Improving Hypertension Treatment in African Americans Using Computational Modeling and Predictive Analytics

使用计算模型和预测分析改善非裔美国人的高血压治疗

• 批准号: 10580094
• 负责人: John S Clemmer
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580094
• 关键词: Acceleration; African American population; Age; Aldosterone; Angiotensin II; Animal Experiments; Antihypertensive Agents; Arterial Disorder; Arteriovenous fistula; Attention; Baroreflex; Blood Pressure; Calcium Channel; Calibration; Cardiac Output; Clinical; Clinical Data; Clinical Treatment; Complex; Computer Models; Computer Simulation; Controlled Study; Data; Denervation; Development; Devices; Dimensions; Disease; Disparity; Diuretics; Endocrine; Feedback; Frequencies; Generations; Genomics; Glean; Glomerular Filtration Rate; Heart Rate; High Prevalence; Hormonal; Human; Hypertension; Jackson Heart Study; Kidney; Laboratories; Literature; Machine Learning; Mentors; Minority; Modeling; Morbidity - disease rate; Obesity; Patients; Pattern; Peptidyl-Dipeptidase A; Peripheral Resistance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiological; Physiology; Population; Predictive Analytics; Prevalence; Probability; Process; Proxy; Publishing; Regimen; Research; Resistance; Resistant Hypertension; Severities; Socioeconomic Factors; Sodium Chloride; System; Techniques; Testing; Treatment Efficacy; Variant; Work; analytical tool; antagonist; blood pressure control; body system; clinically relevant; cohort; comorbidity; computer generated; data warehouse; experimental study; genetic epidemiology; human model; hypertension control; hypertension treatment; hypertensive; improved; in silico; insight; machine learning algorithm; mathematical model; model building; mortality; neural; novel; patient population; patient response; pharmacologic; physiologic model; resistance mechanism; response; simulation; success; therapeutic biomarker; therapy resistant; tool; treatment response; virtual; virtual model; virtual patient

ABSTRACT As compared to whites, African Americans (AA) develop hypertension (HTN) at an earlier age, have a greater frequency and severity of HTN, poorer control of blood pressure (BP), and have twice the mortality rate from HTN. For 47 years our department has been developing computer simulations of integrative physiology for research purposes. The current model, HumMod, is comprised of 14 organ systems, and includes neural, endocrine, circulatory, and renal physiology. We have created tools that generate and analyze large cohorts of computer-generated (virtual) patients. With these techniques HumMod has been used for hypothesis generation and for understanding underlying physiological mechanisms that are not able to be determined in either whole animal or human experiments. This proposed work will use these tools and this mathematical model of human physiology to develop a realistic AA virtual population for studying antihypertensive therapies that have well-known (diuretic or salt reduction), variable (angiotensin converting enzyme, or ACE inhibition), or unclear (renal denervation (RDX), and baroreflex activation therapy (BAT) therapeutic efficacies in AA. Published data from our laboratory show that our model is robust and can realistically simulate salt sensitivity, multiple types of HTN, and device-based antihypertensive therapy. As shown in our preliminary data, we have successfully created a virtual population that was similar to the clinical data (AA population with resistant HTN) in 5-dimensions (blood pressure, heart rate, glomerular filtration rate, cardiac output, and peripheral resistance) and have conducted in silico trials for new device-based therapy currently being evaluated for the treatment of resistant HTN—namely RDX, BAT, and arteriovenous fistula. Based on these preliminary data, we hypothesize that these techniques will allow us to investigate the physiological mechanisms responsible for the variation in response to therapy in a wide range of AA patient types and predict the likelihood of success for a particular treatment. Aim 1 of the proposal will test the hypothesis that a virtual AA population with resistant HTN can be successfully calibrated and validated. Aim 2 of the proposal will test the hypothesis that in silico trials using the calibrated populations from the first Aim can be used for testing and predicting mechanisms of nonresponse to device-based antihypertensive therapies. Aim 3 will test the hypothesis that our predictive analytic techniques can be used to identify mechanisms and proxy markers of therapeutic resistance in hypertensive AA. These proposed studies have clinical relevance because they address a leading cause of morbidity and mortality as well as potential mechanisms of therapeutic resistance in an underserved and understudied minority. Furthermore, these applications and the potential insights gleaned from our physiological model and predictive analytic tools may have broad implications for BP control in other resistant hypertensive populations.

摘要 与白人相比，非裔美国人(AA)患高血压(HTN)的年龄更早，有 HTN的频率和严重性更高，对血压(BP)的控制更差，死亡率是HTN的两倍 来自HTN的费率。47年来，我们部门一直在开发计算机模拟 用于研究目的的生理学。目前的模型HumMod由14个器官系统组成， 包括神经、内分泌、循环和肾脏生理学。我们已经创建了工具来生成和 分析大量计算机生成的(虚拟)患者。有了这些技术，HumMod已经 用于生成假说和理解潜在的生理机制 能够在整个动物或人体实验中确定。这项拟议的工作将使用这些 开发现实的AA虚拟种群的工具和这个人体生理学的数学模型 研究众所周知的降压疗法(利尿剂或降盐)，变量 (血管紧张素转换酶，或ACE抑制)，或不清楚(肾去神经(RDX)，和压力感受性反射 激活疗法(BAT)对再障的治疗效果。我们实验室公布的数据显示，我们的 模型功能强大，可以逼真地模拟盐敏、多种类型的HTN和基于设备的 抗高血压治疗。如我们的初步数据所示，我们已成功创建了虚拟 在5个维度(血液)上与临床数据相似的人群(患有耐药HTN的AA人群) 血压、心率、肾小球滤过率、心输出量和外周阻力)，并具有 在硅胶试验中进行的新的基于设备的治疗目前正在评估的治疗 耐药HTN--即RDX、BAT和动静脉瘘。根据这些初步数据，我们 假设这些技术将使我们能够研究 在广泛的再生障碍性贫血患者类型中对治疗反应的变化并预测 某一特定治疗的成功。该提案的目标1将检验虚拟AA的假设 携带耐药HTN的人群可以成功地进行校准和验证。提案的目标2将测试 假设在使用第一个目标的校准总体的计算机试验中可以用于测试 以及预测基于设备的降压治疗无反应的机制。AIM 3将测试 我们的预测分析技术可以用来识别机制和代理的假设 高血压再生障碍性贫血的治疗耐药标志物。这些建议的研究具有临床意义。 因为它们解决了导致发病率和死亡率的一个主要原因以及 在服务不足和研究不足的少数群体中存在治疗耐药性。此外，这些应用程序和 从我们的生理模型和预测性分析工具中收集的潜在见解可能具有广泛的 对其他抵抗高血压人群的血压控制的影响。