Clinical Informatics to Advance Epidemiology and Pharmacogenetics of Serious Cutaneous Adverse Drug Reactions

临床信息学促进严重皮肤药物不良反应的流行病学和药物遗传学

• 批准号: 10018800
• 负责人: Li Zhou
• 金额: $ 69.62万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018800
• 关键词: Address; Adherence; Adverse event; Adverse reactions; Affect; African American; Alleles; Allergic Reaction; Allopurinol; Antibiotics; Autoimmune Diseases; Autoimmune Process; Biological Markers; Carbamazepine; Case-Control Studies; Cessation of life; Clinical; Clinical Data; Clinical Informatics; Clinical Sciences; Code; Country; Cutaneous; Data; Dermatology; Development; Diagnostic; Disease; Drug Administration Routes; Drug Exposure; Drug Prescriptions; Drug usage; Early Diagnosis; Electronic Health Record; Eosinophilia; Epidemiology; Ethnic group; Female; Future; Genetic; Genetic Risk; Genetic Translation; Genomics; Goals; HLA Antigens; Healthcare; Healthcare Systems; Histocompatibility Antigens Class I; Hypersensitivity; Iatrogenesis; Immunologics; Immunology; Infection; Informatics; Inpatients; Institution; International; Knowledge; Lead; Machine Learning; Mandatory Reporting; Medical Genetics; Methodology; Methods; Minority; Mission; Modeling; Monobactams; Morbidity - disease rate; Natural Language Processing; Nevirapine; Outpatients; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Phenotype; Population; Population Heterogeneity; Prevalence; Prevention; Process; Quality of life; Race; Reaction; Registries; Reporting; Reproducibility; Research; Risk; Risk Factors; Risk stratification; Science; Source; Specificity; Standardization; Stevens-Johnson Syndrome; Sulfonamides; Surveys; Symptoms; Syndrome; System; Techniques; Technology; Text; Toxic Epidermal Necrolysis; Translating; Translations; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; Validation; Vancomycin; Variant; abacavir; adverse drug reaction; antimicrobial; base; beta-Lactams; care burden; case control; case finding; clinical decision-making; clinical phenotype; clinical practice; clinical risk; clinically relevant; cohort; comorbidity; data sharing; data warehouse; design; disability; dosage; genetic association; genetic risk factor; health disparity; immunoreaction; improved; medication compliance; medication safety; minority health; mortality; patient population; patient registry; prevent; racial and ethnic; screening; sex; sharing platform; southeast Asian; targeted treatment

Project Summary Severe cutaneous adverse reactions (SCARs) are morbid immunologic reactions to drugs that confer a mortality of 10-50%. Over the last decade, significant promise for prediction and prevention has come from the discovery that many SCARs are associated with variation within HLA class I alleles. For HLA-B*15:02, this has led to routine pre-prescription screening for carbamazepine in many Southeast Asian countries and a significant reduction in cases of carbamazepine SJS/TEN. Despite this progress, there is little known about genetic and epidemiological risk factors for SCARs related to commonly used drugs such as antibiotics. There is also limited information about HLA risk for SCARs across the diverse populations present in the United States. Furthermore, imprecision of clinical phenotyping and lack of standardized coding has led to challenges in finding SCAR cases in the electronic health record (EHR). Our proposed study aims to address critical challenges and gaps in our knowledge of antibiotic SCARs. In Aim 1, we will leverage advanced informatics and longitudinal EHR data for over 11 million patients from Partners HealthCare System since the 1980s to identify SCAR cases. We will create, optimize and standardize reproducible methods for finding SCAR cases and validating a cohort of SCAR patients. This iterative process will be used to refine and disseminate an electronic phenotype to be validated cross-institutionally. In Aim 2, we will analyze SCAR prevalence and conduct a case-control study to identify drug-specific and patient-specific risk factors for antibiotic-associated SCARs. We will compare clinical sequelae, quality of life and adherence of SCAR patients compared to controls through validated survey instruments. In Aim 3, we will identify candidate HLA and genetic associations from patients with validated antibiotic- associated SCARs. We will examine difference in genetic risk in minority and health disparity populations and predict that we will be powered to establish HLA associations for vancomycin DRESS (i.e., drug reaction with eosinophilia and systemic symptoms) and sulfonamide antimicrobial and beta-lactam SCAR. HLA alone, or in combination with clinical risk factors, can lead to improved SCAR prevention and early diagnosis. We will establish a data sharing platform, in the form of an online electronic phenotype and patient registry, that can be used to enlarge SCAR cohorts for future large-scale genomics studies. The roadmap we develop will translate into the development of electronic phenotypes for serious adverse drug reactions that facilitate genetic discovery. Knowledge gained will be crucial to the translation of genetic data into clinical decision making. This is in close alignment with NIH’s research mission to accelerate genetic discovery for iatrogenic and preventable drug-induced diseases that will translate into prevention, earlier diagnosis and an enhanced mechanistic understanding that may lead to targeted therapeutic approaches.

项目摘要 严重的皮肤广告反应（SCARS）是对会议的药物的病态免疫学反应 死亡率为10-50％。在过去的十年中，预测和预防的重大希望来自 发现许多疤痕与HLA I类等位基因中的变化有关。对于HLA-B*15：02，这有 导致许多东南亚国家的卡马西平进行常规的预选前筛查和重要的 卡马西平SJS/10的病例减少。尽管取得了这种进展，但对遗传和 与常用药物（例如抗生素）有关的疤痕的流行病学风险因素。也有限 有关美国HLA风险在美国存在的疤痕风险的信息。此外， 临床表型的印象和缺乏标准化编码的印象导致了寻找疤痕病例的挑战 在电子健康记录（EHR）中。我们提出的研究旨在解决我们的关键挑战和差距 了解抗生素疤痕。 在AIM 1中，我们将利用超过1100万患者的高级信息和纵向EHR数据 自1980年代以来，合作伙伴的医疗保健系统以识别疤痕病例。我们将创建，优化和标准化 可再现的方法，用于查找疤痕病例和验证疤痕患者的队列。这个迭代过程 将用于完善和传播电子表型以在跨机构上进行验证。 在AIM 2中，我们将分析疤痕患病率并进行一项病例对照研究，以识别药物特异性和 抗生素相关疤痕的患者特异性危险因素。我们将比较临床后遗症，生活质量和 通过经过验证的调查工具，与对照组相比，疤痕患者的依从性。 在AIM 3中，我们将确定来自经过验证抗生素的患者的候选HLA和遗传关联 相关的疤痕。我们将检查少数民族和健康差异人群中遗传风险的差异以及 预测我们将有能力建立万古霉素的HLA关联（即 单独使用HLA，或者 结合临床危险因素，可以改善预防疤痕和早期诊断。我们将 以在线电子表型和患者注册表的形式建立一个数据共享平台，可以是 用于扩大疤痕队列的未来大规模基因组学研究。 我们开发的路线图将转化为用于严重逆境的电子表型的发展 促进遗传发现的药物反应。获得的知识对于遗传数据的翻译至关重要 进入临床决策。这与NIH的研究任务密切一致，以加速遗传 生化性和可预防药物诱导的疾病的发现，这些疾病将转化为预防 诊断和增强的机械理解，可能导致靶向治疗方法。