96 research outputs found
ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra
Background: Many biological systems are modeled qualitatively with discrete
models, such as probabilistic Boolean networks, logical models, Petri nets, and
agent-based models, with the goal to gain a better understanding of the system.
The computational complexity to analyze the complete dynamics of these models
grows exponentially in the number of variables, which impedes working with
complex models. Although there exist sophisticated algorithms to determine the
dynamics of discrete models, their implementations usually require
labor-intensive formatting of the model formulation, and they are oftentimes
not accessible to users without programming skills. Efficient analysis methods
are needed that are accessible to modelers and easy to use. Method: By
converting discrete models into algebraic models, tools from computational
algebra can be used to analyze their dynamics. Specifically, we propose a
method to identify attractors of a discrete model that is equivalent to solving
a system of polynomial equations, a long-studied problem in computer algebra.
Results: A method for efficiently identifying attractors, and the web-based
tool Analysis of Dynamic Algebraic Models (ADAM), which provides this and other
analysis methods for discrete models. ADAM converts several discrete model
types automatically into polynomial dynamical systems and analyzes their
dynamics using tools from computer algebra. Based on extensive experimentation
with both discrete models arising in systems biology and randomly generated
networks, we found that the algebraic algorithms presented in this manuscript
are fast for systems with the structure maintained by most biological systems,
namely sparseness, i.e., while the number of nodes in a biological network may
be quite large, each node is affected only by a small number of other nodes,
and robustness, i.e., small number of attractors
Model Checking to Assess T-Helper Cell Plasticity
Computational modeling constitutes a crucial step toward the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g., stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity. In this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions. As a case study, we consider the cellular network regulating the differentiation of T-helper (Th) cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of Th cell differentiation. We then use symbolic model checking to analyze reachability properties between Th subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of Th cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific Th cell polarizing or reprograming events.LabEx MemoLife, Ecole Normale Supérieure, FCT grants: (PEst-OE/EEI/LA0021/2013, IF/01333/2013), Ph.D.program of the Agence National de Recherche sur Le Sida (ANRS), European Research Council consolidator grant
Logical modelling of cellular decision processes with GINsim
International audienc
SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools
Background:
Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing.
Results:
We present the Systems Biology Markup Language (SBML) Qualitative Models Package (“qual”), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models.
Conclusions:
SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks
Quantification of reachable attractors in asynchronous discrete dynamics
Motivation: Models of discrete concurrent systems often lead to huge and
complex state transition graphs that represent their dynamics. This makes
difficult to analyse dynamical properties. In particular, for logical models of
biological regulatory networks, it is of real interest to study attractors and
their reachability from specific initial conditions, i.e. to assess the
potential asymptotical behaviours of the system. Beyond the identification of
the reachable attractors, we propose to quantify this reachability.
Results: Relying on the structure of the state transition graph, we estimate
the probability of each attractor reachable from a given initial condition or
from a portion of the state space. First, we present a quasi-exact solution
with an original algorithm called Firefront, based on the exhaustive
exploration of the reachable state space. Then, we introduce an adapted version
of Monte Carlo simulation algorithm, termed Avatar, better suited to larger
models. Firefront and Avatar methods are validated and compared to other
related approaches, using as test cases logical models of synthetic and
biological networks.
Availability: Both algorithms are implemented as Perl scripts that can be
freely downloaded from http://compbio.igc.gulbenkian.pt/nmd/node/59 along with
Supplementary Material.Comment: 19 pages, 2 figures, 2 algorithms and 2 table
SyQUAL: a Platform for Qualitative Modelling and Simulation of Biological Systems
Qualitative modelling in systems biology is increasingly adopted as it allows predicting important properties of biological systems even when quantitative information of such systems are unknown. Even though different tools for qualitative modelling have been recently proposed, their lack of automatism and their unstructured simulation core limit their applicability to non-complex biological networks. This paper presents SyQUAL, a platform for qualitative modelling and simulation of biological systems. It consists of two main layers: a Web-based framework that allows users to (i) import models described in the standard Systems Biology Markup Language (SBML), (ii) easily define properties to observe, and (iii) run simulations by hiding the underlying layer, that is, a SystemC-based core simulator that allows simulating the systems through a discrete event-based model of computation at different levels of details. The paper shows how SyQUAL has been applied to identify the attractors and to analyse the system robustness/sensitivity under perturbations of the Colitis-associated Colon Cancer (CAC) network
A modular, qualitative modelling of regulatory networks using Petri nets
International audienceAdvances in high-throughput technologies have enabled the de-lineation of large networks of interactions that control cellular processes. To understand behavioural properties of these complex networks, mathematical and computational tools are required. The multi-valued logical formalism, initially defined by R. Thomas and co-workers, proved well adapted to account for the qualitative knowledge available on regulatory interactions, and also to perform analyses of their dynamical properties. In this context, we present two representations of logical models in terms of Petri nets. In a first step, we briefly show how logical models of regulatory networks can be transposed into standard (place/transition) Petri nets, and discuss the capabilities of such representation. In the second part, we focus on logical regulatory modules and their composition, demonstrating that a high-level Petri net representation greatly facilitates the modelling of interconnected modules. Doing so, we introduce an explicit means to integrate signals from various interconnected modules, taking into account their spatial distribution. This provides a flexible modelling framework to handle regulatory networks that operate at both intra-and intercellular levels. As an illustration, we describe a simplified model of the segment-polarity module involved in the segmentation of the Drosophila embryo
Basins of Attraction, Commitment Sets and Phenotypes of Boolean Networks
The attractors of Boolean networks and their basins have been shown to be
highly relevant for model validation and predictive modelling, e.g., in systems
biology. Yet there are currently very few tools available that are able to
compute and visualise not only attractors but also their basins. In the realm
of asynchronous, non-deterministic modeling not only is the repertoire of
software even more limited, but also the formal notions for basins of
attraction are often lacking. In this setting, the difficulty both for theory
and computation arises from the fact that states may be ele- ments of several
distinct basins. In this paper we address this topic by partitioning the state
space into sets that are committed to the same attractors. These commitment
sets can easily be generalised to sets that are equivalent w.r.t. the long-term
behaviours of pre-selected nodes which leads us to the notions of markers and
phenotypes which we illustrate in a case study on bladder tumorigenesis. For
every concept we propose equivalent CTL model checking queries and an extension
of the state of the art model checking software NuSMV is made available that is
capa- ble of computing the respective sets. All notions are fully integrated as
three new modules in our Python package PyBoolNet, including functions for
visualising the basins, commitment sets and phenotypes as quotient graphs and
pie charts
Reducing Boolean Networks with Backward Boolean Equivalence
Boolean Networks (BNs) are established models to qualitatively describe
biological systems. The analysis of BNs might be infeasible for medium to large
BNs due to the state-space explosion problem. We propose a novel reduction
technique called \emph{Backward Boolean Equivalence} (BBE), which preserves
some properties of interest of BNs. In particular, reduced BNs provide a
compact representation by grouping variables that, if initialized equally, are
always updated equally. The resulting reduced state space is a subset of the
original one, restricted to identical initialization of grouped variables. The
corresponding trajectories of the original BN can be exactly restored. We show
the effectiveness of BBE by performing a large-scale validation on the whole
GINsim BN repository. In selected cases, we show how our method enables
analyses that would be otherwise intractable. Our method complements, and can
be combined with, other reduction methods found in the literature
- …