxiety (n=4), anxiety and anxiety and depression (n=4), anxiety, depression and a learning disorder (n=2), anxiety and a learning disorder (n=3), anxiety, personality disorder and learning disorder (n=1), anxiety, depression, and obsessive compulsive disorder (n=1), attention deficit hyperactivity disorder (n=2) and depression (n=1). Mann Whitney U tests were performed to determine differences in self-report and parent-proxy PedsQLTM scores over time between participants with and without mental health challenges. Results are found in Table 5.11-5.12. Only completed data for all time points were used for analysis, self-report (n=20) and parent-proxy (n=18).     73 Table 5.11. Self-report PedsQLTM comparison. Medians (IQR) are reported.  Mental Health Challenge Physical Functioning No (n=7) Yes (n=13) P-value T0 37.5 (28.1-65.6) 43.8 (35.9-57.8) p=0.721 T1 59.4 (50.0-68.8) 50.0 (28.1-56.3) p=0.141 T2 43.8 (21.9-62.5) 46.9 (26.6-62.5) p=0.781 Emotional Functioning T0 60.0 (45.0-80.0) 50.0 (40.0-72.5) p=0.233 T1 70.0 (55.0-85.0) 35.0 (25.0-72.5) p=0.039* T2 60.0 (50.0-70.0) 50.0 (22.5-70.0) p=0.174 Social Functioning T0 90.0 (70.0-90.0) 55.0 (45.0-77.5) p=0.066 T1 80.0 (65.0-100.0) 70.0 (52.5-75.0) p=0.035* T2 60.0 (50.0-70.0) 65.0 (35.0-72.5) p=0.129 School Functioning T0 60.0 (35.0-70.0) 55.0 (35.0-67.5) p=0.780 T1 60.0 (50.0-75.0) 45.0 (20.0-60.0) p=0.062 T2 65.0 (35.0-80.0) 25.0 (20.0-57.5) p=0.073 Psychosocial Functioning T0 68.3 (61.7-71.7) 61.7 (41.7-63.3) p=0.073 T1 75.0 (55.0-85.0) 50.0 (34.5-65.8) p=0.016* T2 71.8 (48.3-76.7) 36.7 (29.2-68.3) p=0.035* Total Functioning T0 58.7 (52.2-76.1) 53.3 (40.8-62.0) p=0.361 T1 66.3 (54.4-79.4) 52.2 (32.2-58.2) p=0.026* T2 60.9 (39.1-71.7) 37.0 (27.8-64.1) p=0.250  74 Table 5.12. Parent-proxy PedsQLTM comparison. Medians (IQR) are reported.  Mental Health Challenge Physical Functioning No (n=7) Yes (n=11)  T0 28.1 (21.9-46.9) 60.0 (31.3-71.9) p=0.050* T1 53.1 (37.5-62.5) 45.8 (34.4-64.3) p=0.525 T2 46.9 (15.6-62.5) 56.3 (37.5-71.4) p=0.296 Emotional Functioning T0 50.0 (20.0-65.0) 45.0 (37.5-60.0) p=1.000 T1 55.0 (45.0-75.0) 45.0 (30.0-55.0) p=0.275 T2 45.0 (45.0-60.0) 50.0 (30.0-75.0) p=0.855 Social Functioning T0 70.0 (60.0-80.0) 50.0 (45.0-75.0) p=0.172 T1 80.0 (60.0-90.0) 60.0 (30.0-60.0) p=0.024* T2 80.0 (50.0-90.0) 55.0 (30.0-65.0) p=0.112 School Functioning T0 45.0 (40.0-50.0) 35.0 (20.0-55.0) p=0.215 T1 55.0 (45.0-80.0) 35.0 (20.0-55.0) p=0.029* T2 60.0 (35.0-65.0) 45.0 (35.0-55.0) p=0.495 Psychosocial Functioning T0 55.0 (43.3-65.0) 48.3 (32.1-63.3) p=0.277 T1 68.3 (60.0-71.7) 46.7 (30.0-58.3) p=0.006* T2 58.3 (41.7-66.7) 53.3 (36.7-63.3) p=0.297 Total Functioning T0 44.6 (38.0-53.3) 48.9 (35.9-62.5) p=0.751 T1 58.7 (56.5-68.5) 54.4 (31.5-58.0) p=0.013* T2 57.6 (31.5-65.2) 54.6 (42.4-62.0) p=0.821  75  5.4 Discussion To the best of our knowledge, this is the first study to evaluate the impact of CDM technology for support in the care of adolescents with dysautonomia. QoL remained largely unchanged throughout the study period as well as symptom burden with participants experiencing a median of between 12-18 symptoms over the study period. Mental health challenges were prevalent in our study cohort (69%), with significant differences in multiple domains of functioning between participants with and without challenges. We found that the majority of DAOA patients were receptive to and supportive of the implementation of CDM in their clinical care with an initial study enrollment rate of 86%. Throughout the study period, almost all participants (96%) actively used the CDM technology to ask their HCP questions pertaining to their health and 23% of all text messages from participants resulted in a care conversation between participant and HCP. The majority of participants upon completion of the study found the CDM platform useful (96%) and increased their feelings of connection to their health care team (92%).  We choose to use the PedsQLTM as a measure of overall well-being as it is widely used in the pediatric literature and thus allows us to compare the QoL of our participants to other cohorts  of patients and healthy children. As expected, our study cohort displayed a QoL lower than that of healthy children who typically report an average total QoL score of 83.0 ±14.8.44 We expected our cohort’s QoL score to be similar to the scores of children with chronic illness (77.2 ±15.5).44 We found that throughout the study period, QoL remained lower than that of children with chronic illness even after receiving CDM intervention. Furthermore, our participants rated their QoL lower than reports of children with cerebral palsy (66.9±16.7),  76 cancer (72.2±16.4); asthma (74.7±15.8), cyclical vomiting syndrome (74.3±15.2), type 1 and 2 diabetes (80.4±12.9).55-57,68,70 Other conditions with overlapping features of DAOA showed similar results of low QoL PedsQLTM  ratings such as those with chronic fatigue syndrome (49.0±15.2) , Ehlers-Danlos and hypermobility (males 67.9±15.5, females 61.1±19.2).71-75  