论文标题

系统生物学动力学模型的贝叶斯参数估计

Bayesian Parameter Estimation for Dynamical Models in Systems Biology

论文作者

Linden, Nathaniel J., Kramer, Boris, Rangamani, Padmini

论文摘要

动态系统建模,特别是通过普通微分方程的系统,已被用来有效捕获信号转导网络中不同生化成分的时间行为。尽管实验测量最近取得了进步,包括传感器开发和“ - 组学”研究,这些研究有助于详细填充蛋白质 - 蛋白质相互作用网络,但系统生物学的建模缺乏系统的方法来估计动力学参数并量化相关的不确定性。这是由于多种原因,包括稀疏和嘈杂的实验测量,缺乏反应背后的详细分子机制以及缺失的生化相互作用。此外,与与微分方程系统相关的状态和参数相关的固有非线性进一步加剧了参数估计的挑战。在这项研究中,我们为贝叶斯参数估计的综合框架提出了一个综合框架,并完整量化了数据和模型中不确定性的影响。我们将这些方法应用于增加数学复杂性的一系列信号传导模型。对这些动力学系统的系统分析表明,参数估计取决于数据稀疏性,噪声水平和模型结构,包括存在多个稳态。这些结果强调了焦点不确定性定量如何富集系统生物学建模,并启用了参数估计的其他定量分析。

Dynamical systems modeling, particularly via systems of ordinary differential equations, has been used to effectively capture the temporal behavior of different biochemical components in signal transduction networks. Despite the recent advances in experimental measurements, including sensor development and '-omics' studies that have helped populate protein-protein interaction networks in great detail, modeling in systems biology lacks systematic methods to estimate kinetic parameters and quantify associated uncertainties. This is because of multiple reasons, including sparse and noisy experimental measurements, lack of detailed molecular mechanisms underlying the reactions, and missing biochemical interactions. Additionally, the inherent nonlinearities with respect to the states and parameters associated with the system of differential equations further compound the challenges of parameter estimation. In this study, we propose a comprehensive framework for Bayesian parameter estimation and complete quantification of the effects of uncertainties in the data and models. We apply these methods to a series of signaling models of increasing mathematical complexity. Systematic analysis of these dynamical systems showed that parameter estimation depends on data sparsity, noise level, and model structure, including the existence of multiple steady states. These results highlight how focused uncertainty quantification can enrich systems biology modeling and enable additional quantitative analyses for parameter estimation.

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