Clinical and Informatics Research on Large Clinical Databases

大型临床数据库的临床和信息学研究

• 批准号: 10268075
• 负责人: Seo Baik
• 金额: $ 56.09万
• 依托单位: NATIONAL LIBRARY OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268075
• 关键词: 2019-nCoV; Admission activity; Adrenal Cortex Hormones; Adrenergic beta-Antagonists; Adverse drug effect; Adverse effects; Age; Aging; Ambulatory Care; Amoxicillin; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Antibiotics; Anticoagulants; Antidiabetic Drugs; Antihypertensive Agents; Antiplatelet Drugs; Arrhythmia; Aspirin; Azithromycin; Big Data; Biological; COVID-19; Calcium Channel Blockers; Cardiac; Cardiovascular Diseases; Caring; Cephalexin; Cessation of life; Characteristics; Chloroquine; Chronic; Chronic Kidney Failure; Ciprofloxacin; Clavulanate; Clinical; Clinical Informatics; Clinical Trials; Colchicine; Collagen Type I; Complication; Data; Databases; Diabetes Mellitus; Diagnosis; Dimensions; Dipyridamole; Disease; Dissection; Diuretics; Drug Controls; Drug Exposure; Drug Prescriptions; Drug usage; Epidemiology; Event; Exhibits; Exposure to; Female; Fiber; Fluoroquinolones; Fracture; Glucose; Goals; Health; Health Status; Hormone replacement therapy; Hospitals; Hot flushes; Hydroxyl Radical; Impaired cognition; Incidence; Individual; Infection; Inflammation; Inpatients; Insulin; Intensive Care Units; Interleukin-6; Label; Levaquin; Lipids; Long QT Syndrome; Longevity; Malignant Neoplasms; Manuscripts; Marketing; Medicare; Medicare Part A; Menopause; Metformin; Methodology; Moxifloxacin; Night Sweating; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Oral; Osteoporosis; Outcome; Outpatients; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Pneumonia; Population; Prevention; Proton Pump Inhibitors; Publishing; Regression Analysis; Reporting; Research; Risk; Ruptured Aortic Aneurysms; Serious Adverse Event; Severities; Signs and Symptoms; Stroke; Sulfonylurea Compounds; Symptoms; Tendon structure; Tensile Strength; Thiazolidinediones; Ticlopidine; Time; Torsades de Pointes; United States Food and Drug Administration; Veterans; Warfarin; Withdrawal; Woman; analog; base; beneficiary; blood pressure medication; clinical database; clinical risk; clopidogrel; cytokine; diabetic; diabetic patient; drug development; drug market; effective therapy; follow-up; glucagon-like peptide 1; hazard; human study; informatics infrastructure; inhibitor/antagonist; insight; interest; medication safety; mortality; mortality risk; pre-clinical; receptor; rituximab; sociodemographics; tendon rupture

Clinical Projects A. Possible Beneficial and Adverse Drug Effects on SARS-COV-2 Infections (COVID-19) We have identified one set of drugs used in ambulatory care that might that might reduce the incidence and/or the severity of COVID-19. We have identified another set that could aggravate those dimensions. Drugs that might reduce the risk of, or ameliorate COVID-19 include Chloroquine and hydroxyl-chloroquine. This combination is already being teste in clinical trials, but the number of subjects has been small and observational data will likely be needed to support these studies. Drugs that may reduce the inflammation mostly by blocking the cytokine IL-6 or its receptor include Colchicine an IL-6 inhibitor, Corticosteroids, Biologics that treat rheumatologic disease (Tocilizumab, Rituximab, Sarilumab), Anticoagulants (Warfarin, Dabigatran, Rivaroxaban, Apixaban), Anti-platelet drugs (Aspirin, Clopidogrel, Ticagrelor, Prasugrel, dipyridamole, Dipyridamole/aspirin, Ticlopidine, Etifibatide). Some drugs that might aggravate COVID19 include Non-steroidal anti-inflammatory, ACE inhibitors and ARBS. We will study their association with the incidence and severity of COVID 19 infections. B. Metformin and longevity In the last decade, research on aging found that metformin use was associated with a reduction in cognitive decline and a longer survival among diabetics compared to those treated with other oral agent. The U.S Food and Drug Administration (FDA) recently approved the first human study to see if an anti-diabetic medication, Metformin, can protect diabetic patients from the multiple diseases from aging. We identified about 300,000 Medicare beneficiaries who were diagnosed with type 2 diabetes post 12/31/2006 and followed them until death, switching to capitated plans, disenrollment from Medicare or 12/31/2016 whichever comes first. During this follow-up, we also collected patients socio-demographic information as well as the use of prescription drugs. Prescription medications include not only 8 commonly prescribed antidiabetics (metformin, insulin, sulfonylureas, thiazolidinedione, GLP-1 analogues, DPP-4 inhibitors, SGLT-2 inhibitors, and other glucose lowering drugs), but also 5 antihypertensive medications (diuretics, beta-blockers, calcium-channel blockers, ACE inhibitors, and ARBs) and 1 lipid-lowering drug (statin). Controlling for other medication use and patients characteristics in time-varying manner, metformin was not strongly associated with the longer survival (HR=0.95) and the association was not statistically significant. Rather, Compare to the no use of each study