Pediatric Composite Autonomic Symptom Score-Caregiver Questionnaire (Ped-COMPASS-CQ): a new Italian tool for the assessment of dysautonomy in children

Pediatric Composite Autonomic Symptom Score-Caregiver Questionnaire (Ped-COMPASS-CQ): a new Italian tool for the assessment of dysautonomy in children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Pediatric Composite Autonomic Symptom Score-Caregiver Questionnaire (Ped-COMPASS-CQ): a new Italian tool for the assessment of dysautonomy in children Marisa Gazzillo, Gianluca Sesso, Antonio Varone, Emanuele Bartolini, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8613624/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To obtain the standardization and validation of Ped-COMPASS-CQ (Pediatric Composite Autonomic Symptom Score - Caregiver Questionnaire); this new tool was formulated to assess the autonomic symptom profile in the pediatric population. Specifically, we started with the validated COMPASS-31 questionnaire and adapted it for caregiver completion. We added questions to explore additional dysautonomic symptoms not covered in the original questionnaire, including headache, sleep disturbance, neuropathic pain, fatigue, and thermoregulation. Methods We recruited 1888 caregivers of children aged between 5 and 16 years in the period from August 2022 to February 2024. In order to develop a statistically valid instrument, we corroborated the internal structure of the questionnaire through a confirmatory factor analysis; the construct validity of the questionnaire was also confirmed through generalized linear regression models. The internal consistency of the subscales was analyzed by estimating the Cronbach's Alpha as well as by computing Spearman's inter-scale and item-scale correlation coefficients. Results We obtained the standardized reference values of the general population of children, expressed as mean and standard deviation in each autonomic domain and in the total score of the questionnaire. Conclusion Ped-COMPASS-CQ seems to be a sensitive tool for early detection of autonomic dysfunction in children, easy to use and with a low economic impact. The scores obtained represent a starting point to study the function of the autonomic nervous system in pediatric subjects. It could be an ecological tool to be adopted as a first approach to the symptomatic patient with dysautonomia or for monitoring an autonomic dysfunction. dysautonomy pediatric neurology autonomic symptom score COMPASS-31 Figures Figure 1 1. Introduction The Autonomic Nervous System (ANS) is a neuromotor system consisting of a set of nerve cells and fibers distributed throughout the body, whose function is to coordinate bodily homeostasis with autonomic mechanisms that are not under voluntary control. Autonomic dysfunction, also known as dysautonomia, shows itself with very variable and diverse symptoms, even more in children in whom the nervous system has not yet reached its full maturity [ 1 ]. Autonomic function requires intact peripheral receptors, either of the skin or internal organs, and a neuronal network of small afferent fibers capable of adequately transmitting information to the Central Nervous System (CNS). Genetic or acquired conditions that impair development and/or impede migration, differentiation, survival or neuronal function at any point along these pathways, may result in ANS dysfunction [ 2 ]. Studies on the pathology of the ANS are scarce and mainly focused on the description of single apparatus dysfunctions in adult patients, with few studies in the pediatric setting, mostly using instrumental investigations (e.g. tilt table test, pressure monitoring after vagal stimulation, quantitative assessment of the axonal sudomotor reflex [ 3 ]), which are not easy to perform in children with multiple comorbidities or poor compliance. Assessment of the most distressing or prominent features of autonomic dysfunction is important to confirm a diagnosis and to provide objective evidence to support treatment before invasive tests are carried out [ 4 ]. The COMPASS-31 questionnaire [ 5 ] is a new tool that has been validated in the monitoring of dysautonomia in adult patients. It consists of 31 self-administered questions validated to measure orthostatic intolerance, vasomotor function, secretomotor, gastrointestinal, bladder and pupillary contractility, all domains representative of ANS function. The Italian version of COMPASS-31 has been validated [ 6 ] and it is now part of monitoring protocols for diabetic neuropathy and familial amyloidosis. Unfortunately, such a reliable clinical tool for the pediatric age group aimed to capture dysautonomia in its entirety is still missing [ 7 ]. Thus, the present study aimed to develop a tool to detect and monitor the functioning of the pediatric autonomic nervous system similar to COMPASS-31. 2. Materials and methods 2.1. Study Design The present study aimed to validate in Italian language a pediatric adaptation of the COMPASS-31 questionnaire, to be completed by the caregiver, which we named Pediatric Composite Autonomic Symptom Score - Caregiver Questionnaire (Ped-COMPASS-CQ). The Ped-COMPASS-CQ has been standardized for the general population between the ages of 5 and 16, on the reasonable assumption that by the age of 5 the nervous system is fully myelinated and mature to regulate autonomic functions. The Ped-COMPASS-CQ consists of a total of 51 questions, 24 exploratory of the domains of ANS included in COMPASS-31 (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal—mixed upper and diarrhea, bladder and pupillomotor) and 27 additional questions designed to explore other dysautonomic symptoms such as headache [ 8 , 9 ], sleep disturbance [ 10 , 11 ], neuropathic pain [ 12 ], fatigue [ 13 ] and thermoregulation [ 14 ] that seem relevant to ANS dysfunction in children [ 15 ]. In this way, the Ped-COMPASS-CQ will allow us to examine fourteen domains potentially representative of ANS functioning, testing the presence, frequency, severity and location (if applicable) of symptoms and their evolution over time. The validation has been performed in a general population of healthy subjects. Participants were recruited from all over Italy, from family members of patients followed by the IRCCS Stella Maris Foundation or through advertisements or meetings with schools or associations of patients with neuropsychiatric disorders, who were more sensitive to the issue and therefore inclined to disseminate the questionnaire. Inclusion criteria for children to enroll in the study were: (i) age 5–16 years with caregivers available to fill questionnaire; (ii) absence of medical conditions potentially responsible for and/or associated with dysautonomia reported in literature (i.e. inherited or acquired neurological or neuromuscular conditions [ 16 – 26 ], genetic or malformative syndromes [ 27 – 28 ], autism and other neurodevelopmental conditions as well as major emotional and behavioral disorders [ 29 – 31 ] on drug therapy [ 32 ]; medical or systemic conditions [ 33 ] such us oncological or lymphoproliferative diseases [ 34 ], diabetes mellitus [ 35 ], autoimmune/autoinflammatory diseases on immunosuppressive treatment [ 36 , 37 ]. We sent to the family a link to the Google form of the questionnaire or provided it in paper form. In addition, to select healthy subjects, we provided caregivers with a short questionnaire to record data on possible medical conditions (e.g. medications, pathology, etc.) [Supplemental Appendix 1]. The survey was anonymous. The caregivers of the participants were informed about the aims and methods of the study by means of an informed consent, in paper form or by accessing the Google form of the questionnaire. The study was approved by the approved by the Pediatrics Ethics of the Tuscany Region, AOU Meyer, Florence, Italy (protocol code Ped-COMPASS-CQ, date of approval: 20/8/2022). 2.2 Scoring Scheme The scoring of the questionnaire was obtained by following the simplified scoring methods of the COMPASS-31 questionnaire. We assigned a score of 1 or 0 to questions with a 'yes' or 'no' answer, and a score from 0 to 4 for questions describing the frequency, trend and severity of the symptom, depending on the severity of the situation. In the study conducted by researchers at the Mayo Clinic on the original version of the questionnaire, this scoring system has shown a greater ability to generate subscales with high internal consistency. The detailed scoring model can be found in the Supplemental Appendix 2. 2.3 Statistical Methods Descriptive statistics of demographic variables such as means and standard deviations were calculated based on the data obtained from the questionnaire. The internal structure of the questionnaire was corroborated through confirmatory factor analysis, with the aim of accurately confirming the independent subscales defined a priori in the questionnaire construction phase. The fit quality of the factor model was analyzed according to the indexes of the Chi-square adjustment test, degree of freedom (df), comparative fit index (CFI), Tucker–Lewis index (TLI), the root mean square error of approximation (RMSEA) and the standardized root mean square residual (SRMR). We applied conventional cut-offs to determine acceptable fit, including RMSEA < 0.08, SRMR 0.90 [ 37 ]. The internal consistency of the scale was analyzed by estimating Cronbach's alpha. Item-scale correlations were carried out according to the Pearson method with corrected p-value using the Bonferroni method for multiple comparisons at the significance level of 0.05 (corrected p = 0.0005). Inter-subscale Spearman’s rank correlations were also performed with a p-value corrected applying the Bonferroni method for multiple comparisons at the traditional significance level of 0.05. Correlations were considered very small for coefficients lower than 0.30, small for coefficients between 0.30 and 0.50, moderate from 0.50 to 0.70, and strong if higher than 0.70. The construct validity of the questionnaire was confirmed by generalized linear models of Poisson regression. To confirm the reliability of the instrument, the questionnaire was administered again approximately 6 to 24 months later to a subset of subjects randomly selected from the initial sample. We recruited them through an email contact that they left optionally at the end of completing the questionnaire. Test-retest reliability was assessed by computing Spearman’s correlation coefficients for each subscale individually. Once the validity of the instrument was established, we calculated the scores in single domains and in the total questionnaire to obtain standardized reference values for the general pediatric population, expressed as means and standard deviations. Analyses were performed using RStudio software. 