117,609 research outputs found
Towards modular verification of pathways: fairness and assumptions
Modular verification is a technique used to face the state explosion problem
often encountered in the verification of properties of complex systems such as
concurrent interactive systems. The modular approach is based on the
observation that properties of interest often concern a rather small portion of
the system. As a consequence, reduced models can be constructed which
approximate the overall system behaviour thus allowing more efficient
verification.
Biochemical pathways can be seen as complex concurrent interactive systems.
Consequently, verification of their properties is often computationally very
expensive and could take advantage of the modular approach.
In this paper we report preliminary results on the development of a modular
verification framework for biochemical pathways. We view biochemical pathways
as concurrent systems of reactions competing for molecular resources. A modular
verification technique could be based on reduced models containing only
reactions involving molecular resources of interest.
For a proper description of the system behaviour we argue that it is
essential to consider a suitable notion of fairness, which is a
well-established notion in concurrency theory but novel in the field of pathway
modelling. We propose a modelling approach that includes fairness and we
identify the assumptions under which verification of properties can be done in
a modular way.
We prove the correctness of the approach and demonstrate it on the model of
the EGF receptor-induced MAP kinase cascade by Schoeberl et al.Comment: In Proceedings MeCBIC 2012, arXiv:1211.347
A safety analysis approach to clinical workflows : application and evaluation
Clinical workflows are safety critical workflows as they have the potential to cause harm or death to patients. Their safety needs to be considered as early as possible in the development process. Effective safety analysis methods are required to ensure the safety of these high-risk workflows, because errors that may happen through routine workflow could propagate within the workflow to result in harmful failures of the system’s output. This paper shows how to apply an approach for safety analysis of clinic al workflows to analyse the safety of the workflow within a radiology department and evaluates the approach in terms of usability and benefits. The outcomes of using this approach include identification of the root causes of hazardous workflow failures that may put patients’ lives at risk. We show that the approach is applicable to this area of healthcare and is able to present added value through the detailed information on possible failures, of both their causes and effects; therefore, it has the potential to improve the safety of radiology and other clinical workflows
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A Monte Carlo model checker for probabilistic LTL with numerical constraints
We define the syntax and semantics of a new temporal logic called probabilistic LTL with numerical constraints (PLTLc).
We introduce an efficient model checker for PLTLc properties. The efficiency of the model checker is through approximation
using Monte Carlo sampling of finite paths through the model’s state space (simulation outputs) and parallel model checking
of the paths. Our model checking method can be applied to any model producing quantitative output – continuous or
stochastic, including those with complex dynamics and those with an infinite state space. Furthermore, our offline approach
allows the analysis of observed (real-life) behaviour traces. We find in this paper that PLTLc properties with constraints
over free variables can replace full model checking experiments, resulting in a significant gain in efficiency. This overcomes
one disadvantage of model checking experiments which is that the complexity depends on system granularity and number of
variables, and quickly becomes infeasible. We focus on models of biochemical networks, and specifically in this paper on
intracellular signalling pathways; however our method can be applied to a wide range of biological as well as technical
systems and their models. Our work contributes to the emerging field of synthetic biology by proposing a rigourous approach
for the structured formal engineering of biological systems
Multiple verification in computational modeling of bone pathologies
We introduce a model checking approach to diagnose the emerging of bone
pathologies. The implementation of a new model of bone remodeling in PRISM has
led to an interesting characterization of osteoporosis as a defective bone
remodeling dynamics with respect to other bone pathologies. Our approach allows
to derive three types of model checking-based diagnostic estimators. The first
diagnostic measure focuses on the level of bone mineral density, which is
currently used in medical practice. In addition, we have introduced a novel
diagnostic estimator which uses the full patient clinical record, here
simulated using the modeling framework. This estimator detects rapid (months)
negative changes in bone mineral density. Independently of the actual bone
mineral density, when the decrease occurs rapidly it is important to alarm the
patient and monitor him/her more closely to detect insurgence of other bone
co-morbidities. A third estimator takes into account the variance of the bone
density, which could address the investigation of metabolic syndromes, diabetes
and cancer. Our implementation could make use of different logical combinations
of these statistical estimators and could incorporate other biomarkers for
other systemic co-morbidities (for example diabetes and thalassemia). We are
delighted to report that the combination of stochastic modeling with formal
methods motivate new diagnostic framework for complex pathologies. In
particular our approach takes into consideration important properties of
biosystems such as multiscale and self-adaptiveness. The multi-diagnosis could
be further expanded, inching towards the complexity of human diseases. Finally,
we briefly introduce self-adaptiveness in formal methods which is a key
property in the regulative mechanisms of biological systems and well known in
other mathematical and engineering areas.Comment: In Proceedings CompMod 2011, arXiv:1109.104
