Optimization of Helicobacter pylori-related Disease Outcomes in Veterans

退伍军人幽门螺杆菌相关疾病结果的优化

• 批准号: 10782537
• 负责人: SHAILJA C SHAH
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10782537
• 关键词: Accounting; Acids; Adherence; Aftercare; Antibiotic Resistance; Antibiotics; Area; Asian; Big Data; Biological; Cancer Burden; Cancer Etiology; Clinical; Data; Data Analyses; Databases; Dedications; Diabetes Mellitus; Disease; Disease Outcome; Dose; Electronic Health Record; Epidemiologic Methods; Epidemiology; Failure; Frequencies; Funding; Future; Gastroenterologist; Gastrointestinal Hemorrhage; Genetic; Genetic Determinism; Genomics; Genotype; Geography; Goals; Health; Helicobacter Infections; Helicobacter pylori; Helicobacter pylori induced gastric cancer; Immune response; Incidence; Individual; Inflammatory Response; Institution; Interdisciplinary Study; Knowledge; Lead; Life Style; Link; Logistic Regressions; Malignant Neoplasms; Mendelian randomization; Mentors; Metabolism; Methodology; Morbidity - disease rate; Outcome; Pathology; Patient Care; Pattern; Peptic Ulcer; Pharmaceutical Preparations; Physicians; Population; Predisposition; Prevalence; Prospective Studies; Randomized, Controlled Trials; Regimen; Regression Analysis; Regulation; Research; Research Design; Research Personnel; Research Priority; Resource Allocation; Resources; Risk; Risk Factors; Science; Scientist; Smoking; System; Talents; Testing; Time trend; Translating; United States; Variant; Veterans; Work; World Health Organization; adverse outcome; biobank; career; clinically relevant; cohort; comorbidity; data warehouse; design; drug metabolism; ethnic minority; gastric cancer prevention; genetic epidemiology; genetic variant; genome wide association study; genomic locus; geographic difference; human old age (65+); improved; individual response; malignant stomach neoplasm; medication nonadherence; military veteran; mortality; non-genetic; pathogen; personalized approach; personalized therapeutic; predictive modeling; programs; racial minority; success; support tools; treatment optimization; treatment response; trend

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.

PI 是一位医师科学家和胃肠病学家，其长期职业目标是独立 领导一项受人尊敬的多学科研究项目，该项目专注于幽门螺杆菌的个性化研究 幽门螺杆菌（H pylori）管理，以优化疾病、治疗和系统相关的结果 退伍军人。 CDA-2 旨在通过方法论将 PI 转变为 VA 优秀资助的研究人员 熟练掌握大数据分析、遗传流行病学和先进的流行病学方法，以及科学的方法 熟练掌握幽门螺杆菌病理学。 PI 得到导师的大力支持，他们拥有专业知识和丰富的独特知识 资源典型地将她的职业和研究目标联系起来，并通过大力支持和 合作机构。 PI 致力于通过提供卓越的患者来促进退伍军人的健康 床边护理并进行尖端的临床相关科学。 幽门螺杆菌是已知最强的胃癌危险因素，这种恶性肿瘤导致超过 780,000 人死亡 每年都会增加生命，并且仍然是癌症相关死亡的第三大原因。这种病原体也直接 导致其他高发病率和高死亡率的疾病，包括消化性溃疡病。幽门螺杆菌感染 约占所有退伍军人的 28%，在种族和族裔中的患病率超过 50% 少数民族。根除幽门螺杆菌需要 10-14 天使用 2-3 种抗生素和大剂量抑酸。 成功根除幽门螺杆菌导致胃癌和其他疾病的发病率下降 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， 自从消灭抗生素以来，造成了抗生素耐药性的巨大负担和其他不良后果 通过重复疗程来控制失败。事实上，世界卫生组织在 2017 年 将幽门螺杆菌根除失败指定为研究优先领域，这说明了其至关重要性和 广泛的健康影响。根除失败的原因是多因素的，除了抗生素之外 电阻，尚未完全研究。 我们假设定义根除失败的宿主水平决定因素将最大化初始 通过提供一个锚定点来制定个性化的方法来成功根除 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 退伍军人之间的相关结果。在本提案中，PI 将利用两个强大的 VA 数据库： 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，首先从每个数据库中构建一组完成幽门螺杆菌检测的退伍军人 测试（根据初步数据，大约占所有退伍军人的 10%）。退伍军人小组 治疗和治疗后幽门螺杆菌检测以评估根除成功也将基于 特别是 MVP（超过 650,000 名基因分型退伍军人中的约 18,000 名）。使用这两个队列，PI 将定义 幽门螺杆菌的患病率、抗幽门螺杆菌治疗的频率和类型、选择抗生素耐药模式、 根除失败的频率以及时间趋势和区域差异（AIM 1）。这将遵循 通过使用 GWAS (AIM 2) 定义幽门螺杆菌根除失败的遗传和非遗传决定因素， 分别采用多变量逻辑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。这部作品是 意义重大，因为它将填补退伍军人中幽门螺杆菌流行病学和治疗的关键知识空白。 在未来的前瞻性研究中，作为一名独立的 VA 研究者，PI 将整合宿主水平的决定因素 根除失败转化为临床支持工具，可转化为床边幽门螺杆菌个性化 基于个人因素的根除治疗，以优化退伍军人的健康。