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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

基本信息

批准号：
10228607
负责人：
Li Zhou
金额：
$ 69.75万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10228607
关键词：
Address Adherence Adverse event Adverse reactions Affect African American Alleles Allergic Reaction Allopurinol Antibiotics Autoimmune Autoimmune Diseases 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 Groups Mission Modeling Monobactams Morbidity - disease rate Natural Language Processing Nevirapine Outpatients Patients Pharmaceutical Preparations Pharmacogenetics Pharmacology Phenotype Population Heterogeneity Prevalence Prevention Process Quality of life Race Reaction Registries Reporting Reproducibility Research Risk Risk Factors 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 repository data sharing design disability dosage genetic association genetic risk factor health disparity populations immunoreaction improved medication compliance medication safety minority disparity mortality patient population patient registry prevent racial and ethnic risk stratification screening sex sharing platform southeast Asian targeted treatment

项目摘要

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.

项目总结