There was no significant difference in the physical, emotional, school, psychosocial and total functioning scores for our participants as QoL remained stable following the CDM intervention. There was a significant difference in social functioning (p=0.01) with post-hoc Wilcoxon Signed-Rank tests showing the difference between T1 and T2 (p=0.007) with a lower rating in T2. Although there was a decrease in participant’s rating of social function, it remained the highest functioning score, similar to previous literature surrounding QoL ratings of adolescents with chronic fatigue.71-73   Mental health of the cohort may have played a role in the QoL scores of our participants throughout the study intervention period. More than half of the participants had some form of mental health challenge, anxiety was present in 58% of participants. Previous studies indicate an association between mental health and QoL, as well as symptoms experienced by DAOA patients increase emotional distress and anxiety.29,54 For self-report scores, there was significant differences at T1 between Emotional, Social, Psychosocial and Total functioning and significant differences at T2 psychological function of adolescents with mental health challenges compared to those without. This suggests that participants with mental health challenges rate QoL lower than their DAOA peers although a larger sample size would be needed to understand this better.   77  Our study cohort experienced a variety of symptoms which fluctuate over time, although there is no significant difference between the number of presenting symptoms over the study period. Symptoms that were consistently rated as frequent by 50% of the cohort at all study time points T0, T1 and T2 were dizziness, nausea, feelings of weakness and fatigue. Large symptom burdens may have been a contributing factor to unchanged QoL. Despite high symptom burdens some participants increased their school attendance and went back to regular activities following the CDM intervention.  Seventy-one percent of all automated messages sent over the CDM intervention period received a response from participants. Previous research using WelTel technology showed that the average number of responses to the automated messages were 57%, 68% and 69% and 76%. 42,63,65,76 Our data follows a similar pattern in response rate. WelTel has shown previously that approximately 3% of messages from patients require follow-up from a HCP.42 Our participants required 8 times that amount as 23% of messages required follow-up. This may be an indication of the level of support needed by DAOA patients in managing not only their symptoms but other facets of their life as shown by our message themes of symptoms, school, exercise, coping, medication and sleep. Using the open language of “How are you?” for check-in allowed adolescents to direct the conversation to their own needs and acted as a way to reflect on symptoms. While we aimed for CDM to elicit behaviour change and adherence to treatment recommendations as found in other studies,62 participants rated “neutral” on a Likert scale for CDM helping them to increase exercise, fluid intake and salt intake, all of which are treatment recommendations for DAOA. The majority of participants  78 did either “agree” or “strongly agree” that the CDM messaged helped them feel more in charge of their care, manage their symptoms better and improve their well-being.    5.5 Limitations We acknowledge that we need a larger sample size to determine any significant differences across T0, T1 and T2 as the sample size of 20 was not sufficient. Many baseline QoL assessments were not completed by our participants which led to the smaller sample size of 20. When T0 was excluded from analysis sample size increased to 24 and significant differences were found in Social (p=0.014), Psychosocial (p=0.014) and Total (p=0.042) functioning with lower QoL ratings at T2. A larger sample size would allow us to more accurately determine the impact of CDM technology on DAOA patients. Incomplete data and participants lost to follow-up are a known problem in longitudinal studies, which may be mediated by a larger sample size.    The PedsQLTM may not be the best measure for DAOA patients to understand their QoL and well-being. Future studies with DAOA patients using different measures of well-being may be valuable to determine whether the PedsQLTM is an appropriate measure. Responses to CDM indicated that participants felt better supported, more connected and allowed them to feel more in charge of their care. While participants still experienced symptoms, they may have been more accepting of their diagnosis and felt supported which would not have been captured in our QoL measurements for an increase in well-being.    79 Due to circumstances beyond our control, 15 participants (58%) completed the study in the midst of the COVID-19 pandemic and returned their study questionnaires during this time. Participant ratings of QoL may have been negatively affected by the pandemic which could have resulted in a lower QoL during this time period.   