3. Results 3.1 Participants The sample of the study was composed of 2421 respondents. Among these, 288 questionnaires were discarded because the subjects’ age exceeded the age interval of interest (5–16 years old). Of the resulting 2133 questionnaires, we removed subjects with health problems that did not meet inclusion criteria. The final number of respondents included in the study was 1888. Of the 1888 subjects recruited, 787 (41%) were female, 988 (52%) were male, 113 (7%) did not answer the question (NA). The mean age of the sample was 9,57 ± 2,94 years. Of the recruited subjects, 371 (19%) had immunological problems, 127 had respiratory problems (6%), 46 had gastrointestinal problems (2%) and 306 had neuropsychiatric problems (16%) and were excluded. Table 1 Participant characteristics Age Weight Height BMI Gender Min 5,00 14 41 9,73 787 F Max 16,00 110 187 134,56 988 M Mean 9,57 34,32 137,6 17,67 113 NA SD 2,94 13,63 18,95 6,65 Immunological Respiratory Gastrointestinal Other Diseases Neuro-psychiatric conditions No 1517 1761 1841 1838 1582 Yes 371 127 46 50 306 NA 0 0 1 0 0 Immunological disorders: patients with allergies, asthma, dermatitis, Vernal keratoconjunctivitis, celiac disease, autoimmune diseases not in drug therapy. Respiratory diseases include asthma, adeno-tonsillar hypertrophy, recurrent otitis or bronchitis. Gastrointestinal problems: subjects with gastro-esophageal reflux, recurrent gastritis, irritable colon, constipation, celiac disease too. Neuro-psychiatric conditions include condition not in drug therapy, in particular ADHD, anxiety, autism, language disorder, emotional dysregulation or mood disorders, intellectual disability, sleep disorders, enuresis, febrile convulsions, epilepsy not under pharmacological treatment. 3.2 Validation procedure of Ped-COMPASS-CQ 3.2.1 Scale construction and confirmative factor analysis We developed Ped-COMPASS-CQ by adapting the Italian version of COMPASS-31 for caregiver completion. Orthostatic, vasomotor and secretomotor function, pupillary contractility traces the same questions. Bladder subscale includes a new question about sphincter control. The gastrointestinal domain was divided into gastroparesis, constipation and diarrhea. For other domains not assessed in the original COMPASS-31, additional questions were constructed de novo or taking inspiration from validated questionnaires used in pediatric clinical practice. Specifically, for headache, we re-adapted the PedMidas (Pediatric Migraine Disability Assessment Score Questionnaire) [ 40 ] and generated four questions to assess the presence of headache symptoms and their impact on life, especially school and daily activities. For the study of neuropathic pain, questions from the sensory symptoms’ subscale of the Ped-mTNS (Pediatric-modified Total Neuropathy Score) questionnaire [ 41 ] were selected and merged, with the aim of detecting the presence and quality (pain, type of paresthesia) of the neuropathic symptom, assessing its physical destruction and its progression over time. To assess sleep disturbance, questions from the sleep disturbance subscale of the Pittsburgh Sleep Quality Index (PSQI) Italian version [ 42 ] were combined and adapted into a parent report version. To assess fatigue was used some of the core questions of the PedsQL™ Multidimensional Fatigue Scale Parent report divided into two domains: cognitive fatigue and sleep/rest fatigue [ 43 ]. To assess thermoregulation, we formulated three de novo questions following the COMPASS-31 model, investigating the presence of fever outside infectious episodes, the frequency of fever episodes and the trend over time. Thus, we obtained a questionnaire of 51 questions that explores fourteen domains of autonomic function: orthostatic intolerance, vasomotor function, secretomotor, gastroparesis, diarrhea, constipation, bladder contractility, pupillomotor, headache, sleep disturbance, neuropathic pain, sleep/rest fatigue, cognitive fatigue and thermoregulation [Supplemental Appendix 3]. We have applied the scoring system described. The scores for each subscale and the total score were obtained by summing the scores across all included items [Supplemental Appendix 2]. Demographic variables and Ped-COMPASS-CQ score were presented as frequencies, percentages, means and standard deviations (Table 1 ). A confirmatory factor analysis was then performed on the structure of the Ped-COMPASS-CQ. As reported in Table 2 , the χ 2 test was significant for the model (χ 2 = 5420,468, p < 0.0001), indicating that the model fit was found in the confirmatory factor analysis. CFI and TLI values above 0.95 indicate a good fit and RMSEA values of 0.05 indicate a good fit for a confidence interval (CI) of 90% and p-value > 0.05. The SRMR value of 0.046 supported the goodness of fit of the model. Table 2 Confirmatory factor analysis (CFA) CFA Model chi-square 5420,468 p-value < 0,0001 CFI 0,914 TLI 0,904 RMSEA 0,05 90%-IC 0,049 − 0,051 p-value 0,127 SRMR 0,046 3.2.2 Psychometric validation of the questionnaire Internal consistency was assessed by estimating Cronbach's alpha for each subscale. Coefficients were excellent or good for most scales (α > 0.80), except for the secretomotor, gastroparesis and bladder contractility scales. This evidence is also present in the validation study of the original COMPASS-31, probably as a consequence of the low factor loadings obtained in their factor exploratory analysis of the original questionnaire but retained on the basis of clinical importance. However, the total Cronbach's alpha of the Ped-COMPASS-CQ showed an excellent coefficient (Table 3 ). Table 3 Cronbach’s Alpha coefficient Alpha 95-CI low. 95-CI up. Orthostatic 0,9046 0,8873 0,9207 Vasomotor 0,8922 0,8764 0,9082 Secretomotor 0,5208 0,4770 0,5648 Gastroparesis 0,3272 0,2636 0,3831 Diarrhea 0,8215 0,8064 0,8359 Constipation 0,8794 0,8666 0,8912 Bladder 0,5597 0,4664 0,6337 Pupillomotor 0,9317 0,9247 0,9391 Headache 0,8084 0,7907 0,8255 Sleep 0,8919 0,8821 0,9012 Neuropathic 0,9441 0,9366 0,9514 Thermoregulation 0,8913 0,8765 0,9046 Sleep/rest fatigue 0,8390 0,8180 0,8569 Cognitive fatigue 0,9387 0,9312 0,9448 Total 0,9047 0,8954 0,9134 Similarly, item-subscale correlation (Supplemental Appendix 4) coefficients were generally high or moderate (> 0.5) for all subscales, except for secretomotor, gastroparesis and sleep/rest fatigue scales. Inter-subscale Spearman’s rank correlations were also performed; all subscales showed a small and significant positive correlation (< 0.3); only two scales showed a small negative correlation, vesical-headache and orthostatic-vesical. In generalized linear models of Poisson regression, the subscale scores were the outcome variables and the demographic and clinical data of the sample were the predictor variables. There is a significant positive effect of age, height and weight on orthostatic hypotension, bladder function, pupillary contractility, headache, sleep and fatigue scale scores. Immunological dysfunction correlates positively and significantly with neuropathy scale scores. Respiratory dysfunction correlates positively with sleep disturbance and pupillomotor function. Finally, we observed a significant positive effect of the psychiatric disorder variable on bladder, headache, sleep and neuropathy scale scores. Stability over time was assessed using the test-retest method. Reliability was estimated in a subsample of 157 subjects and was found to be significant with an acceptable r coefficient for each subscale, except for the Thermoregulation scale, which showed lower stability (Supplemental Appendix 4). Once the validity of the instrument had been established, the scores in each domain were averaged to produce standardized reference values for the general population, expressed as mean and standard deviation (Table 4 ). Table 4 Normative data Ped-COMPASS-CQ Scale Min. Max. Mean SD Orthostatic 0 7 0,36 1,07 Vasomotor 0 4 0,26 0,78 Secretomotor 0 5 0,34 0,79 Gastroparesis 0 8 1,55 1,24 Diarrhea 0 9 1,46 1,5 Constipation 0 10 1,2 1,83 Bladder 0 8 0,48 1,13 Pupillomotor 0 10 1,25 1,92 Headache 0 15 2,38 2,21 Sleep 0 5 1,49 1,68 Neuropathic 0 8 0,65 1,52 Thermoregulation 0 8 0,63 1,3 Sleep/rest fatigue 0 24 3,24 3,76 Cognitive fatigue 0 32 4,86 7,03 Total 0 103 19,55 14,79 4. Discussion The validation and standardization of the Ped-COMPASS-CQ represents a significant advance in the assessment and understanding of autonomic dysfunction in children. It brings together functions of the ANS that are not currently combined in any clinical tool used to study dysautonomia [ 15 ]. For the construction of the subscales we decided to divide the gastrointestinal domain into gastroparesis, constipation and diarrhea. Gastroparesis is common in adult diabetic patients, but much less common in children, and in about 70% of cases it is functional or related to pediatric problems other than primary enteric autonomic dysfunction (18% drug-induced, 12.5% post-surgical, 5% post-viral); only 4% of cases are diabetic [ 39 ]. Diarrhea in children is common, often transient, combined sometimes with vomiting and abdominal pain and associated with infectious conditions. This led us to consider the clinical importance of dividing the gastrointestinal domain into three subscales, as in the original statistical analysis of COMPASS-31. The questionnaire includes the most prominent diffuse autonomic symptoms such as fatigue, headache and sleep disturbance, which are not assessed together in other clinical tools. Our results indicate that the Ped-COMPASS-CQ is a reliable and sensitive tool for the early detection of autonomic dysfunction in the pediatric population. The internal reliability, confirmed by Cronbach's alpha estimation, the construct validity, verified by Poisson regression analysis, and the assessment of test-retest reliability, which was not investigated in the original questionnaire, support the robustness of this instrument. In particular, the total Cronbach's alpha for the Ped-COMPASS-CQ was excellent, indicating high internal consistency. Most of the subscales also showed good to excellent alpha coefficients, with the exception of the secretomotor, gastroparesis and bladder contractility subscales. This was to be expected as these domains contain items with low factorial loadings that were retained solely based on clinical importance. For example, the gastroparesis subscale includes very heterogeneous symptoms that are not indicative of a single construct, such as vomiting and abdominal pain, which are common in children with infections or functional gastrointestinal disorders and may not specifically indicate autonomic dysfunction. In the secretomotor subscale, the four questions explore two different functions of the ANS, the first being the secretion of sweat (cholinergic sympathetic system) and the second being the secretion of tears and saliva (parasympathetic system). It is reasonable to think that those who show activation of sympathetic function will not show parasympathetic symptoms, and this justifies the low internal consistency of the subscale, but it is also important to consider that subjects who have autonomic dysfunction caused by damage to small fibers may show symptoms in all these apparatuses at the same time. The analysis of the construct validity of the questionnaire, carried out using Poisson regression, revealed some interesting correlations that support the validity of questionnaire. We found positive correlations between immunological dysfunction and neuropathy scale scores, highlighting the potential etiological role of autoinflammatory conditions in pediatric pain syndromes [ 44 ] and consistent with the literature demonstrating the presence of small fiber neuropathy in many conditions with systemic inflammation [ 45 ]. Respiratory conditions have a positive influence on variable sleep disturbance, according to classification of sleep disturbances, which includes sleep-related breathing disorders [ 46 ]. We observed a significant positive effect of the psychiatric disorder variable on bladder function, in accordance with the evidence that psychiatric disorders are a risk factor for incontinence [ 47 ]. The validity analysis confirms the relationship between sleep disturbance and neuropsychiatric disorders, in line with the literature [ 48 ]. A significant positive effect of mental disorder variable is also observed in relation to the fatigue scale, and this evidence is also supported by data in the literature describing the symptom of fatigue in many developmental psychiatric conditions [ 49 ], including mood disorders, anxiety or post-traumatic disorders [ 50 ]. Immunological disorders also correlate positively and significantly with fatigue; we know that chronic inflammatory conditions are typically associated with this symptom, although the data in the literature tends to describe this condition in adults. There is increasing evidence that neuroinflammation is a major contributor to fatigue and justifies the pattern of symptoms associated with systemic and local inflammatory conditions such as diabetes, celiac disease, rheumatic diseases or multiple sclerosis, such as daytime sleepiness, sleep disturbances and mood disorders [ 51 ]. Stability over time was assessed by the test–retest method. Reliability was estimated in a subsample of 157 subjects. The reliability coefficients for each subscale were acceptable, except for the thermoregulation scale, which showed lower stability. This might be attributed to the dynamic nature of thermoregulatory symptoms in children, which can fluctuate more than other autonomic functions. Limitations and Future Directions Despite the development of a new assessment tool that can be used in childhood, our study had several limitations. In particular, i) the exclusion criteria, although necessary to ensure a sample free from conditions directly related to dysautonomia, may have limited the generalizability of the results; ii) the reliance on caregivers reports introduces a potential bias, as subjective perceptions of symptoms may vary.; iii) the Ped-COMPASS-CQ has not been validated in patients with clinically and instrumentally confirmed autonomic nervous system disorders. This last point is a crucial step to further confirm the sensitivity and specificity of the tool in detecting autonomic dysfunction in children. To address these limitations and extend the utility of the Ped-COMPASS-CQ, future research could focus on several areas: 1. First-line screening: the Ped-COMPASS-CQ could be used as a first-line screening tool for symptomatic patients, facilitating early detection and intervention. This would help to identify children at risk of autonomic dysfunction prior to more invasive clinical and instrumental assessments. 2. Monitoring of associated conditions: the questionnaire could be useful in monitoring conditions in which autonomic dysfunction belongs to the phenotypical spectrum, such as Guillain-Barré syndrome [ 52 ] or congenital and acquired encephalopathies with risk of autonomic storm, such as brain tumor, infectious encephalitis, autoimmune encephalitis, metabolic disorders, and hypoxic-ischemic injuries [ 53 ]. This would allow better management and treatment planning for these high-risk patients. 3. Assessment of therapeutic impact: the tool could be valuable in assessing the impact of therapies that may be responsible for autonomic dysfunction, such as chemotherapy in immunoproliferative syndromes or cancer [ 54 ]. This would provide insight into the autonomic side effects of these treatments and help to tailor therapeutic approaches to minimize such risks. 4. Prognostic assessment: Many genetic or acquired conditions are associated with or cause changes in the autonomic nervous system and in dysfunction of one or more subdivisions of the ANS. A worse prognosis is present in the other conditions when ANS is associated [ 4 ]. In some circumstances, or when severe, ANS dysfunction itself leads to symptoms and disability, which in turn may prompt treatment. The Ped-COMPASS-CQ could be used as a prognostic tool to assess the progression of diseases associated with autonomic dysfunction or response to disease-modifying drug therapy, such as multiple sclerosis, mitochondrial diseases, epilepsy and others. By monitoring changes in autonomic symptoms over time, clinicians could better predict disease progression and adjust treatment plans accordingly. Conclusion Autonomic nervous system dysfunction is an under-recognized and under-treated medical problem, particularly in children, with important implications for patient prognosis and quality of life. We constructed a developmentally appropriate questionnaire, the Ped-COMPASS-CQ (Pediatric Composite Autonomic Symptom Score-Caregiver Questionnaire), a parent report aimed at profiling Autonomic Nervous System (ANS) functioning in children and adolescents, resulting in higher Cronbach score. The Ped-COMPASS-CQ is a sensitive, easy to use and inexpensive tool that is well suited for the early detection of autonomic dysfunction in children. It provides a comprehensive approach to profiling ANS function, allowing for better diagnosis, management and understanding of pediatric dysautonomia. 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Pediatr Diabetes 14(4):239–248 Bellocchi C, Carandina A, Montinaro, Beatrice, Targetti E, Furlan, Ludovico, Rodrigues, Gabriel, Tobaldini, Eleonora, Montano, Nicola (2022) The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases. International Journal of Molecular Sciences. 23. 2449. 