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: 10651771
• 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/10651771
• 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计划，该计划敏锐地专注于个性化的螺旋细菌 为了优化疾病，治疗和系统相关结果 退伍军人。该CDA-2旨在将PI转换为具有方法论的VA优异资助的研究人员 精通大数据分析，遗传流行病学和高级流行病学方法以及科学 佩洛里病理生物学的熟练程度。 PI受到导师的良好支持，他们的专业知识和独特的财富 资源典型地弥合她的职业和研究目标，并通过深刻的支持和 协作机构。 PI致力于通过提供出色的患者来提高资深健康 在床边和进行临床相关的尖端，临床科学的护理。 幽门螺杆菌是胃癌最强的已知危险因素，这种恶性肿瘤声称超过780,000 每年生活，仍然是癌症相关死亡率的第三主要原因。该病原体也直接 针对其他发病率和死亡率（包括消化性溃疡病）的疾病的病因。幽门螺杆菌感染 所有退伍军人中约有28％，种族和族裔的患病率超过50％ 少数民族。幽门螺杆菌根除需要10-14天2-3天抗生素和高剂量酸抑制。 成功的根除导致胃癌和其他疾病的发生率降低 幽门螺杆菌是病因。但是，幽门螺杆菌消除失败的速度上升威胁到这些成功， 由于根除而导致抗生素耐药性和其他不利后果的巨大负担 通过重复的治疗过程来控制失败。确实，在2017年世界卫生组织 指定的H幽门螺杆化失败是研究优先领域，它表达了其至关重要的重要性和 广泛的健康影响。根除失败的原因是多因素，除了抗生素外 抗性，尚未完全研究。 我们假设定义宿主水平的决定因素，将最大化初始 通过提供一个锚定点来开发个性化方法来消除的成功 治疗。我们进一步假设，个性化方法将改善个人治疗反应， 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成果。在此提案中，PI将利用两个强大的VA数据库，即 公司数据仓库（CDW）和百万退伍军人计划（MVP），电子健康记录 - 链接的基因组生物库，首先构建了完成H幽门螺杆菌的每个数据库的老兵 测试（根据初步数据，大约有10％的退伍军人）。一群退伍军人 经过治疗并进行了治疗后H幽门螺杆测试以评估根除成功 MVP专门（超过650,000个基因型退伍军人中的18,000个）。使用这两个队列，PI将定义 幽门螺杆菌的患病率，抗H幽门疗法的频率和类型，选择抗生素耐药性模式， 根除失败的频率以及时间趋势和区域变化（AIM 1）。这将遵循 通过定义使用GWAS幽门螺杆菌衰竭的遗传和非遗传决定因素（AIM 2）， 多变量逻辑回归和门德尔随机化（AIM 3）研究设计。预测性 基于非侵入性数据的抗生素抗性模型也将被构建和验证。这项工作是 意义重大，因为它会填补幽门螺杆菌流行病学和退伍军人治疗的关键知识差距。 在未来作为独立VA研究者的前瞻性研究中，PI将整合宿主级别的决定因素 消除失败为临床支持工具，可以将其转化为幽门螺杆菌个性化的床边 基于个人水平因素的根除疗法，以优化退伍军人健康。