Validation of clinical assessment tools for population genetic studies of epileps

描述（由申请人提供）：人们越来越认识到，遗传变异在一系列常见疾病的发展以及对药物的个体反应中起着重要作用。识别癫痫发生的遗传风险因素和抗癫痫药物治疗的反应可以使我们对癫痫发病机制和耐药性的理解取得重大进展，从而产生新的治疗靶点和策略。然而，由于缺乏专业知识和先进的调查技术，发展中国家（如中国农村）癫痫遗传学研究和应用的进展受到准确诊断和表型分析不足的阻碍。为了克服这一关键的研究和临床障碍，本研究旨在通过开发和验证临床评估工具来开发必要的基础设施，以进行准确的表型分析和建立遗传学研究能力，包括研究后勤，网络和人员培训。开发的研究模型有可能应用于其他低收入和中等收入国家，世界上5000万癫痫患者中有80%生活在这些国家。将开发临床评估工具（问卷）用于癫痫的表型分析，重点关注对药物选择和预后有影响的各种癫痫发作类型和癫痫综合征的分类。为了验证评估工具，乡村医生将在培训后将其应用于从中国政府国家癫痫治疗项目中选出的600名患者。临床评估工具在表型分析中的有效性将通过与金标准进行比较来确定，金标准包括专家评估、脑电图记录和大脑磁共振成像。为了获得鉴定预测癫痫易感性增加的遗传标记基因座的初步数据，将从每例患者中获得口腔涂片/唾液样本，用于DNA提取和随后的基因分型。将在患者和对照之间比较多态性的频率。候选多态性将从在中国癫痫患者的独立队列中进行的全基因组关联研究中鉴定的显著变体中选择。 公共卫生相关性：癫痫影响全球5000万人，其中80%生活在资源贫乏的国家，是最常见的神经系统疾病，也是一个重大的全球公共卫生问题。了解诱发癫痫和耐药性的遗传风险因素可以帮助医生找到更好的治疗方法和潜在的预防性疗法，但发展中国家的患者往往被排除在此类研究之外，因为缺乏对不同类型癫痫进行分类的专业知识和复杂的调查技术。该研究旨在通过开发和验证用于准确表型分析的临床评估工具，建立遗传学研究能力，包括研究后勤，网络和人员培训，为在中国农村开展大规模遗传学研究建立必要的基础设施。

DESCRIPTION (provided by applicant): It is increasingly recognized that genetic variants play a significant role in the development of a range of common diseases as well as in the individual response to medications. Identifying genetic risk factors for the development of epilepsy and response to antiepileptic drug therapy can lead to major advances in our understanding of the pathogenesis of epilepsy and of drug resistance, leading to new treatment targets and strategies. However, progress in the research as well as application of findings in epilepsy genetics in developing countries, such as rural China, is hampered by deficiency in accurate diagnosis and phenotyping because of lack of specialist expertise and sophisticated investigation techologies. To overcome this critical research and clinical barrier, this research aims to develop the necessary infrastructure through the development and validation of clinical assessment tools for accurate phenotyping and building genetics research capacity, including research logistics, network and personnel training. The research model developed has the potential to be applied in other low- and middle-income countries, where 80% of the world's 50 million epilepsy patients live. Clinical assessment tools (questionnaires) will be developed for phenotyping of epilepsy, focusing on the classification of various seizure types and epilepsy syndromes which have implications for drug choice and prognosis. To validate the assessment tools, they will be applied by village doctors after training to 600 patients selected from the Chinese government's national epilepsy treatment programs. The validity of the clinical assessment tools in phenotyping will be determined by comparing with the gold standard, comprising of specialist evaluation, electroencephalography recording and magnetic resonance imaging of the brain. To obtain preliminary data in identifying genetic marker loci predictive of increased susceptibility to epilepsy, a buccal smear/saliva sample will be obtained from each patient for DNA extraction and subsequent genotyping. Frequencies of the polymorphisms will be compared between patients and controls. Candidate polymorphisms will be selected from significant variants identified in a genome wide association study being carried out in an independent cohort of Chinese epilepsy patients. PUBLIC HEALTH RELEVANCE: Affecting 50 million people worldwide with 80% living in resource poor countries, epilepsy is the most common neurological disorder and a major global public health issue. Understanding the genetic risk factors predisposing to epilepsy and drug resistance can help doctors find better treatment and potentially preventive therapy, but patients in developing countries are often excluded from such research because of lack of expertise and sophisticated investigation technologies to classify the different types of epilepsy. This research aims to develop the necessary infrastructure for conducting large scale genetics research in rural China through the development and validation of clinical assessment tools for accurate phenotyping and building genetics research capacity, including research logistics, network and personnel training.