10.3390/ijms23052449. Zielinski MR, Systrom DM, Rose NR Fatigue, Sleep, and Autoimmune and Related Disorders. Front Immunol (2019) ;10:1827 George D, Mallery P (2016) IBM SPSS statistics 23 step by step: a simple guide and reference, 14th edn. Routledge, New York Saliakellis E, Fotoulaki M Gastroparesis in children. Ann Gastroenterol (2013) ;26(3):204–211 Livingston RD, Shockey D, Morton L, Rao S Pediatric Headache Management and Use of the PedMIDAS. J Dr Nurs Pract (2019) ;12(1):24–30 Gilchrist LS, Tanner L (2013) The pediatric-modified total neuropathy score: a reliable and valid measure of chemotherapy-induced peripheral neuropathy in children with non-CNS cancers. Support Care Cancer. ;21(3):847 – 56. Scialpi A et al Italian Validation of the Pittsburgh Sleep Quality Index (PSQI) in a Population of Healthy Children: A Cross Sectional Study. Int J Environ Res Public Health. (2022) Varni JW, Limbers CA The PedsQL multidimensional fatigue scale in young adults: feasibility, reliability and validity in a University student population. Qual Life Res 2008 2007/November /21;17 ( 1 ):105–114 Shinkarevsky Fleitman I, Nevo Y, Harel L, Amarilyo G, Dori A, Agmon-Levin N, Kachko L, Zaks Hoffer G, Dabby R, Rabie M, Aharoni S Small-fiber neuropathy associated with autoinflammatory syndromes in children and adolescents. Muscle Nerve (2020) ;61(6):791–796 Oaklander AL, Klein MM Evidence of small-fiber polyneuropathy in unexplained, juvenile-onset, widespread pain syndromes. Pediatrics (2013) ;131:e1091–e1100 Trosman I et al Classification and Epidemiology of Sleep Disorders in Children and Adolescents. Psychiatr Clin North Am 2024 PMID 38302213 Review. Nieuwhof-Leppink AJ, Schroeder RPJ, van de Putte EM, de Jong TPVM, Schappin R (2019) Daytime urinary incontinence in children and adolescents. Lancet Child Adolesc Health. doi: 10.1016/S2352-4642(19)30113-0 Baglioni C, Nanovska S, Regen W, Spiegelhalder K, Feige B, Nissen C, Reynolds CF, Riemann D Sleep and mental disorders: A meta-analysis of polysomnographic research. Psychol Bull. (2016) ;142(9):969–990 and fatigue within child and adolescent mental health services: A qualitative study. Addressing sleep problems, Higson-Sweeney N, Loades ME, Hiller R, Read R Clin Child Psychol Psychiatry (2020) ;25(1):200–212 Zielinski MR, Systrom DM, Rose NR Fatigue, Sleep, and Autoimmune and Related Disorders. Front Immunol (2019) ;10:1827 Bhatt SP, Guleria R, Kabra SK Metabolic alterations and systemic inflammation in overweight/obese children with obstructive sleep apnea. PLoS ONE (2021) ;16(6):e0252353 Demichelis C et al Abnormal sweating and skin flushing as possible predictive factor for treatment related fluctuations in Guillain-Barré syndrome: a case series and a review of the literature. J Neurol Sci 2021 PMID 34325159 Review. Burton JM, Morozova OM Calming the Storm: Dysautonomia for the Pediatrician. Curr Probl Pediatr Adolesc Health Care (2017) ;47(7):145–150 Ellen ML, Smith L, Li RJ, Hutchinson R, Ho WB, Burnette E, Wells (2013) Celia Bridges, Jamie Renbarger. Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. Cancer Nurs. Sep-Oct ;36(5):E49-60. Supplementary Files Appendix1AnamnesticquestionnaireEng.docx Appendix2ScoringAlgorithm.docx Appendix3PedCOMPASSCQ.docx Appendix4Statisticalanalysis.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8613624","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":608559203,"identity":"a187868b-ab92-47dc-9126-2b1ba08ed8cb","order_by":0,"name":"Marisa Gazzillo","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0007-6968-0656","institution":"AORN Santobono Pausilipon: Azienda Ospedaliera di Rilievo Nazionale Santobono Pausilipon","correspondingAuthor":true,"prefix":"","firstName":"Marisa","middleName":"","lastName":"Gazzillo","suffix":""},{"id":608559204,"identity":"8dcce5f2-3d6f-4cfd-98e9-6faac1ef8e66","order_by":1,"name":"Gianluca Sesso","email":"","orcid":"","institution":"Scuola IMT Alti Studi Lucca","correspondingAuthor":false,"prefix":"","firstName":"Gianluca","middleName":"","lastName":"Sesso","suffix":""},{"id":608559205,"identity":"2f6a0660-ebed-4ccf-88cb-e54840bfa298","order_by":2,"name":"Antonio Varone","email":"","orcid":"","institution":"AORN Santobono Pausilipon: Azienda Ospedaliera di Rilievo Nazionale Santobono Pausilipon","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Varone","suffix":""},{"id":608559206,"identity":"5fee1cd8-86c0-4a36-8c15-1e2fc09ea200","order_by":3,"name":"Emanuele Bartolini","email":"","orcid":"","institution":"IRCCS Fondazione Stella Maris","correspondingAuthor":false,"prefix":"","firstName":"Emanuele","middleName":"","lastName":"Bartolini","suffix":""},{"id":608559207,"identity":"edb7b91e-1a66-4370-98df-28107bacd3ca","order_by":4,"name":"Filippo Maria Santorelli","email":"","orcid":"","institution":"IRCCS Foundation Stella Maris: IRCCS Fondazione Stella Maris","correspondingAuthor":false,"prefix":"","firstName":"Filippo","middleName":"Maria","lastName":"Santorelli","suffix":""},{"id":608559208,"identity":"f789a575-ddbe-43c7-b29a-92d1dc64386f","order_by":5,"name":"Roberta Battini","email":"","orcid":"","institution":"IRCCS Foundation Stella Maris: IRCCS Fondazione Stella Maris","correspondingAuthor":false,"prefix":"","firstName":"Roberta","middleName":"","lastName":"Battini","suffix":""}],"badges":[],"createdAt":"2026-01-15 21:10:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8613624/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8613624/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105295051,"identity":"689b4f23-a83f-484f-b0db-0cc8b4005dcc","added_by":"auto","created_at":"2026-03-24 12:57:28","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74953,"visible":true,"origin":"","legend":"\u003cp\u003eParticipant recruitment Flowchart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8613624/v1/4d54aec145da160daf074ec4.png"},{"id":107484531,"identity":"537e2868-0792-46c1-87d0-348c6d2d6c9f","added_by":"auto","created_at":"2026-04-22 02:32:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":490146,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8613624/v1/3d4e75aa-b660-4d4d-b882-a9d027e7677e.pdf"},{"id":105295063,"identity":"692b3daa-19bd-4d6a-8147-6b9b02fbe93b","added_by":"auto","created_at":"2026-03-24 12:57:33","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":16512,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix1AnamnesticquestionnaireEng.docx","url":"https://assets-eu.researchsquare.com/files/rs-8613624/v1/40eb2ec3b1e0d92d0fc69618.docx"},{"id":105295062,"identity":"06132440-3aa3-4d8e-904c-f7ed986adbdb","added_by":"auto","created_at":"2026-03-24 12:57:33","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":35332,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix2ScoringAlgorithm.docx","url":"https://assets-eu.researchsquare.com/files/rs-8613624/v1/517a622c76df2c70b06d18b4.docx"},{"id":105295017,"identity":"65d31eb3-f84b-4228-9f3d-c3d3f01ce0ae","added_by":"auto","created_at":"2026-03-24 12:57:18","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":32059,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix3PedCOMPASSCQ.docx","url":"https://assets-eu.researchsquare.com/files/rs-8613624/v1/c582ed90f86db76ecf0d53d0.docx"},{"id":105295019,"identity":"f0df488e-07f2-4633-a718-14e8e8f229a7","added_by":"auto","created_at":"2026-03-24 12:57:19","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":36743,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix4Statisticalanalysis.docx","url":"https://assets-eu.researchsquare.com/files/rs-8613624/v1/98bf917017ef4279d271ab6c.docx"}],"financialInterests":"","formattedTitle":"Pediatric Composite Autonomic Symptom Score-Caregiver Questionnaire (Ped-COMPASS-CQ): a new Italian tool for the assessment of dysautonomy in children","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe Autonomic Nervous System (ANS) is a neuromotor system consisting of a set of nerve cells and fibers distributed throughout the body, whose function is to coordinate bodily homeostasis with autonomic mechanisms that are not under voluntary control. Autonomic dysfunction, also known as dysautonomia, shows itself with very variable and diverse symptoms, even more in children in whom the nervous system has not yet reached its full maturity [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Autonomic function requires intact peripheral receptors, either of the skin or internal organs, and a neuronal network of small afferent fibers capable of adequately transmitting information to the Central Nervous System (CNS). Genetic or acquired conditions that impair development and/or impede migration, differentiation, survival or neuronal function at any point along these pathways, may result in ANS dysfunction [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Studies on the pathology of the ANS are scarce and mainly focused on the description of single apparatus dysfunctions in adult patients, with few studies in the pediatric setting, mostly using instrumental investigations (e.g. tilt table test, pressure monitoring after vagal stimulation, quantitative assessment of the axonal sudomotor reflex [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]), which are not easy to perform in children with multiple comorbidities or poor compliance. Assessment of the most distressing or prominent features of autonomic dysfunction is important to confirm a diagnosis and to provide objective evidence to support treatment before invasive tests are carried out [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe COMPASS-31 questionnaire [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] is a new tool that has been validated in the monitoring of dysautonomia in adult patients. It consists of 31 self-administered questions validated to measure orthostatic intolerance, vasomotor function, secretomotor, gastrointestinal, bladder and pupillary contractility, all domains representative of ANS function. The Italian version of COMPASS-31 has been validated [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and it is now part of monitoring protocols for diabetic neuropathy and familial amyloidosis. Unfortunately, such a reliable clinical tool for the pediatric age group aimed to capture dysautonomia in its entirety is still missing [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, the present study aimed to develop a tool to detect and monitor the functioning of the pediatric autonomic nervous system similar to COMPASS-31.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study Design\u003c/h2\u003e \u003cp\u003eThe present study aimed to validate in Italian language a pediatric adaptation of the COMPASS-31 questionnaire, to be completed by the caregiver, which we named Pediatric Composite Autonomic Symptom Score - Caregiver Questionnaire (Ped-COMPASS-CQ).