This was a small cohort study in DAOA patients using pre-post data in which the participants acted as their own controls. A larger, randomized control trial should be completed as a future study to more effectively understand the clinical and health implications of using CDM in the adolescent DAOA population. Future prospective studies should include measures of resilience, self-perception, and adolescent support systems as this may be a factor in how well adolescents participate and well as give indication to the levels of support individual adolescent patients need.   5.6 Conclusion Results from this study demonstrate that participants were receptive and supportive of the use of CDM in their clinical care. Results show that the CDM platform is a feasible method to support patients between clinical appointments. This study highlights the debilitation of adolescents affected by DAOA through their low QoL and high symptom burden. It shows us the need for continued support throughout adolescents’ journey with DAOA. The high level of engagement with the CDM platform tells us that adolescents need to be supported in between their clinical appointments and have access to their HCP readily available. We recognize that CDM can be a valuable tool in conjunction with regular clinical care to  80 provide an outlet for adolescent patients to ask questions, manage their symptoms and improve their connection with HCP.    81 Chapter 6: Conclusions  6.1 Summary of Chapters In this Master’s thesis, we intended to gain a better understanding of Dysautonomia of Adolescence (DAOA) though an overview of the DAOA condition with the treatment recommendations of the multidisciplinary approach along with its potential problems  (Chapter 1), a small follow-up study of the long-term outcomes of the multidisciplinary approach (Chapter 2),  a comprehensive review of the Dysautonomia Clinic and its multidisciplinary approach (Chapter 3), a review of the mental health of our study cohort (Chapter 4) and then the implementation of a novel approach to communication between patient and health care provider (HCP) (Chapter 5).   In Chapter 1, we reviewed the autonomic nervous system (ANS), dysautonomia, DAOA, current treatments and its difficulties. The ANS is divided into two main divisions, the parasympathetic nervous system and the sympathetic nervous system. These branches work collaboratively to maintain functional homeostasis. Dysautonomia occurs when there is dysfunction in the ANS leading to an abnormal sympathetic response causing a variety of symptoms such as dizziness, nausea, stomach pain and feelings of weakness. During adolescence, transient dysfunction within the ANS may be trigged by hormonal changes, illness, stress and trauma and is termed DAOA. Adolescents with this condition report disruption to their daily lives such that they no longer attend school, play sports and no longer participate in recreational activities. Treatment for DAOA, like other dysautonomias, are comprised of consistent lifestyle changes to aid in symptom management. Specifically, an increase of fluid and salt, increase in lower-body strength training and support of mental  82 health as well as improved nutrition and sleep. Lifestyle changes for adolescents have difficulties and adolescents must be willing to adopt these changes. Currently, there is a lack of direct communication between adolescent patients and their HCP which may hinder the facilitation of needed changes.   In 2017, Armstrong et al published a study which showed a significant improvement in quality of life (QoL) of DAOA patients following an 8-week lower body strength training program with the Dysautonomia Clinic’s multidisciplinary approach. In Chapter 2, we sought to determine the sustainability of QoL changes at least two years after participation in the original study. Seven of the original 17 participants completed study questionnaires. We found that QoL remained stable over time in these DAOA patients. There was a small improvement in median QoL scores, but the improvement in scores was not statistically significant. We found that symptom burden remained similar and, although there was a slight improvement in QoL, it still remained below average indicating low QoL. We concluded that ongoing work must be done for these patients as they transition from pediatric to adult care and new ways to support patients must be found.   In Chapter 3, our aim was to characterize DAOA patients presenting in the Dysautonomia Clinic to gain a more thorough understanding of our patient cohort. We found that patients presented with low QoL, high symptom burdens and poor exercise tolerance. DAOA patients were shown to frequently miss school, have long times between initial symptom presentation and diagnosis/treatment and try multiple medications for symptom relief without improvements. We concluded that patients were debilitated by their condition and  83 functioning lower than healthy children in terms of QoL and exercise. We recognized that we must look for other ways to intervene earlier and support DAOA patients more effectively in order to improve outcomes.   