Background: 

Type 1 diabetes (T1D) affects 8.75 million individuals worldwide, including an increasing number of pediatric patients. Switzerland has 26,600 affected individuals, with numbers increasing. Among the long-term complications of T1D, diabetic neuropathy (DN), which includes diabetic peripheral neuropathy (DPN) and cardiac autonomic neuropathy (CAN), is the most common one, impacting quality of life and increasing healthcare costs. Prevention is paramount as no specific medical treatment options are available. Yet current diagnostic methods are either burdensome, costly, and infrequently performed, such as nerve conduction studies (NCSs), or are not sensitive enough for the clinically inconspicuous stage of DN typically found in children and adolescents, limiting their effectiveness in pediatric populations. Objective: This study aims to enhance our understanding of DN in pediatric T1D patients through holistic longitudinal monitoring, combining state-of-the-art clinical assessments with innovative digital biomarkers. The research objectives are: (1) determine how clinical factors affect peripheral nervous system (PNS) development over time in children and adolescents with T1D, including the differential impact on motor, sensory, and autonomic compartments of the nervous system; (2) develop a novel digital biomarker from real-world lifestyle tracking using wearables (e.g. physical activity) and continuous glucose monitoring (CGM) metrics that can predict DN onset and progression. We seek to better understand the pathophysiology of DN in a pediatric population and establish low-burden, individualized screening tools that can improve early detection and long-term prevention and progression of DPN and CAN in pediatric T1D patients, making monitoring more accessible and cost-effective. Methods: We will conduct a 24-month prospective observational study with children and adolescents (age ≥5 years) with T1D at the Children’s Hospital of Eastern Switzerland (OKS). Our comprehensive assessment integrates multiple data sources: (1) the gold standards for clinical measurement of structural – nerve cross-sectional area (CSA) via high-resolution ultrasonography – and functional – nerve conduction velocity (NCV) via NCS – changes of the PNS; (2) CGM and metabolic parameters (e.g. C-Peptide); (3) wearables capturing relevant lifestyle factors; and (4) demographic data. Assessments will occur at baseline, 12 months, and 24 months, with wearable monitoring for one month preceding the main annual examination. Our interdisciplinary approach combines the neurophysiological and diabetological expertise of the OKS team with the digital biomarker and data science capabilities of the University of St. Gallen (HSG) team. For analyzing the relationship between biological factors and nerve function (RQ1), we will employ multiple regression models. For designing predictive digital biomarkers (RQ2), we will develop personalized machine learning models. This research builds on previous collaborations between OKS and HSG, in which the data collection infrastructure was developed and first pilot studies were conducted successfully. Expected outcomes: This research will yield: (1) comprehensive characterization of DN onset and progression in pediatric T1D, including structural and functional changes in (un)myelinated nerve fibers; (2) novel digital biomarkers for early detection of DN using low-burden, continuous monitoring outside clinical settings; (3) identification of modifiable risk factors with the strongest influence on various components of nerve function; and (4) foundation for targeted, individualized preventive strategies. Findings will be disseminated through peer-reviewed publications, and presentations at international conferences. Ultimately, this research aims to establish new standards for patient-centered DN monitoring and prevention in pediatric diabetes care, reducing the long-term health and economic burden.

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