\u003c/p\u003e \u003cp\u003eThe Ped-COMPASS-CQ has been standardized for the general population between the ages of 5 and 16, on the reasonable assumption that by the age of 5 the nervous system is fully myelinated and mature to regulate autonomic functions. The Ped-COMPASS-CQ consists of a total of 51 questions, 24 exploratory of the domains of ANS included in COMPASS-31 (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal\u0026mdash;mixed upper and diarrhea, bladder and pupillomotor) and 27 additional questions designed to explore other dysautonomic symptoms such as headache [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], sleep disturbance [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], neuropathic pain [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], fatigue [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and thermoregulation [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] that seem relevant to ANS dysfunction in children [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In this way, the Ped-COMPASS-CQ will allow us to examine fourteen domains potentially representative of ANS functioning, testing the presence, frequency, severity and location (if applicable) of symptoms and their evolution over time.\u003c/p\u003e \u003cp\u003eThe validation has been performed in a general population of healthy subjects. Participants were recruited from all over Italy, from family members of patients followed by the IRCCS Stella Maris Foundation or through advertisements or meetings with schools or associations of patients with neuropsychiatric disorders, who were more sensitive to the issue and therefore inclined to disseminate the questionnaire.\u003c/p\u003e \u003cp\u003eInclusion criteria for children to enroll in the study were: (i) age 5\u0026ndash;16 years with caregivers available to fill questionnaire; (ii) absence of medical conditions potentially responsible for and/or associated with dysautonomia reported in literature (i.e. inherited or acquired neurological or neuromuscular conditions [\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], genetic or malformative syndromes [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], autism and other neurodevelopmental conditions as well as major emotional and behavioral disorders [\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] on drug therapy [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]; medical or systemic conditions [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] such us oncological or lymphoproliferative diseases [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], diabetes mellitus [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], autoimmune/autoinflammatory diseases on immunosuppressive treatment [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe sent to the family a link to the Google form of the questionnaire or provided it in paper form. In addition, to select healthy subjects, we provided caregivers with a short questionnaire to record data on possible medical conditions (e.g. medications, pathology, etc.) [Supplemental Appendix 1].\u003c/p\u003e \u003cp\u003eThe survey was anonymous. The caregivers of the participants were informed about the aims and methods of the study by means of an informed consent, in paper form or by accessing the Google form of the questionnaire. The study was approved by the approved by the Pediatrics Ethics of the Tuscany Region, AOU Meyer, Florence, Italy (protocol code Ped-COMPASS-CQ, date of approval: 20/8/2022).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Scoring Scheme\u003c/h2\u003e \u003cp\u003eThe scoring of the questionnaire was obtained by following the simplified scoring methods of the COMPASS-31 questionnaire. We assigned a score of 1 or 0 to questions with a 'yes' or 'no' answer, and a score from 0 to 4 for questions describing the frequency, trend and severity of the symptom, depending on the severity of the situation. In the study conducted by researchers at the Mayo Clinic on the original version of the questionnaire, this scoring system has shown a greater ability to generate subscales with high internal consistency. The detailed scoring model can be found in the Supplemental Appendix 2.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical Methods\u003c/h2\u003e \u003cp\u003eDescriptive statistics of demographic variables such as means and standard deviations were calculated based on the data obtained from the questionnaire. The internal structure of the questionnaire was corroborated through confirmatory factor analysis, with the aim of accurately confirming the independent subscales defined a priori in the questionnaire construction phase. The fit quality of the factor model was analyzed according to the indexes of the Chi-square adjustment test, degree of freedom (df), comparative fit index (CFI), Tucker\u0026ndash;Lewis index (TLI), the root mean square error of approximation (RMSEA) and the standardized root mean square residual (SRMR). We applied conventional cut-offs to determine acceptable fit, including RMSEA\u0026thinsp;\u0026lt;\u0026thinsp;0.08, SRMR\u0026thinsp;\u0026lt;\u0026thinsp;0.08, and CFI\u0026thinsp;\u0026gt;\u0026thinsp;0.90 [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The internal consistency of the scale was analyzed by estimating Cronbach's alpha. Item-scale correlations were carried out according to the Pearson method with corrected p-value using the Bonferroni method for multiple comparisons at the significance level of 0.05 (corrected p\u0026thinsp;=\u0026thinsp;0.0005). Inter-subscale Spearman\u0026rsquo;s rank correlations were also performed with a p-value corrected applying the Bonferroni method for multiple comparisons at the traditional significance level of 0.05. Correlations were considered very small for coefficients lower than 0.30, small for coefficients between 0.30 and 0.50, moderate from 0.50 to 0.70, and strong if higher than 0.70. The construct validity of the questionnaire was confirmed by generalized linear models of Poisson regression. To confirm the reliability of the instrument, the questionnaire was administered again approximately 6 to 24 months later to a subset of subjects randomly selected from the initial sample. We recruited them through an email contact that they left optionally at the end of completing the questionnaire. Test-retest reliability was assessed by computing Spearman\u0026rsquo;s correlation coefficients for each subscale individually. Once the validity of the instrument was established, we calculated the scores in single domains and in the total questionnaire to obtain standardized reference values for the general pediatric population, expressed as means and standard deviations. Analyses were performed using RStudio software.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Participants\u003c/h2\u003e\n \u003cp\u003eThe sample of the study was composed of 2421 respondents. Among these, 288 questionnaires were discarded because the subjects\u0026rsquo; age exceeded the age interval of interest (5\u0026ndash;16 years old). Of the resulting 2133 questionnaires, we removed subjects with health problems that did not meet inclusion criteria. The final number of respondents included in the study was 1888.\u003c/p\u003e\n \u003cp\u003eOf the 1888 subjects recruited, 787 (41%) were female, 988 (52%) were male, 113 (7%) did not answer the question (NA). The mean age of the sample was 9,57\u0026thinsp;\u0026plusmn;\u0026thinsp;2,94 years.\u003c/p\u003e\n \u003cp\u003eOf the recruited subjects, 371 (19%) had immunological problems, 127 had respiratory problems (6%), 46 had gastrointestinal problems (2%) and 306 had neuropsychiatric problems (16%) and were excluded.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eParticipant characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eWeight\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eHeight\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eBMI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eMin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e5,00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e9,73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e787 F\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eMax\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e16,00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e187\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e134,56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e988 M\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e9,57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e34,32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e137,6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e17,67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003e113 NA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eSD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e2,94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e13,63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e18,95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e6,65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eImmunological\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eRespiratory\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eGastrointestinal\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eOther Diseases\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c6\"\u003e\n \u003cp\u003eNeuro-psychiatric conditions\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e1517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e1761\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e1841\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1838\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\n \u003cp\u003e1582\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eYes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e371\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\n \u003cp\u003e306\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eNA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" 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strokecolor=\"#bfbfbf [2412]\" strokeweight=\".26mm\"\u003e\u0026nbsp;\u003cv:textbox\u003e\u0026nbsp;\u003ctable style=\"width: 100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cdiv style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;font-size:11.0pt;font-family:\"Calibri\",sans-serif;'\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Calibri\",sans-serif;margin-top:0in;margin-bottom:8.0pt;font-size:11.0pt;'\u003e\u003cem\u003e\u003cspan style=\"font-size:13px;font-family:Calibri;\"\u003eImmunological disorders: patients with allergies, asthma, dermatitis,\u0026nbsp;\u003c/span\u003e\u003c/em\u003e\u003ca href=\"https://pubmed.ncbi.nlm.nih.gov/30550738/\"\u003e\u003cspan style='font-family:\"Calibri\",sans-serif;font-style:italic;'\u003e\u003cspan style=\"font-size:13px;line-height: 107%;color:windowtext;text-decoration:none;\"\u003eVernal\u0026nbsp;keratoconjunctivitis,\u003c/span\u003e\u003c/span\u003e\u003c/a\u003e\u003cem\u003e\u003cspan style=\"font-size:13px;font-family:Calibri;\"\u003e\u0026nbsp;celiac disease, autoimmune diseases not in drug therapy.