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Mathematical and Statistical Modeling to Inform Design of HIV Clinical Trials

数学和统计模型为艾滋病毒临床试验的设计提供信息

基本信息

批准号：
8472745
负责人：
H. THOMAS BANKS
金额：
$ 67.93万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8472745
关键词：
Acute Address Anti-Retroviral Agents Basic Science Behavior Biological Biological Models CD4 Lymphocyte Count CD4 Positive T Lymphocytes Cells Chronic Clinical Clinical Research Clinical Sciences Clinical Trials Clinical Trials Design Collaborations Complex Conduct Clinical Trials Coupled Cytotoxic T-Lymphocytes Data Death Rate Development Disease Equation Excision Goals HIV HIV Infections Helper-Inducer T-Lymphocyte Immune response Immune system Immunologics Immunology Individual Infection Interruption Joints Kinetics Lead Life Linear Models Modeling Non-linear Models Outcome Pathogenesis Patients Pharmacotherapy Population Predisposition Principal Investigator Process Production Protease Inhibitor Publishing RNA Research Reverse Transcriptase Inhibitors Science Seminal Series Solutions Source Statistical Methods Statistical Models Suggestion System T-Lymphocyte Time Treatment Efficacy Viral Viral Load result Virion Virus Work base cost design improved insight interdisciplinary approach macrophage mathematical model mathematical theory models and simulation multidisciplinary neutralizing antibody optimal control theory programs theories tool treatment effect treatment strategy vector

项目摘要

DESCRIPTION (provided by applicant): Despite the advent of potent anti-retroviral therapy (ARV) and extensive efforts characterizing the mechanisms of HIV disease, unresolved, complex challenges in HIV research remain that demand a multidisciplinary approach integrating the basic and clinical sciences. In this spirit, the premise of this application is that mathematical nonlinear dynamical system models of within-host HIV dynamics coupled with statistical population models, integrated with clinical and biological expertise and informative data can accelerate breakthroughs in HIV research. A unique, multidisciplinary team merging expertise in immunology and clinical investigation with expertise in mathematical and statistical modeling, whose record of fruitful collaboration is already established, will carry out joint research on mathematical, statistical, immunological, and clinical developments toward this common goal through five interwoven specific aims. Although approximations, mathematical models of within-subject HIV dynamics can yield insights into mechanisms underlying HIV pathogenesis. A model developed in the last project period yields accurate long- term predictions of individual subject longitudinal immunologic and virologic profiles. The first aim involves extending the model to incorporate more realistic representation of body's immune response to the virus, enhancing its predictive ability. Applying the models to data in this way requires an appropriate statistical framework and mastery of the accompanying computational challenges. The second aim is to develop and implement practical statistical methods that can address these challenges and be used to gain information on dynamics in the population, so that the models can be used as the basis for the next aim. The predictive capability of these models when applied to data suggests that they can be a powerful tool in the design of clinical trials. The third aim involves development of a systematic strategy for using model-based simulation to inform the design and conduct of clinical trials, which has the potential to lead to more time- and cost- efficient HIV clinical research. Both to prove this principle and to address a key, outstanding clinical question, the fourth aim is to use this approach to design and conduct a clinical trial to determine whether treatment initiated during acute infection followed by terminal interruption at time(s) determined by the models, results in a lower viral load set point and higher CD4 cell count than no treatment. Finally, the fifth aim is to develop and use optimal control theory, mathematical theory for modifying the behavior of nonlinear dynamical systems through control of system inputs, to suggest new, practical adaptive HIV treatment strategies that may lead to improved long-term outcomes. The rich longitudinal data collected during the trial will be used to facilitate development of these strategies.

描述（由申请人提供）：尽管出现了有效的抗逆转录病毒疗法（ARV）和广泛的努力，艾滋病毒疾病的机制，在艾滋病毒研究中尚未解决的复杂挑战仍然需要一个多学科的方法整合基础和临床科学。本着这种精神，本申请的前提是，宿主内HIV动力学的数学非线性动力系统模型与统计群体模型相结合，结合临床和生物学专业知识和信息数据，可以加速HIV研究的突破。一个独特的多学科团队将免疫学和临床研究的专业知识与数学和统计建模的专业知识相结合，其富有成效的合作记录已经建立，将通过五个相互交织的具体目标，对数学，统计，免疫学和临床发展进行联合研究。虽然近似，数学模型内的主题艾滋病毒的动态可以产生深入了解艾滋病毒发病机制的基础。在上一个项目期间开发的模型产生了对个体受试者纵向免疫学和病毒学特征的准确长期预测。第一个目标是扩展模型，以更真实地表示人体对病毒的免疫反应，增强其预测能力。以这种方式将模型应用于数据需要适当的统计框架和掌握伴随的计算挑战。第二个目标是制定和实施实用的统计方法，以应对这些挑战，并用于获取关于人口动态的信息，以便将模型用作下一个目标的基础。这些模型应用于数据时的预测能力表明，它们可以成为临床试验设计中的强大工具。第三个目标是制定一项系统性战略，利用基于模型的模拟为临床试验的设计和实施提供信息，这有可能导致更具时间和成本效益的艾滋病毒临床研究。为了证明这一原则并解决一个关键的、突出的临床问题，第四个目标是使用这种方法设计和进行临床试验，以确定在急性感染期间开始治疗，然后在模型确定的时间终止治疗，是否会导致较低的病毒载量设定点和较高的CD4细胞计数。最后，第五个目标是开发和使用最优控制理论，通过控制系统输入来修改非线性动力系统行为的数学理论，提出新的，实用的自适应艾滋病毒治疗策略，可能会改善长期结果。试验期间收集的丰富纵向数据将用于促进这些策略的制定。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Information content in data sets for a nucleated-polymerization model.

成核聚合模型数据集中的信息内容。

DOI：
10.1080/17513758.2015.1050465
发表时间：
2015
期刊：
Journal of biological dynamics
影响因子：
2.8
作者：
Banks,HT;Doumic,Marie;Kruse,Carola;Prigent,Stephanie;Rezaei,Human
通讯作者：
Rezaei,Human

A new model for the estimation of cell proliferation dynamics using CFSE data.

DOI：
10.1016/j.jim.2011.08.014
发表时间：
2011-10-28
期刊：
JOURNAL OF IMMUNOLOGICAL METHODS
影响因子：
2.2
作者：
Banks, H. T.;Sutton, Karyn L.;Thompson, W. Clayton;Bocharov, Gennady;Doumic, Marie;Schenkel, Tim;Argilaguet, Jordi;Giest, Sandra;Peligero, Cristina;Meyerhans, Andreas
通讯作者：
Meyerhans, Andreas

Acute HIV-1 infection: a call to action.

急性 HIV-1 感染：行动呼吁。