In Chapter 4, we conducted a preliminary chart review of the mental health of our patient cohort. While we support patient’s mental health through our clinical psychologist in the multidisciplinary clinic, there was lack of research looking at underlying mental health challenges DAOA patients experience. Our aim was to better understand the mental health of DAOA patients as it may contribute to the low QoL as seen in Chapter 2 and 3. We found that 65% of adolescents with dysautonomia are affected by mental health challenges, some of which were diagnosed (43%) and others which were present but not substantial enough to receive a diagnosis or was suspected (22%). We found suicidal ideation occurred in 15% of our cohort. This study highlighted the prevalence of mental health challenges in our DAOA patients which pushes us to implement more supports for mental health.    Conclusions from Chapter 2, 3 and 4 displayed a common theme throughout. Adolescents with dysautonomia need more support throughout their journey with this condition. We have concluded that the QoL of adolescents continues to be low, symptoms affect daily living and, with prevalent mental health challenges in DAOA patients, increased support from HCP may be beneficial to facilitate better outcomes. These chapters form the background and rationale for Chapter 5, a novel approach to communication between patients and their HCP.    84  In Chapter 5, we conducted a pre-post study to evaluate the implementation of a clinical digital messaging (CDM) platform to support DAOA patients. We concluded that while QoL and symptom burden remained stable throughout the study period, CDM was a valuable clinical resource in communication with adolescents affected by dysautonomia. The majority of participants in our study felt they were better supported, that the use and access to CDM improved their well-being and allowed them to manage their symptoms better. Compared to other studies using the same CDM technology, our patient cohort needed considerable follow-up from HCP and were active in using CDM to reach out for help/advice.  6.2 Overall Summary First and foremost, the DAOA patients have a relatively stable, low QoL. Multiple factors may play a role in this including high symptom burden, extended periods between symptom onset and treatment, mental health challenges and removal from regular adolescent activities such as school and sport. DAOA patients need support in managing their condition as shown by low QoL and high symptom burden. The CDM tool by WelTel has allowed adolescents within the Dysautonomia Clinic to directly contact their HCP using an easy and accessible form of communication, which previously has not been utilized for this purpose. The use of CDM has been successful in facilitating feelings of support for our study cohort with overwhelmingly positive feedback from participants.   6.3 Future Directions Currently, a study is being conducted to assess the mental health of DAOA patients using validated mental health measures to screen for depression and anxiety, an initial limitation of  85 Chapter 4. This study is in progress and aims to assess all current patients in the Dysautonomia Clinic.   A larger, randomized control trial of the use of CDM as a communication tool in DAOA patients should be considered. This will allow us to more accurately determine the differences in well-being between participants given weekly check-ins by their HCP and those that receive standard of care. DAOA produces a variety of symptoms which may be different for each individual as well as the frequency in which symptoms occur. Based on this, intervention participants should be matched with a standard of care control that has similar areas of symptom burden to account for the diversity of DAOA patients. We must also consider the mental health of DAOA patients with equal numbers of participants affected and unaffected by challenges in each arm of the study.   6.4 Clinical Significance The knowledge accumulated from Chapters 1-5 has the potential to change clinical practice for DAOA patients. The re-evaluation of clinical tools used to describe DAOA patients such as QoL measures (PedsQLTM) as a proxy for well-being should be considered. Current QoL measures may not be the most appropriate for DAOA patients. As stated in Chapter 3, discharge of patients occurred when there was an improvement in overall functioning (based on patient, parent and HCP reflection). The reported improvement has not been captured by our current measures of well-being. More appropriate measures may focus on how symptoms interfered with adolescents’ daily lives and coping as we know from Chapters 2, 3 and 5 symptom burden is similar following Dysautonomia Clinic treatment and intervention.  