\u0026nbsp;\u003cbr\u003e\u0026nbsp;Respiratory diseases include asthma, adeno-tonsillar hypertrophy, recurrent otitis or bronchitis.\u003cbr\u003e\u0026nbsp;Gastrointestinal problems: subjects with gastro-esophageal reflux, recurrent gastritis, irritable colon, constipation, celiac disease too.\u0026nbsp;\u003cbr\u003e\u0026nbsp;Neuro-psychiatric conditions include condition not in drug therapy, in particular ADHD, anxiety, autism, language disorder, emotional dysregulation or mood disorders, intellectual disability, sleep disorders, enuresis, febrile convulsions, epilepsy not under pharmacological treatment.\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u0026nbsp;\u003c/v:textbox\u003e\u0026nbsp;\u003c/v:rect\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Validation procedure of Ped-COMPASS-CQ\u003c/h2\u003e\n \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n \u003ch2\u003e3.2.1 Scale construction and confirmative factor analysis\u003c/h2\u003e\n \u003cp\u003eWe developed Ped-COMPASS-CQ by adapting the Italian version of COMPASS-31 for caregiver completion. Orthostatic, vasomotor and secretomotor function, pupillary contractility traces the same questions. Bladder subscale includes a new question about sphincter control. The gastrointestinal domain was divided into gastroparesis, constipation and diarrhea. For other domains not assessed in the original COMPASS-31, additional questions were constructed de novo or taking inspiration from validated questionnaires used in pediatric clinical practice. Specifically, for headache, we re-adapted the PedMidas (Pediatric Migraine Disability Assessment Score Questionnaire) [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] and generated four questions to assess the presence of headache symptoms and their impact on life, especially school and daily activities. For the study of neuropathic pain, questions from the sensory symptoms\u0026rsquo; subscale of the Ped-mTNS (Pediatric-modified Total Neuropathy Score) questionnaire [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] were selected and merged, with the aim of detecting the presence and quality (pain, type of paresthesia) of the neuropathic symptom, assessing its physical destruction and its progression over time. To assess sleep disturbance, questions from the sleep disturbance subscale of the Pittsburgh Sleep Quality Index (PSQI) Italian version [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] were combined and adapted into a parent report version. To assess fatigue was used some of the core questions of the PedsQL\u0026trade; Multidimensional Fatigue Scale Parent report divided into two domains: cognitive fatigue and sleep/rest fatigue [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. To assess thermoregulation, we formulated three de novo questions following the COMPASS-31 model, investigating the presence of fever outside infectious episodes, the frequency of fever episodes and the trend over time. Thus, we obtained a questionnaire of 51 questions that explores fourteen domains of autonomic function: orthostatic intolerance, vasomotor function, secretomotor, gastroparesis, diarrhea, constipation, bladder contractility, pupillomotor, headache, sleep disturbance, neuropathic pain, sleep/rest fatigue, cognitive fatigue and thermoregulation [Supplemental Appendix 3].\u003c/p\u003e\n \u003cp\u003eWe have applied the scoring system described. The scores for each subscale and the total score were obtained by summing the scores across all included items [Supplemental Appendix 2]. Demographic variables and Ped-COMPASS-CQ score were presented as frequencies, percentages, means and standard deviations (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eA confirmatory factor analysis was then performed on the structure of the Ped-COMPASS-CQ. As reported in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the \u0026chi; 2 test was significant for the model (\u0026chi; 2\u0026thinsp;=\u0026thinsp;5420,468, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), indicating that the model fit was found in the confirmatory factor analysis. CFI and TLI values above 0.95 indicate a good fit and RMSEA values of 0.05 indicate a good fit for a confidence interval (CI) of 90% and p-value\u0026thinsp;\u0026gt;\u0026thinsp;0.05. The SRMR value of 0.046 supported the goodness of fit of the model.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eConfirmatory factor analysis (CFA)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCFA\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eModel\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003echi-square\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e5420,468\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0,0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eCFI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0,914\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eTLI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0,904\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eRMSEA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0,05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003e90%-IC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0,049\u0026thinsp;\u0026minus;\u0026thinsp;0,051\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0,127\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eSRMR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003e0,046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\"\u003e\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e\n \u003ch2\u003e3.2.2 Psychometric validation of the questionnaire\u003c/h2\u003e\n \u003cp\u003eInternal consistency was assessed by estimating Cronbach\u0026apos;s alpha for each subscale. Coefficients were excellent or good for most scales (\u0026alpha;\u0026thinsp;\u0026gt;\u0026thinsp;0.80), except for the secretomotor, gastroparesis and bladder contractility scales. This evidence is also present in the validation study of the original COMPASS-31, probably as a consequence of the low factor loadings obtained in their factor exploratory analysis of the original questionnaire but retained on the basis of clinical importance. However, the total Cronbach\u0026apos;s alpha of the Ped-COMPASS-CQ showed an excellent coefficient (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\u0026nbsp;\u0026nbsp;\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCronbach\u0026rsquo;s Alpha coefficient\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eAlpha\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003e95-CI low.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003e95-CI up.\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOrthostatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,9046\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8873\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9207\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eVasomotor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,8922\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9082\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSecretomotor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,5208\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,4770\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,5648\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eGastroparesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,3272\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,2636\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,3831\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,8215\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8064\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,8359\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,8794\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8666\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,8912\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eBladder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,5597\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,4664\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,6337\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003ePupillomotor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,9317\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,9247\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9391\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,8084\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,7907\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,8255\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSleep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,8919\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8821\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eNeuropathic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,9441\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,9366\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9514\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eThermoregulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,8913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8765\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSleep/rest fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,8390\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8180\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,8569\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCognitive fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,9387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,9312\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9448\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0,9047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e0,8954\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,9134\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003eSimilarly, item-subscale correlation (Supplemental Appendix 4) coefficients were generally high or moderate (\u0026gt;\u0026thinsp;0.5) for all subscales, except for secretomotor, gastroparesis and sleep/rest fatigue scales. Inter-subscale Spearman\u0026rsquo;s rank correlations were also performed; all subscales showed a small and significant positive correlation (\u0026lt;\u0026thinsp;0.3); only two scales showed a small negative correlation, vesical-headache and orthostatic-vesical. In generalized linear models of Poisson regression, the subscale scores were the outcome variables and the demographic and clinical data of the sample were the predictor variables. There is a significant positive effect of age, height and weight on orthostatic hypotension, bladder function, pupillary contractility, headache, sleep and fatigue scale scores. Immunological dysfunction correlates positively and significantly with neuropathy scale scores. Respiratory dysfunction correlates positively with sleep disturbance and pupillomotor function. Finally, we observed a significant positive effect of the psychiatric disorder variable on bladder, headache, sleep and neuropathy scale scores.\u003c/p\u003e\n \u003cp\u003eStability over time was assessed using the test-retest method. Reliability was estimated in a subsample of 157 subjects and was found to be significant with an acceptable r coefficient for each subscale, except for the Thermoregulation scale, which showed lower stability (Supplemental Appendix 4). Once the validity of the instrument had been established, the scores in each domain were averaged to produce standardized reference values for the general population, expressed as mean and standard deviation (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eNormative data Ped-COMPASS-CQ\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eScale\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c2\"\u003e\n \u003cp\u003eMin.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c3\"\u003e\n \u003cp\u003eMax.\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c4\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colname=\"c5\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eOrthostatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eVasomotor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e0,78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSecretomotor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e0,79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eGastroparesis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e1,55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e1,46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eConstipation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e1,2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eBladder\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003ePupillomotor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e1,25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eHeadache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e2,38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e2,21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSleep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e1,49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eNeuropathic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,52\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eThermoregulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e0,63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e1,3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eSleep/rest fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e3,24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e3,76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003eCognitive fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e4,86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e7,03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colname=\"c1\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\n \u003cp\u003e103\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\n \u003cp\u003e19,55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\n \u003cp\u003e14,79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe validation and standardization of the Ped-COMPASS-CQ represents a significant advance in the assessment and understanding of autonomic dysfunction in children. It brings together functions of the ANS that are not currently combined in any clinical tool used to study dysautonomia [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. For the construction of the subscales we decided to divide the gastrointestinal domain into gastroparesis, constipation and diarrhea. Gastroparesis is common in adult diabetic patients, but much less common in children, and in about 70% of cases it is functional or related to pediatric problems other than primary enteric autonomic dysfunction (18% drug-induced, 12.5% post-surgical, 5% post-viral); only 4% of cases are diabetic [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Diarrhea in children is common, often transient, combined sometimes with vomiting and abdominal pain and associated with infectious conditions. This led us to consider the clinical importance of dividing the gastrointestinal domain into three subscales, as in the original statistical analysis of COMPASS-31. The questionnaire includes the most prominent diffuse autonomic symptoms such as fatigue, headache and sleep disturbance, which are not assessed together in other clinical tools. Our results indicate that the Ped-COMPASS-CQ is a reliable and sensitive tool for the early detection of autonomic dysfunction in the pediatric population.\u003c/p\u003e \u003cp\u003eThe internal reliability, confirmed by Cronbach's alpha estimation, the construct validity, verified by Poisson regression analysis, and the assessment of test-retest reliability, which was not investigated in the original questionnaire, support the robustness of this instrument.\u003c/p\u003e \u003cp\u003eIn particular, the total Cronbach's alpha for the Ped-COMPASS-CQ was excellent, indicating high internal consistency. Most of the subscales also showed good to excellent alpha coefficients, with the exception of the secretomotor, gastroparesis and bladder contractility subscales. This was to be expected as these domains contain items with low factorial loadings that were retained solely based on clinical importance.\u003c/p\u003e \u003cp\u003eFor example, the gastroparesis subscale includes very heterogeneous symptoms that are not indicative of a single construct, such as vomiting and abdominal pain, which are common in children with infections or functional gastrointestinal disorders and may not specifically indicate autonomic dysfunction. In the secretomotor subscale, the four questions explore two different functions of the ANS, the first being the secretion of sweat (cholinergic sympathetic system) and the second being the secretion of tears and saliva (parasympathetic system). It is reasonable to think that those who show activation of sympathetic function will not show parasympathetic symptoms, and this justifies the low internal consistency of the subscale, but it is also important to consider that subjects who have autonomic dysfunction caused by damage to small fibers may show symptoms in all these apparatuses at the same time. The analysis of the construct validity of the questionnaire, carried out using Poisson regression, revealed some interesting correlations that support the validity of questionnaire. We found positive correlations between immunological dysfunction and neuropathy scale scores, highlighting the potential etiological role of autoinflammatory conditions in pediatric pain syndromes [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] and consistent with the literature demonstrating the presence of small fiber neuropathy in many conditions with systemic inflammation [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Respiratory conditions have a positive influence on variable sleep disturbance, according to classification of sleep disturbances, which includes sleep-related breathing disorders [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. We observed a significant positive effect of the psychiatric disorder variable on bladder function, in accordance with the evidence that psychiatric disorders are a risk factor for incontinence [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe validity analysis confirms the relationship between sleep disturbance and neuropsychiatric disorders, in line with the literature [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. A significant positive effect of mental disorder variable is also observed in relation to the fatigue scale, and this evidence is also supported by data in the literature describing the symptom of fatigue in many developmental psychiatric conditions [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e], including mood disorders, anxiety or post-traumatic disorders [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. Immunological disorders also correlate positively and significantly with fatigue; we know that chronic inflammatory conditions are typically associated with this symptom, although the data in the literature tends to describe this condition in adults. There is increasing evidence that neuroinflammation is a major contributor to fatigue and justifies the pattern of symptoms associated with systemic and local inflammatory conditions such as diabetes, celiac disease, rheumatic diseases or multiple sclerosis, such as daytime sleepiness, sleep disturbances and mood disorders [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Stability over time was assessed by the test\u0026ndash;retest method.