Optimization of Helicobacter pylori-related Disease Outcomes in Veterans

PI是一名内科科学家和胃肠病专家，他的长期职业目标是独立 领导一个受人尊敬的、多学科的研究计划，敏锐地专注于个性化幽门螺杆菌 幽门螺杆菌(幽门螺杆菌)管理，以优化疾病、治疗和系统相关的结果 退伍军人。此CDA-2旨在将PI转变为VA功勋资助的研究人员，具有方法论 精通大数据分析、遗传流行病学和先进的流行病学方法，并科学 精通幽门螺杆菌的病理生物学。PI得到了导师的大力支持，他们的专业知识和财富独一无二 资源典型地将她的职业和研究目标联系起来，并通过深切的支持和 协作性机构。PI致力于通过提供特殊的患者来促进退伍军人的健康 在床边进行护理，并开展尖端的临床相关科学研究。 幽门螺杆菌是已知的患胃癌的最强风险因素，这种恶性肿瘤声称有超过78万人 每年都活着，仍然是癌症相关死亡的第三大原因。这种病原体也直接 引起其他发病率和死亡率高的疾病，包括消化性溃疡疾病。幽门螺杆菌感染 约28%的退伍军人，在种族和族裔中的流行率超过50% 少数族裔。根除幽门螺杆菌需要10-14天的2-3个抗生素和大剂量的酸抑制。 成功的根除导致了胃癌和其他疾病的发病率下降，对于H 幽门螺杆菌是致病因素。然而，幽门螺杆菌根除失败率的上升威胁着这些成功和 自根除以来，加剧了抗生素耐药性的巨大负担和其他不利后果 失败可以通过反复疗程的治疗来处理。事实上，2017年世界卫生组织 将根除幽门螺杆菌失败列为研究优先领域，这说明了它的极端重要性和 对健康的广泛影响。根除失败的原因是多方面的，除了抗生素之外 抗性，还没有完全调查过。 我们假设，确定宿主水平的根除失败的决定因素将最大化最初的 通过提供一个锚点来制定个性化的方法，从而成功根除 心理治疗。我们进一步假设个性化方法将改善个体治疗反应， 减少根除失败的意外下游后果，从而改善幽门螺杆菌- 退伍军人中的相关结果。在本提案中，PI将利用两个强大的退伍军人数据库，即 企业数据仓库(CDW)和百万退伍军人计划(MVP)，电子健康记录- 连接基因组生物库，首先从每个完成幽门螺杆菌的数据库中构建退伍军人队列 测试(根据初步数据，约占所有退伍军人的10%)。一群退伍军人，他们是 接受治疗并在治疗后进行幽门螺杆菌检测以评估根除成功的方法也将从 特别是MVP(超过650,000名基因分型的退伍军人中约18,000人)。使用这两个队列，PI将定义 幽门螺杆菌的流行，抗幽门螺杆菌治疗的频率和类型，抗生素耐药模式的选择， 根除失败的频率以及时间趋势和区域变化(目标1)。这将是遵循的 通过使用GWAS(AIM 2)定义根除幽门螺杆菌失败的遗传和非遗传决定因素， 多变量Logistic回归和孟德尔随机化(AIM 3)研究设计。预测性 还将构建和验证基于非侵入性数据的抗生素耐药性模型。这项工作是 这具有重要意义，因为它将填补退伍军人在幽门螺杆菌流行病学和治疗方面的关键知识空白。 在未来的前瞻性研究中，作为独立的退伍军人管理局调查员，PI将整合宿主水平的决定因素 根除失败成为临床支持工具，可转换到床边进行个性化的幽门螺杆菌 基于个体因素的根除治疗，以努力优化退伍军人健康。

The PI is a physician-scientist and gastroenterologist whose long-term career goal is to independently lead a respected, multidisciplinary research program that is keenly focused on personalizing Helicobacter pylori (H pylori) management in order to optimize disease-, treatment-, and systems-related outcomes among Veterans. This CDA-2 is designed to transform the PI into VA Merit-funded researcher with methodologic proficiency in big data analysis, genetic epidemiology, and advanced epidemiologic methods, and scientific proficiency in H pylori pathobiology. The PI is well-supported by mentors whose expertise and wealth of unique resources quintessentially bridge her career and research objectives, and by deeply supportive and collaborative institutions. The PI is committed to advancing Veteran health by providing exceptional patient care at the bedside and by conducting cutting-edge, clinically relevant science. H pylori is the strongest known risk factor for gastric cancer, a malignancy which claims over 780,000 lives annually and remains the 3rd leading cause of cancer-related mortality. This pathogen is also directly causative for other diseases with high morbidity and mortality, including peptic ulcer disease. H pylori infects approximately 28% of all Veterans, with the prevalence exceeding 50% among racial and ethnic minorities. H pylori eradication necessitates 10-14 days of 2-3 antibiotics and high-dose acid suppression. Successful eradication has led to a decreased incidence of gastric cancer and other diseases for which H pylori is causative. However, rising rates of H pylori eradication failure threaten these successes and contribute to the massive burden of antibiotic resistance and other adverse consequences, since eradication failure is managed with repeated courses of therapy. Indeed, in 2017 the World Health Organization designated H pylori eradication failure a research priority area, which speaks to its critical importance and broad health impact. The reasons underlying eradication failure are multifactorial and, apart from antibiotic resistance, have not been completely investigated. We hypothesize that defining host-level determinants of eradication failure will maximize the initial success of eradication by providing an anchoring point on which to develop a personalized approach to therapy. We further hypothesize that a personalized approach will improve individual treatment response, reduce the unintended downstream consequences of eradication failure and, consequently, improve H pylori- related outcomes among Veterans. In this proposal, the PI will leverage two powerful VA databases, the Corporate Data Warehouse (CDW) and the Million Veteran Program (MVP), the electronic health record- linked genomic biobank, to first construct a cohort of Veterans from each database who completed H pylori testing (approximately 10% of all Veterans based on preliminary data). A sub-cohort of Veterans who were treated and had post-treatment H pylori testing to assess eradication success will also be constructed from MVP specifically (~18,000 of the over 650,000 genotyped Veterans). Using these two cohorts, the PI will define the prevalence of H pylori, the frequency and type of anti-H pylori therapy, select antibiotic resistance patterns, the frequency of eradication failure as well as time trends and regional variations (AIM 1). This will be followed by defining the genetic and non-genetic determinants of H pylori eradication failure using GWAS (AIM 2), multivariable logistic regression and Mendelian randomization (AIM 3) study designs, respectively. Predictive models for antibiotic resistance based on non-invasive data will also be constructed and validated. This work is significant because it will fill critical knowledge gaps of H pylori epidemiology and treatment among Veterans. In future prospective studies as an independent VA investigator, the PI will integrate host-level determinants of eradication failure into a clinical support tool that can be translated to the bedside for personalization of H pylori eradication therapy based on individual-level factors in an effort to optimize Veteran health.