86 Symptom interference has been reported by patients to lessen over time as they learn to manage symptoms and cope more effectively. This change is not captured in our current use of clinical tools. Thus, we may have to adopt measures that evaluate symptom interference in daily activities which patients have expressed changes rather than overall symptom burden which remains relatively similar.  Furthermore, our Chapter 5 study showed high levels of patient engagement and satisfaction with the WelTel CDM platform. The use of CDM in the Dysautonomia Clinic has now been established as a way to directly support patients in-between their clinical appointments. 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J Asthma. 2018:1-13.  97 Appendices Appendix A  Symptom Burden     CHILDREN’S HEART CENTRE -DYSAUTONOMIA CLINIC- Clinical Questionnaire  Patient Name:    Date:  Age:  Please have your child circle the appropriate answer below:  Five-Point Scale  0 Never or almost never have the symptom 1 Occassionally have it, effect is not severe 2 Occassionally have it, effect is severe 3 Frequently have it, effect is not severe 4 Frequently have it, effect is severe N/A Not applicable  NEUROLOGIC Headaches 0 1 2 3 4 N/A Syncope (passing out) 0 1 2 3 4 N/A Dizziness (light-headedness) 0 1 2 3 4 N/A Vision changes 0 1 2 3 4 N/A Vertigo (room moving) 0 1 2 3 4 N/A Paresthesias (numbness or tingling) 0 1 2 3 4 N/A Poor memory 0 1 2 3 4 N/A Brain fog 0 1 2 3 4 N/A Confusion, poor concentration 0 1 2 3 4 N/A  98 Poor physical coordination 0 1 2 3 4 N/A Slurred speech 0 1 2 3 4 N/A Learning disabilities 0 1 2 3 4 N/A  CARDIAC Fast heartbeat 0 1 2 3 4 N/A Slow heartbeat 0 1 2 3 4 N/A High blood pressure 0 1 2 3 4 N/A Low blood pressure 0 1 2 3 4 N/A Skipped heartbeat 0 1 2 3 4 N/A Pounding heartbeat 0 1 2 3 4 N/A Chest pain/tightness 0 1 2 3 4 N/A   GASTROINTESTINAL Nausea 0 1 2 3 4 N/A Vomiting 0 1 2 3 4 N/A Intestinal/Stomach pain 0 1 2 3 4 N/A Irritable bowel 0 1 2 3 4 N/A Constipation 0 1 2 3 4 N/A Diarrhea 0 1 2 3 4 N/A Post-meal symptoms 0 1 2 3 4 N/A Heart burn 0 1 2 3 4 N/A Bloating 0 1 2 3 4 N/A  SKIN Flushing, hot flashes 0 1 2 3 4 N/A Paleness of face 0 1 2 3 4 N/A Blue extremeties 0 1 2 3 4 N/A Pale extremeties 0 1 2 3 4 N/A Cold extremeties 0 1 2 3 4 N/A Swelling of extremeties 0 1 2 3 4 N/A Excessive sweating (clammy) 0 1 2 3 4 N/A Heat intolerance 0 1 2 3 4 N/A Cold intolerance 0 1 2 3 4 N/A  JOINTS/MUSCLES Pain or aches in joints 0 1 2 3 4 N/A Pain or aches in muscles 0 1 2 3 4 N/A Feeling of weakness 0 1 2 3 4 N/A Painful trigger points 0 1 2 3 4 N/A   99 ENERGY/ACTIVITY Fatigue,  sluggishness 0 1 2 3 4 N/A Apathy, lethargy 0 1 2 3 4 N/A Hyperactivity 0 1 2 3 4 N/A Sleep disturbance 0 1 2 3 4 N/A Exercise intolerance (sports/activities) 0 1 2 3 4 N/A Missing school 0 1 2 3 4 N/A Not able to see friends 0 1 2 3 4 N/A       100 Appendix B  PedsQLTM Self-Report for Teens  101    102 Appendix C  PedsQLTM Parent-proxy report for Teens     103       104 Appendix D  PRE-Survey           Texting and Connecting PRE-SMS Survey (Participants):   Communicating with the Health Care Team  Please answer as truthfully as you can:  1. Do you feel that it would be beneficial to be able to text message your health care team? a. Yes b. No 2. Do you feel that being able to text your health care team would increase your wellbeing? a. Yes b. No 3. Would you respond to a weekly text message? a. Yes b. No 4. Do you feel that receiving a weekly text message would increase you motivation to: a. Increase water intake i) Yes ii) No b. Increase salt intake i) Yes  ii) No c. Increase exercise i) Yes ii) No 5. Can you foresee any problems communicating via text message? Children’s Heart Centre B.C. Children’s Hospital 4480 Oak Street, 1F Clinic Vancouver, B.C.   V6H 3V4  105 Please list: _______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________  6. Do you have any concerns about communicating with your health care provider by text messaging?    ______________________________________________________________________________  ______________________________________________________________________________  ______________________________________________________________________________                             106 Appendix E  POST-Survey           Texting and Connecting POST-SMS Survey:   Please answer as truthfully as you can:  1. Did you find it useful to be able to text your health care team? a. Yes b. No Please explain why: ______________________________________________________________________________  ______________________________________________________________________________  ______________________________________________________________________________  2. Would it be helpful to continue to be able to text message your health care team? a. Yes b. No During the intervention (ie text messaging study): 1. Did you have any problems receiving text messages from the clinic? a. Yes b. No              Please explain: ____________________________________________________________________________  ______________________________________________________________________________  ______________________________________________________________________________  Children’s Heart Centre B.C. Children’s Hospital 4480 Oak Street, 1F Clinic Vancouver, B.C.   