Ceccarelli Michele, Cerulo Luigi, Santone Antonella
Dept. of Science and Technology, University of Sannio, Benevento, Italy; BioGeM, Institute of Genetic Research "Gaetano Salvatore", Ariano Irpino, AV, Italy.
Dept. of Science and Technology, University of Sannio, Benevento, Italy; BioGeM, Institute of Genetic Research "Gaetano Salvatore", Ariano Irpino, AV, Italy.
Methods. 2014 Oct 1;69(3):298-305. doi: 10.1016/j.ymeth.2014.06.005. Epub 2014 Jun 21.
Reverse engineering of gene regulatory relationships from genomics data is a crucial task to dissect the complex underlying regulatory mechanism occurring in a cell. From a computational point of view the reconstruction of gene regulatory networks is an undetermined problem as the large number of possible solutions is typically high in contrast to the number of available independent data points. Many possible solutions can fit the available data, explaining the data equally well, but only one of them can be the biologically true solution. Several strategies have been proposed in literature to reduce the search space and/or extend the amount of independent information. In this paper we propose a novel algorithm based on formal methods, mathematically rigorous techniques widely adopted in engineering to specify and verify complex software and hardware systems. Starting with a formal specification of gene regulatory hypotheses we are able to mathematically prove whether a time course experiment belongs or not to the formal specification, determining in fact whether a gene regulation exists or not. The method is able to detect both direction and sign (inhibition/activation) of regulations whereas most of literature methods are limited to undirected and/or unsigned relationships. We empirically evaluated the approach on experimental and synthetic datasets in terms of precision and recall. In most cases we observed high levels of accuracy outperforming the current state of art, despite the computational cost increases exponentially with the size of the network. We made available the tool implementing the algorithm at the following url: http://www.bioinformatics.unisannio.it.
从基因组学数据逆向工程基因调控关系是剖析细胞中复杂潜在调控机制的一项关键任务。从计算角度来看，基因调控网络的重建是一个不确定问题，因为与可用的独立数据点数量相比，可能的解决方案数量通常很多。许多可能的解决方案都能拟合可用数据，对数据的解释同样良好，但其中只有一个可能是生物学上真正的解决方案。文献中已经提出了几种策略来减少搜索空间和/或扩展独立信息的数量。在本文中，我们提出了一种基于形式化方法的新颖算法，形式化方法是工程中广泛采用的数学上严格的技术，用于指定和验证复杂的软件和硬件系统。从基因调控假设的形式化规范开始，我们能够从数学上证明一个时间进程实验是否属于该形式化规范，从而实际上确定基因调控是否存在。该方法能够检测调控的方向和符号（抑制/激活），而大多数文献方法仅限于无向和/或无符号关系。我们根据精度和召回率对实验数据集和合成数据集进行了实证评估。在大多数情况下，我们观察到高精度，优于当前的技术水平，尽管计算成本随着网络规模呈指数增长。我们在以下网址提供了实现该算法的工具：http://www.bioinformatics.unisannio.it。