medication, mortality risk declined with use of 3 diabetes drugs (SGLT-2 inhibitors, GLP-1 analogues and DPP-4 Inhibitors) 3 blood pressure medications (diuretics, ARBs, and ACEI inhibitors) and statins. Statin exhibited most consistent, reduction in all-cause mortality risk but 20% of study patients never took a statin, suggesting missed prevention opportunities. This study was published at BMJ Open Diabetes Research & Care. C. Proton Pump Inhibitors (PPIs) and mortality Proton pump inhibitors (PPIs) have been associated with increases in the incidence of pneumonia, C Decile infection and osteoporosis/fractures, probable chronic renal failure and cardiac events. Xie et al reported that PPIs could also increase the risk of death using Veterans Affairs (VA) data (HR of 1.15 1.25). From 2007-2016 Medicare Parts A, B and D data, we identified 1.2 million Medicare beneficiaries. We also defined a set of covariates: use of PPIs, use of H2 blockers as a control drug, admission to intensive care units or inpatient hospitals, socio-demographics, presence of 58 chronic conditions and treated them as time-dependent covariates in our main analysis of Cox proportion hazard regression. In addition to treating covariates in time-varying manner, we used the concept of lag-time to define drug exposure period in order to control for protopathic bias which occurs when the outcome of interest is associated with an exposure that actually results from early signs and symptoms of the outcome under study. This study is going to be an example of obtaining an accurate estimate of the association between drug exposure and health status. D. Fluoroquinolones and tendon complication Fluoroquinolones (FQ) are among the most widely prescribed antibiotics in the outpatient setting. Several studies have reported the plausible associations between the use of FQs and tendon complications. The U.S FDA issued black box warning labels to FQs since 2008. Several observational studies associate the use of FQ with an increased risk for tendon rupture, aortic aneurysm or dissections (AA/AD). The fact that collagen type I and III fibers provide tensile strength to both tendons and aortic walls, and that FQs can disrupt these fibers in some circumstances, magnify concerns about these reported associations. Some prior studies described the relationship between FQs and tendon rupture as a class effect and included amoxicillin as a control drug to determine whether these complications are specific to FQs. We separately included 3 FQs (ciprofloxacin, levofloxacin, moxifloxacin) and 4 non-FQ antibiotics (amoxicillin, amoxicillin-clavulanate, azithromycin or cephalexin), 5 of which were top 5 antibiotic agents in US. Using Fine-Gray competing risk regression analyses treating death as a competing risk, we assessed the independent risk of tendon rupture for each antibiotic use in a 1.2 million Medicare population. Precisely, we assessed the risk by temporal exposure within study antibiotics (within 30 days, 31-60 days, more than 60 days) to avoid non-differential misclassification that can occur with too simple (yes/no) drug exposure. We just submitted the second revision. It will appear in BMJ Open soon. E. Association between Hormone replacement therapy and Longevity, cardiovascular diseases and cancers Hormone replacement therapy (HRT) is an effective treatment for the typical menopause-related symptoms (such as hot flashes, night sweats, irregular periods and etc.) and long-term health problems associated with the menopause (the risk of osteoporosis, cardiovascular disease and stroke). Its effects on various outcomes such as cardiovascular diseases, cancers and all-cause mortality is unclear. Initiation of HRT in women over 60 is generally not recommended but is found to be ok for some women after age 65. In this study, we traced about 700,000 female Medicare beneficiaries from Medicare Part D entry to the onset of each outcome, death, switching to capitated plan, disenrollment from Medicare, or 12/31/2017 whichever comes first and then we compared each risk among women treated with HRT to those not treated. Individuals in the study were grouped based on the number of days exposed to HRT (none, less than a year, more than a year) and it was treated as a time-dependent covariates in a Cox proportional hazard regression analysis. This study will explore whether or not HRT in women over 65, which is generally not recommended, reduce the risk of outcomes of interest. The manuscript will be submitted soon. F. Characterizing the cardiac risks of commonly-prescribed QT-prolonging drugs Drug-induced long QT syndrome is one of the most frequent cause of withdrawal or relabeling of marketed drugs. It is difficult to detect serious adverse events associated with QT prolongation during drug development, both in the preclinical and clinical phases of drug trials. The clinical risks of many QT-prolonging drugs are only discovered by post-marketing surveillance. This study leverages the large CMS database (over 1.2 million subjects) to provide insight into the cardiac risks of some QT-prolonging drugs with known risk of severe cardiac arrhythmia (Torsades de pointes).