V6H 3V4  107 2. Did you have any problems sending text messages? a. Yes b. No              Please explain: ______________________________________________________________________________  ______________________________________________________________________________   3. Did receiving weekly texts help you: a. Increase your water intake i. Strongly Agree ii. Agree iii. Neutral iv. Disagree v. Strongly Disagree b. Increase your salt intake i. Strongly Agree ii. Agree iii. Neutral iv. Disagree v. Strongly Disagree c. Increase your exercise i. Strongly Agree ii. Agree iii. Neutral iv. Disagree v. Strongly Disagree d. Manage your symptoms better i. Strongly Agree ii. Agree iii. Neutral iv. Disagree v. Strongly Disagree e. Increase your wellbeing i. Strongly Agree ii. Agree iii. Neutral iv. Disagree v. Strongly Disagree  108 f. Help you remember your clinic appointments i. Strongly Agree ii. Agree iii. Neutral iv. Disagree v. Strongly Disagree g. Feel more in charge of your own care i. Strongly Agree ii. Agree iii. Neutral iv. Disagree v. Strongly Disagree  4. Did you feel better connected to your health care team by receiving text messages? a. Yes b. No c. No difference Please explain what was useful or not useful about them: ______________________________________________________________________________  ______________________________________________________________________________  ______________________________________________________________________________  5. How did you feel about the frequency of the text messages you received?   a. Too frequent b. Just right c. Not frequent enough  If you think the messages were sent too frequently, or not frequently enough, what frequency would you prefer? ______________________________________________________________________________  ______________________________________________________________________________     109 6. Did you feel comfortable asking for help using a text message? a. Yes b. No If no, why not? ______________________________________________________________________________  ______________________________________________________________________________       7. Would you recommend this text messaging program to a friend with a long-term medical condition?        a. Yes b. No If no, why not? ______________________________________________________________________________  ______________________________________________________________________________       8. How often do you think future check in text message should be sent? a. Daily   b. Twice a week  c. Once a week d. Monthly             e. Not at all   f. Other (specify): ______________________     9. What was the greatest obstacle to participating in this study?   ______________________________________________________________________________  ______________________________________________________________________________  ______________________________________________________________________________    110 10. What was the greatest benefit that you received from the weekly text messages? ______________________________________________________________________________  ______________________________________________________________________________       ______________________________________________________________________________    11. Is there anything about this program you did not like?  ______________________________________________________________________________  ______________________________________________________________________________  ______________________________________________________________________________                            1 Appendix F  Participant Symptom Burden 0=never present, 1=occasionally present, 2=frequently present  P1  P2 P3 P4 P5 P6 P7 P8 P9  T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 Neurologic                            Headaches 2 2 1 2 2 0 2 1 1 2 1 2 2 2 2 1 2 1 2 2 2 1 2 2  2 0 Syncope 2 1 2 1 1 0 1 1 2 0 0 1 0 0 0 2 0 0 2 2 1 0 0 0  0 0 Dizziness 2 2 2 2 2 2 1 2 2 2 1 2 2 1 2 2 2 2 2 2 1 1 2 2  1 1 Vision changes 2 2 1 2 2 2 2 1 2 1 0 2 2 1 2 1 2 2 0 1 0 0 0 0  0 0 Vertigo 2 2 2 2 2 1 1 2 0 2 1 1 1 0 1 0 1 0 1 1 1 0 0 0  1 0 Paresthesia 1 1 2 2 2 2 1 1 1 0 0 1 1 1 1 0 0 1 1 1 1 1 1 0  1 1 Poor memory 2 1 2 2 2 2 1 1 1 0 1 1 1 1 2 0 0 1 0 1 1 2 2 2  1 2 Brain fog 2 2 2 2 2 2 1 2 2 1 1 1 2 1 2 1 2 2 1 1 2 0 2 2  1 2 Confusion/Poor concentration 2 2 1 2 2 2 1 2 2 1 0 1 1 2 2 1 2 1 1 1 2 2 2 2  2 2 Poor physical coordination 1 1 1 1 2 2 0 1 1 1 1 1 1 1 2 2 0 0 0 1 1 0 1 0  0 0 Slurred speech 0 0 0 1 1 2 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0  0 1 Learning disabilities 0 0 0 2 2 2 1 0 0 1 0  0 0 2 0 0 0 0 0 0 0 0 0  0 2 Cardiac                            