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.

项目概要 严重皮肤不良反应（SCAR）是对药物产生的病态免疫反应， 死亡率为10-50%。在过去的十年中，预测和预防的重大承诺来自于 发现许多 SCAR 与 HLA I 类等位基因内的变异有关。对于 HLA-B*15:02，这有 导致许多东南亚国家对卡马西平进行常规处方前筛查，并取得了重大进展 卡马西平 SJS/TEN 病例减少。尽管取得了这些进展，但人们对遗传和遗传知之甚少。 与抗生素等常用药物相关的 SCAR 流行病学危险因素。还有限量的 有关美国不同人群中 SCAR 的 HLA 风险的信息。此外， 临床表型分析的不精确性和缺乏标准化编码给寻找 SCAR 病例带来了挑战 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 抗生素 SCAR 的知识。 在目标 1 中，我们将利用先进的信息学和纵向 EHR 数据为超过 1100 万患者提供服务。 自 20 世纪 80 年代起就与医疗保健系统合作，以识别 SCAR 病例。我们将创建、优化和标准化 用于查找 SCAR 病例并验证 SCAR 患者队列的可重复方法。这个迭代过程 将用于完善和传播电子表型以进行跨机构验证。 在目标 2 中，我们将分析 SCAR 患病率并进行病例对照研究，以确定药物特异性和 抗生素相关疤痕的患者特定危险因素。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，将 SCAR 患者与对照患者的依从性进行比较。 在目标 3 中，我们将从使用经过验证的抗生素的患者中鉴定候选 HLA 和遗传关联 - 相关的 SCAR。我们将研究少数群体和健康差异人群的遗传风险差异， 预测我们将有能力建立万古霉素 DRESS 的 HLA 关联（即与 嗜酸性粒细胞增多和全身症状）和磺酰胺类抗菌药物和 β-内酰胺 SCAR。单独的 HLA，或 结合临床危险因素，可以改善 SCAR 预防和早期诊断。我们将 建立一个数据共享平台，以在线电子表型和患者登记的形式，可以 用于扩大 SCAR 队列以进行未来大规模基因组学研究。 我们制定的路线图将转化为针对严重不良反应的电子表型的开发 促进基因发现的药物反应。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 加速遗传研究的使命密切相关 发现医源性和可预防的药物引起的疾病，并将其转化为更早的预防 诊断和增强的机制理解可能会导致有针对性的治疗方法。