Michigan Hepatotoxicity Clinical Research Network Renewal 2013

描述（由申请人提供）：药物性肝损伤网络（DILIN）成立于2003年，旨在促进对DILI的病因、发病机制和自然史的理解和研究。正在进行的回顾性研究从8种药物中的一种引起肝损伤的受试者中收集了109份DNA样本。此外，在正在进行的DILIN前瞻性研究中，1215例因100多种单一药物和草药及膳食补充剂（HDS）导致的肝损伤患者被纳入研究，并进行了至少6个月的随访。已经发表了描述整个队列的表现特征和临床结果以及归因于特定药物的DILI的手稿。辅助研究探索牵连HDS产品的化学含量已经开始。收集的DNA、淋巴细胞、血清、血浆和肝组织也被用于进行信息机制研究。目前申请的主要目的是在肝损伤发生后尽可能早地继续招募和招募疑似DILI患者，收集生物样本用于遗传学、免疫学、转录组学和蛋白质组学研究。假设这些研究将改善DILI易感性、机制和结果的生物标志物。我们还建议进行新的肝弹性成像研究，以纵向评估疾病严重程度，并对严重急性DILI患者进行试点临床试验。密歇根大学DILI发病2周内的病例招募和登记将通过使用自然语言处理算法来搜索住院和门诊电子医疗记录以及来自密歇根肝毒性研究网络140名医生成员的患者转诊来完成。本应用程序的第二个目的是继续探索宿主遗传变异在DILI易感性中的作用，并在高因果关系评分病例中使用下一代测序技术。外显子组阵列、全基因组和全外显子组测序被建议用于鉴定与DILI易感性相关的罕见遗传多态性，然后进行表达系统和途径分析研究。本应用程序的第三个目标是进一步开发一种准确可靠的计算机化因果关系评估工具，与专家意见和其他目前使用的方法相比，该工具将具有更高的灵敏度和特异性。该工具的特定变量的系数将从DILIN数据库中开发出来，并使用未来的DILIN病例和其他非dili肝炎急性病例进行测试和验证。此应用程序的第四个目标是进一步发展LiverTox网站，使其成为DILI的全面和权威资源。建议成立一个LiverTox执行委员会来监督和协调计算机因果关系评估工具的开发，以及关于处方药和HDS产品引起的肝损伤章节的开发和维护。最后，LiverTox网站门户网站被提议允许提交真实的DILI病例进行因果关系评估和潜在的纳入未来DILIN研究。

DESCRIPTION (provided by applicant): The Drug Induced Liver Injury Network (DILIN) was established in 2003 to advance understanding and research into the causes, pathogenesis, and natural history of DILI. The ongoing Retrospective study has collected 109 DNA samples from subjects with liver injury attributed to one of 8 drugs. In addition, 1215 patients with liver injuy attributed to over 100 individual drugs and herbal and dietary supplements (HDS) have been enrolled and followed for at least 6 months in the ongoing DILIN Prospective study. Manuscripts describing the presenting features and clinical outcomes in the overall cohort and with DILI attributed to specific agents have been published. Ancillary studies exploring the chemical content of implicated HDS products have been initiated. The collected DNA, lymphocytes, serum, plasma, and liver tissue have also been used to conduct informative mechanistic studies. The primary aim of the current application is to continue to recruit and enroll suspected DILI patients as early as possible after liver injury onset for collection of biological samples tobe used in genetic, immunological, transcriptomic, and proteomic studies. It is hypothesized that these studies will lead to improved biomarkers of DILI susceptibility, mechanisms, and outcomes. We also propose novel studies of liver elastography to longitudinally assess disease severity and a pilot clinical trial for patients with severe acute DILI. Recruiting and enrolling cases within 2 weeks of DILI onset at the University of Michigan will be accomplished via use of natural language processing algorithms to search inpatient and outpatient electronic medical records as well as the referral of patients from the 140 physician member Michigan Hepatotoxicity Research Network. A second aim of this application is to continue to explore the role of host genetic variation in DILI susceptibility and outcomes using next generation sequencing techniques in high causality score cases. Exome arrays, whole genome, and whole exome sequencing are proposed to identify rare genetic polymorphisms associated with DILI susceptibility followed by expression system and pathway analysis studies. The third aim of this application is to further develop an accurate and reliable computerized causality assessment instrument that will have improved sensitivity and specificity compared to expert opinion and other currently used methods. The coefficients for specific variables of this instrument will be developed from the DILIN database and tested and validated using future DILIN cases and other acute cases of non-DILI hepatitis. The fourth aim of this application is to further develop the LiverTox website as a comprehensive and authoritative resource on DILI. A LiverTox Executive Committee is proposed to oversee and coordinate the development of a computerized causality assessment instrument as well as the development and maintenance of chapters on liver injury due to prescription drugs and HDS products. Finally, a LiverTox website portal is proposed to allow for the submission of bona-fide DILI cases for causality assessment and potential enrollment into future DILIN studies.