Fast heartbeat 2 2 2 2 2 2 1 1 1 1 1 2 0 0 1 2 1 1 0 2 2 0 0 0  2 2 Slow heartbeat 0 0 0 2 2 0 2 2 1 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0  0 0 High blood pressure 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0  0 0 Low blood pressure 2 2 2 2 2 2 1 0 1 0 0 0 2 2 2 2 0 1 0 0 0 0 0 0  0 2 Skipped heartbeat 0 1 1 2 1 0 1 0 1 0 0 0 0 0 1 0 0 0 2 2 1 0 0 0  0 0 Pounding heartbeat 2 2 2 2 2 2 2 1 1 2 1 1 1 0 1 2 1 1 2 2 2 0 0 0  0 2 Chest pain/tightness 2 2 2 2 2 0 2 2 2 0 1 1 1 1 1 2 2 1 2 1 2 0 0 0  0 1 Gastrointestinal                            Nausea 2 2 2 2 1 2 2 2 2 2 2 2 0 1 1 2 2 2 1 1 0 0 1 0  2 0 Vomiting 1 2 2 0 1 2 2 2 2 1 1 1 1 1 2 0 0 0 0 0 0 0 0 0  0 0 Intestinal/Stomach pain 2 2 2 2 2 2 2 2 2 2 0 0 1 1 1 0 2 1 2 0 1 0 0 1  1 0 Irritable bowel 0 0 0 2 2 2 2 2 2 1 0 0 1 1 0 2 2 2 1 2 2 0 0 0  1 0 Constipation 0 0 0 2 2 2 1 2 2 1 0 0 1 0 1 2 2 2 1 1 1 0 2 0  1 0  2 Diarrhea 0 0 0 2 2 2 2 2 2 0 0 0 1 0 1 0 0 1 1 2 2 1 1 0  1 0 Post-meal symptoms 2 2 2 2 2 2 2 2 2 2 1 1 0 1 0 2 2 2 2 1 2 0 0 0  1 0 Heart burn 1 2 2 2 2 2 2 2 2 1 1 1 0 1 0 2 2 1 1 1 0 0 1 1  1 0 Bloating 0 1 2 2 2 2 2 2 2 0 0 0 1 1 0 2 1 2 1 0 1 0 2 2  1 0 Skin                            Flushing, hot flashes 2 0 1 2 2 2 2 1 2 1 0 1 1 0 1 2 2 2 1 2 1 0 0 0  1 2 Paleness of face 2 2 2 2 2 2 2 2 2 0 0 0 2 2 2 2 2 1 1 1 0 0 0 1  2 2 Blue extremities 0 0 2 0 1 1 0 0 0 0 0 0 1 2 1 2 2 2 1 1 1 0 0 0  2 2 Pale extremities 2 2 2 2 2 2 1 2 2 0 0 0 0 1 2 2 2 2 0 0 0 0 1 1  2 2 Cold extremities 2 2 2 2 2 2 1 1 2 1 0 0 1 1 1 2 2 2 1 2 1 0 0 0  2 2 Swelling of extremities 0 0 1 2 2 0 1 1 0 0 0 0 1 2 1 0 0 2 2 0 1 0 0 0  0 0 Excessive sweating (clammy) 2 1 2 2 2 2 2 2 2 1 0 1 1 2 2 2 1 2 2 2 2 0 0 1  0 2 Heat intolerance 2 1 2 2 2 2 2 2 2 1 0 1 2 2 2 2 2 2 2 2 0 1 0 2  2 2 Cold intolerance 2 1 2 2 2 2 1 2 1 1 0 1 0 2 2 0 0 1 2 0 1 0 0 2  2 2 Joints/Muscle                            Pain or aches in joints 2 2 2 2 2 2 2 2 1 1 1 1 1 2 1 2 1 1 0 1 2 0 0 0  2 2 Pain or aches in muscles 2 2 2 2 2 2 2 2 1 1 1 1 1 2 1 2 2 2 0 1 0 2 1 2  2 2 Feeling of weakness 2 2 2 2 2 2 2 2 2 2 1 1 1 2 1 2 2 2 0 1 2 2 2 2  2 2 Painful trigger points 2 1 2 2 2 2 1 2 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0  2 2 Energy/Activity                            Fatigue, sluggishness 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 2 2 2 2 2 2 2 2 2  2 1 Apathy, lethargy 2 2 2 2 2 2 2 2 2 2 1 1 1 1 1 2 0 0 1 1 2 2 0 2  2 0 Hyperactivity 0 0 0 0 0 0 1 0 0 0 0 0 1 0 1 0 0 0 1 1 0 0 0 0  0 0 Sleep disturbance 0 1 2 2 2 2 2 2 1 1 0 1 2 2 1 1 0 1 1 1 0 0 0 1  0 2 Exercise intolerance (sports/activities) 0 1 2 2 2 2 2 1 1 2 2 1 2 2 1 2 1 1 1 2 2 2 2 2  1 1 Missing school 2 2 2 2 2 2 2 2 2 0 1 0 2 2 2 2 1 0 1 2 1 2 1 1  1 1 Not able to see friends 2 2 2 2 2 1 2 2 2 1 1 0 2 2 2 2 0 1 1 1 0 0 1 2  1 1    3   P10  P11 P12 P13 P14 P15 P16 P17 P18  T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 Neurologic                            Headaches 1 1 1 2 2  2 2 2 2 1 1 1 1 2  2 2 0 0 0 1 0 0 2 2 2 Syncope 2 0 2 0 0 2 0 0 0 0 0 0 0 0 0  1 1 1 1 0 0 0 0 1 0 1 Dizziness 0 0 1 2 2 1 2 2 2 2 2 2 2 2 2  2 2 2 2 2 2 2 0 2 1 2 Vision changes 0 0 0 2 1 2 2 2 2 1 0 1 1 1 1  2 2 2 2 0 2 0 0 1 0 1 Vertigo 0 0 0 1 1 2 2 2 1 0 2 2 2 1 2  0 2 1 2 1 1 1 0 1 0 1 Paresthesia 1 0 0 1 0 1 2 2 2 1 1 1 1 1 2  1 2 0 0 1 2 1 0 1 0 2 Poor memory 0 0 0 1 1 2 1 2 2 1 1 2 0 1 0  1 1 2 2 2 0 0 0 2 2 2 Brain fog 0 0 0 1 1 2 1 2 2 2 2 2 1 2 2  1 1 2 2 1 0 0 0 1 2 2 Confusion/Poor concentration 0 0 0 2 2 2 1 2 2 2 1 2 1 1 1  1 1 2 2 2 0 0 0 1 2 2 Poor physical coordination 0 0 0 1 1 2 0 1 0 1 2 0 1 2 1  0 1 1 1 0 0 0 0 2 0 1 Slurred speech 0 0 0 0 0 1 0 1 0 1 0 0 0 0 0  0 1 2 0 0 0 0 0 1 0 0 Learning disabilities 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0  0 0 2 0 2 0 0 0 2 2 2 Cardiac                            Fast heartbeat 1 0 0 2 1 0 2 1 2 2 2 2 2 2 2  2 2 0 2 0 2 1 1 2 2 2 Slow heartbeat 0 0 0 1 1 2 1 1 0 0 0 0 0 0 0  1 2 0 2 0 0 0 0 1 0 0 High blood pressure 0 0 0 0 0 1 0 1 1 0 0 0 0 0 0  0 2 0 0 0 0 0 0 0 0 0 Low blood pressure 1 1 1 1 0 1 2 1 2 2 2 2 2 2 2  2 2 0 2 2 0 0 0 2 2 2 Skipped heartbeat 0 0 0 1 1 1 0 1 2 0 0 1 0 0 0  0 2 0 0 0 0 0 0 2 1 1 Pounding heartbeat 0 0 0 2 2 2 2 2 2 2 2 2 1 2 2  2 2 0 2 1 1 0 1 2 1 2 Chest pain/tightness 0 0 0 2 2 2 2 2 2 1 1 1 0 1 2  2 2 0 2 2 0 1 1 1 0 1 Gastrointestinal                            Nausea 0 0 1 2 2 2 2 1 2 2 2 2 2 2 2  2 2 1 2 1 2 0 0 1 2 2 Vomiting 0 0 0 1 1 2 0 0 1 1 0 1 1 1 0  0 1 0 0 0 0 0 0 1 0 1 Intestinal/Stomach pain 1 1 0 2 1 0 2 2 2 2 1 1 1 2 2  1 2 2 2 1 1 1 0 1 0 0 Irritable bowel 0 0 0 1 0 2 2 2 2 2 1 2 2 0 1  0 2 2 2 2 0 0 0 0 0 0 Constipation 0 0 0 2 1 2 2 2 2 1 1 2 0 0 0  0 1 2 2 1 0 0 0 1 0 0 Diarrhea 0 0 0 0 0 2 2 2 2 1 1 2 1 1 0  1 2 2 1 1 0 0 0 1 0 1  4 Post-meal symptoms 0 0 0 0 1 0 2 2 1 2 2 2 0 1 0  0 1 1 2 1 0 0 0 0 0 1 Heart burn 0 0 0 2 2 2 1 2 1 1 2 1 0 0 0  0 1 2 1 1 0 0 0 1 0 1 Bloating 0 0 0 1 0 2 0 1 0 1 1 2 1 2 1  1 1 2 2 1 0 0 0 0 0 0 Skin                            Flushing, hot flashes 0 0 0 