论文标题

对部分指定的布尔网络的强大控制

Robust Control of Partially Specified Boolean Networks

论文作者

Brim, Luboš, Pastva, Samuel, Šafránek, David, Šmijáková, Eva

论文摘要

监管网络(RNS)是计算系统生物学中受过良好接受的建模形式主义。 RN的控制目前正在引起广泛关注,因为它为细胞重编程提供了计算基础,这是一种在再生医学中开发的有吸引力的技术。通过解决控制问题,我们了解了应扰动生物系统的哪些部分以稳定所需表型中的系统。 我们允许代表给定RN的布尔模型的规范是不完整的。为此,我们利用了部分指定的布尔网络的形式主义,该网络涵盖了系统未指定部分的所有可能行为。这种方法会导致严重的状态爆炸。通过使用符号方法来解决该问题,以表示未指定的模型零件和系统的所有可能扰动。 此外,为了使控制设计有效且实际上适用,最佳控制应在大小方面最小。此外,在部分指定的模型中,控制只能仅对可能完全指定的模型实例的子集实现所需的稳定。为了解决这些方面,我们采用了几种定量措施。除了扰动的大小外,我们还检查了它的鲁棒性 - 适用该控制的一部分实例化。 我们表明,解决部分指定BN的控制控制问题的拟议符号方法有效且尺寸很好。在所有三种研究类型的情况下,我们还评估了鲁棒性指标。稳健性指标告诉我们给定的扰动起作用的完全定义的系统有多大。我们的实验支持以下假设:一步扰动可能不如临时或永久扰动稳健。 这是提交给日记的纸张的完整版本。

Regulatory networks (RNs) are a well-accepted modelling formalism in computational systems biology. The control of RNs is currently receiving a lot of attention because it provides a computational basis for cell reprogramming -- an attractive technology developed in regenerative medicine. By solving the control problem, we learn which parts of a biological system should be perturbed to stabilise the system in the desired phenotype. We allow the specification of the Boolean model representing a given RN to be incomplete. To that end, we utilise the formalism of partially specified Boolean networks which covers every possible behaviour of unspecified parts of the system. Such an approach causes a significant state explosion. This problem is addressed by using symbolic methods to represent both the unspecified model parts and all possible perturbations of the system. Additionally, to make the control design efficient and practically applicable, the optimal control should be minimal in terms of size. Moreover, in a partially specified model, a control may achieve the desired stabilisation only for a subset of the possible fully specified model instantiations. To address these aspects, we utilise several quantitative measures. Apart from the size of perturbation, we also examine its robustness -- a portion of instantiations for which the control is applicable. We show that proposed symbolic methods solving the control problem for partially specified BNs are efficient and scale well. We also evaluate the robustness metrics in cases of all three studied control types. The robustness metric tells us how big a proportion of fully defined systems the given perturbation works. Our experiments support the hypothesis that one-step perturbations may be less robust than temporary or permanent perturbations. This is a full version of a paper that is submitted to a journal.

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