pathPSA: A Dynamical Pathway-Based Parametric Sensitivity

in Industrial and Engineering Chemistry (2014)

Normal functioning of biological systems relies on coordinated activities of biomolecules participating in a complex network of biological interactions. As human intuition is often incapable in analyzing ... [more ▼]

Normal functioning of biological systems relies on coordinated activities of biomolecules participating in a complex network of biological interactions. As human intuition is often incapable in analyzing how biological functions emerge from such complex interactions, the use of mathematical models and systems analysis tools has become critical in understanding biological system behavior. While biological functions have been associated with the connectivity (structure) and pathways of the network and the kinetics of the processes involved, most model analyses address each of these aspects separately. In contrast, we present a novel sensitivity analysis, called pathway-based parametric sensitivity analysis (pathPSA), which combines the analysis of both network structure and kinetics. Unlike existing sensitivity analyses, pathPSA relies on perturbing the kinetics of pathways in the network, using persistent perturbations or impulse perturbations at varying time. Consequently, the sensitivity coefficients can give insights on the dominant pathways in a network and any transient shift in the rate controlling mechanism. The efficacy of pathPSA is demonstrated through an application to understand competing signaling pathways in programmed cell death network. [less ▲]

The Parkinson's Disease Map: A Framework for Integration, Curation and Exploration of Disease-related Pathways

Poster (2013, March 09)

Objectives: The pathogenesis of Parkinson's Disease (PD) is multi-factorial and age-related, implicating various genetic and environmental factors. It becomes increasingly important to develop new ... [more ▼]

Objectives: The pathogenesis of Parkinson's Disease (PD) is multi-factorial and age-related, implicating various genetic and environmental factors. It becomes increasingly important to develop new approaches to organize and explore the exploding knowledge of this field. Methods: The published knowledge on pathways implicated in PD, such as synaptic and mitochondrial dysfunction, alpha-synuclein pathobiology, failure of protein degradation systems and neuroinflammation has been organized and represented using CellDesigner. This repository has been linked to a framework of bioinformatics tools including text mining, database annotation, large-scale data integration and network analysis. The interface for online curation of the repository has been established using Payao tool. Results: We present the PD map, a computer-based knowledge repository, which includes molecular mechanisms of PD in a visually structured and standardized way. A bioinformatics framework that facilitates in-depth knowledge exploration, extraction and curation supports the map. We discuss the insights gained from PD map-driven text mining of a corpus of over 50 thousands full text PD-related papers, integration and visualization of gene expression in post mortem brain tissue of PD patients with the map, as well as results of network analysis. Conclusions: The knowledge repository of disease-related mechanisms provides a global insight into relationships between different pathways and allows considering a given pathology in a broad context. Enrichment with available text and bioinformatics databases as well as integration of experimental data supports better understanding of complex mechanisms of PD and formulation of novel research hypotheses. [less ▲]

Understanding dynamics using sensitivity analysis: caveat and solution

in BMC Systems Biology (2011), 5

BACKGROUND: Parametric sensitivity analysis (PSA) has become one of the most commonly used tools in computational systems biology, in which the sensitivity coefficients are used to study the parametric ... [more ▼]

BACKGROUND: Parametric sensitivity analysis (PSA) has become one of the most commonly used tools in computational systems biology, in which the sensitivity coefficients are used to study the parametric dependence of biological models. As many of these models describe dynamical behaviour of biological systems, the PSA has subsequently been used to elucidate important cellular processes that regulate this dynamics. However, in this paper, we show that the PSA coefficients are not suitable in inferring the mechanisms by which dynamical behaviour arises and in fact it can even lead to incorrect conclusions. RESULTS: A careful interpretation of parametric perturbations used in the PSA is presented here to explain the issue of using this analysis in inferring dynamics. In short, the PSA coefficients quantify the integrated change in the system behaviour due to persistent parametric perturbations, and thus the dynamical information of when a parameter perturbation matters is lost. To get around this issue, we present a new sensitivity analysis based on impulse perturbations on system parameters, which is named impulse parametric sensitivity analysis (iPSA). The inability of PSA and the efficacy of iPSA in revealing mechanistic information of a dynamical system are illustrated using two examples involving switch activation. CONCLUSIONS: The interpretation of the PSA coefficients of dynamical systems should take into account the persistent nature of parametric perturbations involved in the derivation of this analysis. The application of PSA to identify the controlling mechanism of dynamical behaviour can be misleading. By using impulse perturbations, introduced at different times, the iPSA provides the necessary information to understand how dynamics is achieved, i.e. which parameters are essential and when they become important. [less ▲]

Robustness analysis of cellular systems for in silico drug discovery

Scientific Conference (2008)