临床项目 A. 药物对 SARS-COV-2 感染 (COVID-19) 可能产生的有益和不利影响 我们已经确定了一组用于门诊护理的药物，可能会降低 COVID-19 的发病率和/或严重程度。我们已经确定了另一组可能会加剧这些维度的问题。可能降低感染 COVID-19 风险或改善症状的药物包括氯喹和羟氯喹。这种组合已经在临床试验中进行测试，但受试者数量很少，可能需要观察数据来支持这些研究。主要通过阻断细胞因子 IL-6 或其受体来减轻炎症的药物包括秋水仙碱（一种 IL-6 抑制剂）、皮质类固醇、治疗风湿性疾病的生物制剂（托珠单抗、利妥昔单抗、沙里鲁单抗）、抗凝剂（华法林、达比加群、利伐沙班、阿哌沙班） , 抗血小板药物（阿司匹林、氯吡格雷、替格瑞洛、普拉格雷、双嘧达莫、双嘧达莫/阿司匹林、噻氯匹定、依替巴肽）。一些可能加重新冠肺炎病情的药物包括非甾体类抗炎药、ACE抑制剂和ARBS。我们将研究它们与 COVID 19 感染的发生率和严重程度的关系。 B. 二甲双胍与长寿 在过去的十年中，关于衰老的研究发现，与使用其他口服药物治疗的患者相比，二甲双胍的使用与糖尿病患者认知能力下降的减少和更长的生存期有关。美国食品和药物管理局 (FDA) 最近批准了第一项人体研究，旨在了解抗糖尿病药物二甲双胍是否可以保护糖尿病患者免受多种衰老疾病的侵害。我们确定了约 300,000 名 Medicare 受益人，他们在 2006 年 12 月 31 日后被诊断患有 2 型糖尿病，并对他们进行跟踪直至死亡，转为按人头计划、退出 Medicare 或 2016 年 12 月 31 日（以先到者为准）。在此随访期间，我们还收集了患者的社会人口统计信息以及处方药的使用情况。处方药不仅包括8种常用抗糖尿病药（二甲双胍、胰岛素、磺酰脲类、噻唑烷二酮类、GLP-1类似物、DPP-4抑制剂、SGLT-2抑制剂和其他降糖药），还包括5种降压药（利尿剂、β-阻滞剂、钙通道阻滞剂、ACE 抑制剂和 ARB）和 1 种降脂药（他汀类药物）。以随时间变化的方式控制其他药物使用和患者特征后，二甲双胍与较长生存期没有很强的相关性（HR=0.95），并且这种相关性不具有统计学意义。相反，与不使用每种研究药物相比，使用 3 种糖尿病药物（SGLT-2 抑制剂、GLP-1 类似物和 DPP-4 抑制剂）、3 种血压药物（利尿剂、ARB 和 ACEI 抑制剂）可降低死亡风险和他汀类药物。他汀类药物在全因死亡风险方面表现出最一致的降低作用，但 20% 的研究患者从未服用过他汀类药物，这表明错过了预防机会。这项研究发表在 BMJ Open Diabetes Research & Care 上。 C. 质子泵抑制剂 (PPI) 和死亡率 质子泵抑制剂 (PPI) 与肺炎、C Decile 感染和骨质疏松/骨折、可能的慢性肾功能衰竭和心脏事件的发病率增加有关。 Xie 等人使用退伍军人事务部 (VA) 数据报告称，PPIs 还可能增加死亡风险（HR 为 1.15 1.25）。根据 2007 年至 2016 年 Medicare A、B 和 D 部分的数据，我们确定了 120 万 Medicare 受益人。我们还定义了一组协变量：使用 PPI、使用 H2 阻滞剂作为对照药物、入住重症监护病房或住院医院、社会人口统计、58 种慢性病的存在，并将它们视为时间依赖性协变量。 