Model-based dependability analysis : state-of-the-art, challenges and future outlook
Abstract: Over the past two decades, the study of model-based dependability analysis has gathered significant research interest. Different approaches have been developed to automate and address various limitations of classical dependability techniques to contend with the increasing complexity and challenges of modern safety-critical system. Two leading paradigms have emerged, one which constructs predictive system failure models from component failure models compositionally using the topology of the system. The other utilizes design models - typically state automata - to explore system behaviour through fault injection. This paper reviews a number of prominent techniques under these two paradigms, and provides an insight into their working mechanism, applicability, strengths and challenges, as well as recent developments within these fields. We also discuss the emerging trends on integrated approaches and advanced analysis capabilities. Lastly, we outline the future outlook for model-based dependability analysis
Petri nets for systems and synthetic biology
We give a description of a Petri net-based framework for
modelling and analysing biochemical pathways, which uni¯es the qualita-
tive, stochastic and continuous paradigms. Each perspective adds its con-
tribution to the understanding of the system, thus the three approaches
do not compete, but complement each other. We illustrate our approach
by applying it to an extended model of the three stage cascade, which
forms the core of the ERK signal transduction pathway. Consequently
our focus is on transient behaviour analysis. We demonstrate how quali-
tative descriptions are abstractions over stochastic or continuous descrip-
tions, and show that the stochastic and continuous models approximate
each other. Although our framework is based on Petri nets, it can be
applied more widely to other formalisms which are used to model and
analyse biochemical networks
BigraphER: rewriting and analysis engine for bigraphs
BigraphER is a suite of open-source tools providing an effi-
cient implementation of rewriting, simulation, and visualisation for bigraphs,
a universal formalism for modelling interacting systems that
evolve in time and space and first introduced by Milner. BigraphER consists
of an OCaml library that provides programming interfaces for the
manipulation of bigraphs, their constituents and reaction rules, and a
command-line tool capable of simulating Bigraphical Reactive Systems
(BRSs) and computing their transition systems. Other features are native
support for both bigraphs and bigraphs with sharing, stochastic reaction
rules, rule priorities, instantiation maps, parameterised controls, predicate
checking, graphical output and integration with the probabilistic
model checker PRISM
Complementary approaches to understanding the plant circadian clock
Circadian clocks are oscillatory genetic networks that help organisms adapt
to the 24-hour day/night cycle. The clock of the green alga Ostreococcus tauri
is the simplest plant clock discovered so far. Its many advantages as an
experimental system facilitate the testing of computational predictions.
We present a model of the Ostreococcus clock in the stochastic process
algebra Bio-PEPA and exploit its mapping to different analysis techniques, such
as ordinary differential equations, stochastic simulation algorithms and
model-checking. The small number of molecules reported for this system tests
the limits of the continuous approximation underlying differential equations.
We investigate the difference between continuous-deterministic and
discrete-stochastic approaches. Stochastic simulation and model-checking allow
us to formulate new hypotheses on the system behaviour, such as the presence of
self-sustained oscillations in single cells under constant light conditions.
We investigate how to model the timing of dawn and dusk in the context of
model-checking, which we use to compute how the probability distributions of
key biochemical species change over time. These show that the relative
variation in expression level is smallest at the time of peak expression,
making peak time an optimal experimental phase marker. Building on these
analyses, we use approaches from evolutionary systems biology to investigate
how changes in the rate of mRNA degradation impacts the phase of a key protein
likely to affect fitness. We explore how robust this circadian clock is towards
such potential mutational changes in its underlying biochemistry. Our work
shows that multiple approaches lead to a more complete understanding of the
clock
Experimental Biological Protocols with Formal Semantics
Both experimental and computational biology is becoming increasingly
automated. Laboratory experiments are now performed automatically on
high-throughput machinery, while computational models are synthesized or
inferred automatically from data. However, integration between automated tasks
in the process of biological discovery is still lacking, largely due to
incompatible or missing formal representations. While theories are expressed
formally as computational models, existing languages for encoding and
automating experimental protocols often lack formal semantics. This makes it
challenging to extract novel understanding by identifying when theory and
experimental evidence disagree due to errors in the models or the protocols
used to validate them. To address this, we formalize the syntax of a core
protocol language, which provides a unified description for the models of
biochemical systems being experimented on, together with the discrete events
representing the liquid-handling steps of biological protocols. We present both
a deterministic and a stochastic semantics to this language, both defined in
terms of hybrid processes. In particular, the stochastic semantics captures
uncertainties in equipment tolerances, making it a suitable tool for both
experimental and computational biologists. We illustrate how the proposed
protocol language can be used for automated verification and synthesis of
laboratory experiments on case studies from the fields of chemistry and
molecular programming
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