1 0  0 0 1 2 2 2 2 2 1  0 2 1 0 0 2 2 1 0 0 0 Paleness of face 1 0 0 1 0 1 2 1 2 2 2 2 2 2 2  1 2 2 1 0 2 1 1 2 1 2 Blue extremities 0 0 0 0 0 1 2 1 2 2 0 0 0 0 0  0 2 0 0 0 2 0 0 1 1 2 Pale extremities 0 0 1 0 0 0 2 1 2 2 0 2 1 1 2  0 2 0 0 0 2 0 0 2 1 2 Cold extremities 0 1 1 0 0  2 1 2 2 2 2 0 0 0  1 2 2 2 2 0 0 0 2 1 2 Swelling of extremities 0 0 0 0 0 0 0 0 0 0 2 2 0 0 0  0 2 0 0 0 0 0 0 0 0 0 Excessive sweating (clammy) 0 0 0 0 0 0 1 0 2 2 0 1 2 2 2  1 2 1 1 1 2 0 1 2 2 0 Heat intolerance 0 0 0 1 0 0 0 0 1 2 2 2 0 0 0  0 2 0 2 0 0 0 0 2 2 2 Cold intolerance 0 0 1 1 0 0 0 0 1 2 2 2 0 0 0  0 2 2 0 0 0 0 0 0 0 0 Joints/Muscle                            Pain or aches in joints 0 0 0 1 2 1 2 1 2 2 0 1 0 0 1  2 1 2 2 0 2 0 0 2 1 1 Pain or aches in muscles 0 0 0 1 2  2 1 2 2 0 1 0 1 1  2 1 0 2 0 1 1 0 1 1 1 Feeling of weakness 0 1 1 1 2  2 2 2 2 2 2 0 1 1  2 2 2 2 0 2 2 1 1 1 1 Painful trigger points 0 0 0 0 2  1 1 0 0 0 0 0 0 0  2 1 2 2 0 0 0 0 0 0 0 Energy/Activity                            Fatigue, sluggishness 1 2 2 1 2  2 2 2 2 2 2 2 1 2  2 1 2 2 2 2 2 0 1 1 2 Apathy, lethargy 1 1 0 0 1 2 2 2 2 2 2 1 1 0 1  0 0 2 2 2 0 0 0 1 2 0 Hyperactivity 0 0 0 1 1 2 1 0 0 2 0 0 0 0 0  0 1 0 1 0 0 0 0 1 1 1 Sleep disturbance 2 2  2 2 2 2 2 2 2 2 1 2 2 1  2 1 2 0 1 1 2 0 2 2 2 Exercise intolerance (sports/activities) 0 0 1 1 1 2 2 1 2 2 1 2 2 1 2  0 0 2 2 0 1 1 1 2 2 2 Missing school 2 1 2 2 1 2 2 2 2 0 0 0 1 1 1  0 1 2 2 1 1 1 0 1 2 1 Not able to see friends 2 1 2 1 1 0 2 2 2 0 0 0 0 0 0  0 1 1 2 1 1 1 0 0 1 0                               5   P19  P20 P21 P22 P23 P24 P25 P26  T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 T0 T1 T2 Neurologic                         Headaches 2  2 2 2 2 0 0 0 1 1 0 1 1 1 2 1 1 2  1 1 1 2 Syncope 1  1 0 0 0 1 1 1 0 0 0 0 0 1 0 0 0 1  1 1 0 2 Dizziness 2  2 2 2 1 1 2 2 2 2 1 2 1 1 1 1 1 2  2 2 2 2 Vision changes 2  2 2 1 0 0 0 1 1 1 1 1 1 2 0 0 1 2  1 2 2 2 Vertigo 0  1 1 1 1 0 0 0 2 2 1 1 1 2 0 0 0 2  1 1 0 1 Paresthesia 2  2 0 0 1 0 1 1 0 0 0 1 1 2 1 1 2 2  1 2 2 2 Poor memory 0  1 0 0 1 0 1 2 2 2 2 1 1 2 1 1 2 2  2 2 2 2 Brain fog 1  2 1 0 1 0 2 2 2 2 0 1 2 2 0 2 2 2  2 1 2 1 Confusion/Poor concentration 1  2 1 0 1 1 2 2 1 1 1 1 1 2 2 1 1 2  2 2 2 1 Poor physical coordination 1  1 1 1 2 0 1 1 0 0 0 1 0 1 0 1 1 1  2 2 2 1 Slurred speech 0  0 0 0 0 0 0 0 1 2 1 0 0 1 0 0 1 1  2 0 0 0 Learning disabilities 1  0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 2  1 0 0 0 Cardiac                         Fast heartbeat 0  1 1 1 1 0 0 1 2 2 2 2 2 1 1 1 2 2  2 2 2 2 Slow heartbeat 0  0 0 0 0 0 1 0 0 0 1 0 2 1 0 0 0 0  0 0 0 0 High blood pressure 0  0 0 0 1 0 0 0 1 0 0 0 2 1 1 0 0 0  1 0 0 0 Low blood pressure 2  2 1 0 1 2 2 2 0 1 0 2 1 1 1 1 2 2  2 2 2 2 Skipped heartbeat 0  0 0 0 0 0 0 0 1 0 0 2 0 0 0 0 0 0  2 1 0 0 Pounding heartbeat 1  1 2 2 2 0 0 1 2 2 2 2 0 2 1 1 1 1  2 1 0 1 Chest pain/tightness 1  1 1 1 1 1 1 1 0 0 0 2 2 2 1 2 2 1  2 1 0 1 Gastrointestinal                         Nausea 2  2 2 2 2 0 0 0 2 1 1 2 2 2 1 2 1 2  2 0 0 2 Vomiting 2  2 0 1 0 0 0 0 2 1 1 0 1 1 0 0 0 2  0 0 0 0 Intestinal/Stomach pain 2  2 2 2 2 0 0 0 1 0 1 2 2 2 1 0 1 2  1 0 0 0 Irritable bowel 0  0 0 0 0 0 0 0 0 0 0 2 2 2 0 0 0 0  0 0 0 0 Constipation 0  0 0 1 2 0 0 0 0 0 0 1 1 2 1 1 0 0  0 0 0 0 Diarrhea 0  0 0 0 0 0 0 0 0 0 0 1 2 2 1 1 1 0  0 0 0 0 Post-meal 2  2 0 2 2 0 0 0 1 1 0 1 0 0 0 1 2 2  0 1 0 1  6 symptoms Heart burn 1  1 1 0 0 0 1 1 0 0 0 0 1 0 0 0 0 1  1 1 0 1 Bloating 1  1 1 1 2 0 0 0 0 0 0 1 1 1 0 1 1 1  0 0 0 0 Skin                         Flushing, hot flashes 1  1 2 1 2 0 0 1 0 1 0 0 1 2 0 1 1 2  2 0 1 0 Paleness of face 0  0 0 0 0 0 2 2 1 2 1 0 1 1 1 1 0 2  2 2 2 2 Blue extremities 0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2  1 1 1 2 Pale extremities 0  0 0 0 1 0 0 0 0 2 0 0 0 1 1 0 0 2  2 1 1 0 Cold extremities 1  2 0 1 2 0 0 2 0 1 0 1 1 2 2 2 2 1  2 2 2 2 Swelling of extremities 0  0 0 0 0 0 0 0 0 0 0 2 2 2 0 1 2 1  1 0 0 0 Excessive sweating (clammy) 1  1 0 0 0 0 0 0 0 0 0 1 2 2 0 1 2 2  2 1 1 2 Heat intolerance 1  2 0 0 0 1 1 1 0 1 1 0 0 1 1 2 2 2  2 2 2 1 Cold intolerance 1  2 0 1 1 0 0 0 0 0 1 2 2 2 0 1 0 0  1 2 1 1 Joints/Muscle                         Pain or aches in joints 2  2 0 0 0 1 0 2 0 0 0 0 1 1 0 1 2 2  2 1 1 2 Pain or aches in muscles 1  2 1 1 1 1 0 1 1 1 0 1 1 1 0 1 1 2  2 2 1 1 Feeling of weakness 2  2 2 1 2 0 0 0 0 2 1 1 1 2 2 1 2 2  2 2 2 2 Painful trigger points 0  0 0 0 2 0 0 0 0 0 0 1 1 0 0 0 0 2  1 0 0 0 Energy/Activity                         Fatigue, sluggishness 2  2 2 2 2 0 1 0 1 2 1 2 2 2 2 1 2 2  2 2 2 2 Apathy, lethargy 1  2 0 0 2 0 1 0 2 2 0 0 2 2 2 1 1 2  1 1 0 1 Hyperactivity 0  1 0 0 2 1 0 2 2 0 0 1 2 2 0 0 0 1  1 1 0 1 Sleep disturbance 1  2 2 2 2 1 0 0 1 0 1 2 2 1 1 1 0 1  2 2 2 0 Exercise intolerance (sports/activities) 2  2 0 1 2 1 0 1 1 2 0 2 2 2 2 1 1 1  2 2 2 2 Missing school 2  2 1 1 1 0 0 0 1 1 1 1 1 1 2 0 0 2  1 2 2 2 Not able to see friends 2  2 0 0 1 0 0 0 1 0 1 0 1 1 2 1 1 2  2 2 2 1  

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