Cannon LaMont, Jagarapu Aditya, Vargas-Garcia Cesar A, Piovoso Michael J, Zurakowski Ryan
University of Delaware Biomedical Engineering Department, Newark, DE 19716, USA.
University of Delaware Electrical and Computer Engineering Department Newark, DE 19716, USA.
Proc IEEE Conf Decis Control. 2017 Dec;2017:4106-4111. doi: 10.1109/CDC.2017.8264262. Epub 2018 Jan 23.
Time series measurements of circular viral episome (2-LTR) concentrations enable indirect quantification of persistent low-level Human Immunodeficiency Virus (HIV) replication in patients on Integrase-Inhibitor intensified Combined Antiretroviral Therapy (cART). In order to determine the magnitude of these low level infection events, blood has to be drawn from a patients at a frequency and volume that is strictly regulated by the Institutional Review Board (IRB). Once the blood is drawn, the 2-LTR concentration is determined by quantifying the amount of HIV DNA present in the sample via a PCR (Polymerase Chain Reaction) assay. Real time quantitative Polymerase Chain Reaction (qPCR) is a widely used method of performing PCR; however, a newer droplet digital Polymerase Chain Reaction (ddPCR) method has been shown to provide more accurate quantification of DNA. Using a validated model of HIV viral replication, this paper demonstrates the importance of considering DNA quantification assay type when optimizing experiment design conditions. Experiments are optimized using a Genetic Algorithm (GA) to locate a family of suboptimal sample schedules which yield the highest fitness. Fitness is defined as the expected information gained in the experiment, measured by the Kullback-Leibler Divergence (KLD) between the prior and posterior distributions of the model parameters. We compare the information content of the optimized schedules to uniform schedules as well as two clinical schedules implemented by researchers at UCSF and the University of Melbourne. This work shows that there is a significantly greater gain information in experiments using a ddPCR assay vs. a qPCR assay and that certain experiment design considerations should be taken when using either assay.
对环状病毒附加体（2 - LTR）浓度进行时间序列测量，能够间接定量接受整合酶抑制剂强化联合抗逆转录病毒疗法（cART）的患者体内持续性低水平人类免疫缺陷病毒（HIV）复制情况。为了确定这些低水平感染事件的规模，必须按照机构审查委员会（IRB）严格规定的频率和血量从患者身上采集血液。采集血液后，通过聚合酶链反应（PCR）测定法对样本中存在的HIV DNA量进行定量，从而确定2 - LTR浓度。实时定量聚合酶链反应（qPCR）是一种广泛使用的PCR方法；然而，一种更新的数字液滴聚合酶链反应（ddPCR）方法已被证明能提供更准确的DNA定量。本文使用经过验证的HIV病毒复制模型，证明了在优化实验设计条件时考虑DNA定量测定类型的重要性。使用遗传算法（GA）对实验进行优化，以找到一系列次优样本采集计划，这些计划具有最高的适应性。适应性定义为实验中预期获得的信息，通过模型参数的先验分布和后验分布之间的库尔贝克 - 莱布勒散度（KLD）来衡量。我们将优化后的计划的信息含量与均匀计划以及加州大学旧金山分校和墨尔本大学的研究人员实施的两个临床计划进行比较。这项工作表明，与qPCR测定法相比，使用ddPCR测定法的实验能显著获得更多信息，并且在使用任何一种测定法时都应考虑某些实验设计因素。
