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的原因、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种药物之一导致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例肝损伤患者因超过100种药物和草药及膳食补充剂（HDS）而入选并随访至少6个月。已发表了描述总体队列中的表现特征和临床结局以及归因于特定药物的DILI的报告。已启动探索涉及HDS产品的化学含量的辅助研究。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。本申请的主要目的是在肝损伤发作后尽早继续招募和入组疑似DILI患者，以收集用于遗传学、免疫学、转录组学和蛋白质组学研究的生物样本。假设这些研究将导致DILI易感性、机制和结局的生物标志物的改善。我们还提出了肝脏弹性成像的新研究，以纵向评估疾病的严重程度和严重急性DILI患者的试点临床试验。在密歇根大学DILI发作2周内招募和入组病例将通过使用自然语言处理算法搜索住院和门诊电子病历以及从140名医生成员密歇根肝毒性研究网络转诊患者来完成。本申请的第二个目的是在高因果关系评分病例中使用下一代测序技术继续探索宿主遗传变异在DILI易感性和结局中的作用。建议使用外显子组阵列、全基因组和全外显子组测序来鉴定与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。本申请的第三个目的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。将根据DILIN数据库开发该工具特定变量的系数，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。本申请的第四个目的是进一步开发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，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产品引起的肝损伤的章节的开发和维护。最后，建议建立一个LiverTox网站门户，以便提交真实的DILI病例进行因果关系评估，并可能纳入未来的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.