\u003c/p\u003e \u003cp\u003eReliability was estimated in a subsample of 157 subjects. The reliability coefficients for each subscale were acceptable, except for the thermoregulation scale, which showed lower stability. This might be attributed to the dynamic nature of thermoregulatory symptoms in children, which can fluctuate more than other autonomic functions.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations and Future Directions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eDespite the development of a new assessment tool that can be used in childhood, our study had several limitations. In particular, i) the exclusion criteria, although necessary to ensure a sample free from conditions directly related to dysautonomia, may have limited the generalizability of the results; ii) the reliance on caregivers reports introduces a potential bias, as subjective perceptions of symptoms may vary.; iii) the Ped-COMPASS-CQ has not been validated in patients with clinically and instrumentally confirmed autonomic nervous system disorders. This last point is a crucial step to further confirm the sensitivity and specificity of the tool in detecting autonomic dysfunction in children.\u003c/p\u003e \u003cp\u003eTo address these limitations and extend the utility of the Ped-COMPASS-CQ, future research could focus on several areas: 1. First-line screening: the Ped-COMPASS-CQ could be used as a first-line screening tool for symptomatic patients, facilitating early detection and intervention. This would help to identify children at risk of autonomic dysfunction prior to more invasive clinical and instrumental assessments.\u003c/p\u003e \u003cp\u003e2. Monitoring of associated conditions: the questionnaire could be useful in monitoring conditions in which autonomic dysfunction belongs to the phenotypical spectrum, such as Guillain-Barr\u0026eacute; syndrome [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e] or congenital and acquired encephalopathies with risk of autonomic storm, such as brain tumor, infectious encephalitis, autoimmune encephalitis, metabolic disorders, and hypoxic-ischemic injuries [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. This would allow better management and treatment planning for these high-risk patients. 3. Assessment of therapeutic impact: the tool could be valuable in assessing the impact of therapies that may be responsible for autonomic dysfunction, such as chemotherapy in immunoproliferative syndromes or cancer [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. This would provide insight into the autonomic side effects of these treatments and help to tailor therapeutic approaches to minimize such risks. 4. Prognostic assessment: Many genetic or acquired conditions are associated with or cause changes in the autonomic nervous system and in dysfunction of one or more subdivisions of the ANS. A worse prognosis\u003c/p\u003e \u003cp\u003eis present in the other conditions when ANS is associated [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In some circumstances, or when severe, ANS dysfunction itself leads to symptoms and disability, which in turn may prompt treatment.\u003c/p\u003e \u003cp\u003eThe Ped-COMPASS-CQ could be used as a prognostic tool to assess the progression of diseases associated with autonomic dysfunction or response to disease-modifying drug therapy, such as multiple sclerosis, mitochondrial diseases, epilepsy and others. By monitoring changes in autonomic symptoms over time, clinicians could better predict disease progression and adjust treatment plans accordingly.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAutonomic nervous system dysfunction is an under-recognized and under-treated medical problem, particularly in children, with important implications for patient prognosis and quality of life. We constructed a developmentally appropriate questionnaire, the Ped-COMPASS-CQ (Pediatric Composite Autonomic Symptom Score-Caregiver Questionnaire), a parent report aimed at profiling Autonomic Nervous System (ANS) functioning in children and adolescents, resulting in higher Cronbach score. The Ped-COMPASS-CQ is a sensitive, easy to use and inexpensive tool that is well suited for the early detection of autonomic dysfunction in children. It provides a comprehensive approach to profiling ANS function, allowing for better diagnosis, management and understanding of pediatric dysautonomia.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAutonomic Nervous System (ANS); Central Nervous System (CNS); Composite Autonomic Symptom Score-31 (COMPASS-31); Ped-COMPASS-CQ (Pediatric Composite Autonomic Symptom Score - Caregiver Questionnaire).\u003c/em\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDeclaration of competing interest\u003c/h2\u003e \u003cp\u003eConflicts of interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e \u003cp\u003eThis work was partially support by the Italian Ministry of Health, Ricerca Corrente 2024 to IRCCS Fondazione Stella Maris (EB, FMS, RB).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAxelrod FB, Chelimsky GG, Weese-Mayer DE Pediatric autonomic disorders. \u003cem\u003ePediatrics. 2006;118(1):309\u0026thinsp;\u0026ndash;\u0026thinsp;21.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAxelrod FB Genetic autonomic disorders. 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J Neurol Sci 2021 PMID 34325159 \u003cem\u003eReview.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBurton JM, Morozova OM Calming the Storm: Dysautonomia for the Pediatrician. Curr Probl Pediatr Adolesc Health Care (2017) ;47(7):145\u0026ndash;150\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEllen ML, Smith L, Li RJ, Hutchinson R, Ho WB, Burnette E, Wells (2013) Celia Bridges, Jamie Renbarger. Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. \u003cem\u003eCancer Nurs. Sep-Oct ;36(5):E49-60.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"dysautonomy, pediatric neurology, autonomic symptom score, COMPASS-31","lastPublishedDoi":"10.21203/rs.3.rs-8613624/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8613624/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eObjective\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo obtain the standardization and validation of Ped-COMPASS-CQ (Pediatric Composite Autonomic Symptom Score - Caregiver Questionnaire); this new tool was formulated to assess the autonomic symptom profile in the pediatric population. Specifically, we started with the validated COMPASS-31 questionnaire and adapted it for caregiver completion. We added questions to explore additional dysautonomic symptoms not covered in the original questionnaire, including headache, sleep disturbance, neuropathic pain, fatigue, and thermoregulation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003e We recruited 1888 caregivers of children aged between 5 and 16 years in the period from August 2022 to February 2024. In order to develop a statistically valid instrument, we corroborated the internal structure of the questionnaire through a confirmatory factor analysis; the construct validity of the questionnaire was also confirmed through generalized linear regression models. The internal consistency of the subscales was analyzed by estimating the Cronbach's Alpha as well as by computing Spearman's inter-scale and item-scale correlation coefficients.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe obtained the standardized reference values of the general population of children, expressed as mean and standard deviation in each autonomic domain and in the total score of the questionnaire.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003ePed-COMPASS-CQ seems to be a sensitive tool for early detection of autonomic dysfunction in children, easy to use and with a low economic impact. The scores obtained represent a starting point to study the function of the autonomic nervous system in pediatric subjects. It could be an ecological tool to be adopted as a first approach to the symptomatic patient with dysautonomia or for monitoring an autonomic dysfunction.\u003c/p\u003e","manuscriptTitle":"Pediatric Composite Autonomic Symptom Score-Caregiver Questionnaire (Ped-COMPASS-CQ): a new Italian tool for the assessment of dysautonomy in children","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 12:53:59","doi":"10.21203/rs.3.rs-8613624/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a86317a0-8f9e-4229-afec-774097439ed5","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-19T09:45:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 12:53:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8613624","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8613624","identity":"rs-8613624","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}