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General introduction 191 including vascular, hematological, endocrine diseases, and movement and eye disorders.81,82 Screening of common comorbidities associated with specific RGNDs thus contributes to preventive care and allows for personalized medicine. Furthermore, knowing the genetic etiology reveals important information about treatments, since some may have different requirements, efficacy, and adverse events.83 Next to advances in medical care, a diagnosis enables disorder-specific care by behavioral experts and caregivers and can improve targeted neuropsychological examinations, psychoeducation, behavioral interventions, and anticipation on supportive care, such as housing facilities. Questions addressed in this thesisInterventional research for individuals with complex, rare and heterogeneous disorders faces challenges with regard to trial methodology, outcome measures, and licensing and reimbursement, leading to patients missing out on possibly effective interventions. Personalized medicine has gained emerging interest, especially now underlying pathophysiological mechanisms and targeted treatments are increasingly identified and developed. Methodological quality, an N-of-1 framework, generalizability, feasibility and personalization are of paramount importance to realize the sorely needed evidence-based interventions for these vulnerable patients, enabling personalized medicine in both research and clinical practice. In this thesis, three main questions are addressed:1. How should N-of-1 studies be performed in RGNDs?2. How should outcome measures be used for individuals with RGNDs and ID? 3. To what extent have genetic diagnoses been reported in multidisciplinary ID care to enable disorder-specific care?Thesis outlineThis thesis is divided in three parts. Part I (Chapters 2 to 4) focuses on N-of-1 studies in RGNDs. Chapter 2 describes the current literature on N-of-1 trials in RGNDs and provides recommendations for future N-of1 studies to ultimately optimize evidence-based and personalized care. Annelieke Muller sHL.indd 19 14-11-2023 09:07