Cox比例风险回归分析。除了以随时间变化的方式处理协变量之外，我们还使用滞后时间的概念来定义药物暴露期，以控制原病性偏差，当感兴趣的结果与实际由早期体征和实际结果引起的暴露相关时，就会发生原病性偏差。研究结果的症状。这项研究将成为准确估计药物暴露与健康状况之间关系的一个例子。 D. 氟喹诺酮类药物和肌腱并发症 氟喹诺酮类药物 (FQ) 是门诊中最广泛使用的抗生素之一。几项研究报告了 FQ 的使用与肌腱并发症之间的合理关联。自 2008 年以来，美国 FDA 对 FQ 发布了黑框警告标签。多项观察性研究表明，使用 FQ 会增加肌腱断裂、主动脉瘤或夹层 (AA/AD) 的风险。 I 型和 III 型胶原蛋白纤维为肌腱和主动脉壁提供抗拉强度，并且 FQ 在某些情况下会破坏这些纤维，这一事实加剧了人们对这些已报道的关联的担忧。之前的一些研究将 FQ 与肌腱断裂之间的关系描述为类效应，并使用阿莫西林作为对照药物，以确定这些并发症是否是 FQ 特有的。我们分别纳入了 3 种 FQ 抗生素（环丙沙星、左氧氟沙星、莫西沙星）和 4 种非 FQ 抗生素（阿莫西林、阿莫西林克拉维酸、阿奇霉素或头孢氨苄），其中 5 种是美国前 5 名抗生素药物。使用 Fine-Gray 竞争风险回归分析，将死亡视为竞争风险，我们评估了 120 万医疗保险人群中每种抗生素使用情况下肌腱断裂的独立风险。准确地说，我们通过研究抗生素的时间暴露（30 天、31-60 天、60 天以上）来评估风险，以避免因过于简单（是/否）药物暴露而可能发生的非差异性错误分类。我们刚刚提交了第二次修订。它很快就会出现在 BMJ Open 上。 E. 激素替代疗法与长寿、心血管疾病和癌症之间的关联 激素替代疗法（HRT）是针对典型的更年期相关症状（如潮热、盗汗、月经不调等）和更年期相关的长期健康问题（骨质疏松、心血管疾病的风险）的有效治疗方法。和中风）。它对心血管疾病、癌症和全因死亡率等各种结果的影响尚不清楚。一般不建议 60 岁以上的女性开始 HRT，但发现对于 65 岁以后的一些女性来说是可以的。在这项研究中，我们追踪了约 700,000 名女性 Medicare 受益人，从 Medicare D 部分进入到每个结果、死亡、转换的发生。人均计划、退出医疗保险或 2017 年 12 月 31 日，以先到者为准，然后我们比较了接受 HRT 治疗的女性的每种风险对于那些没有接受治疗的人。研究中的个体根据接触 HRT 的天数（无、少于一年、多于一年）进行分组，并在 Cox 比例风险回归分析中被视为时间依赖性协变量。本研究将探讨 65 岁以上女性的 HRT（通常不推荐）是否可以降低相关结果的风险。稿件将很快提交。 F. 描述常用 QT 延长药物的心脏风险 药物引起的长 QT 综合征是上市药物撤回或重新标签的最常见原因之一。无论是在药物试验的临床前阶段还是临床阶段，在药物开发过程中都很难检测到与 QT 延长相关的严重不良事件。许多 QT 延长药物的临床风险只能通过上市后监测来发现。本研究利用大型 CMS 数据库（超过 120 万受试者）深入了解一些已知存在严重心律失常（尖端扭转型室性心动过速）风险的 QT 延长药物的心脏风险。