Analysis of parametric biological models with non-linear dynamics

In this paper we present recent results on parametric analysis of biological models. The underlying method is based on the algorithms for computing trajectory sets of hybrid systems with polynomial dynamics. The method is then applied to two case studies of biological systems: one is a cardiac cell model for studying the conditions for cardiac abnormalities, and the second is a model of insect nest-site choice.Comment: In Proceedings HSB 2012, arXiv:1208.315

Reachability in Biochemical Dynamical Systems by Quantitative Discrete Approximation (extended abstract)

In this paper, a novel computational technique for finite discrete approximation of continuous dynamical systems suitable for a significant class of biochemical dynamical systems is introduced. The method is parameterized in order to affect the imposed level of approximation provided that with increasing parameter value the approximation converges to the original continuous system. By employing this approximation technique, we present algorithms solving the reachability problem for biochemical dynamical systems. The presented method and algorithms are evaluated on several exemplary biological models and on a real case study.Comment: In Proceedings CompMod 2011, arXiv:1109.104

Algorithmic Verification of Continuous and Hybrid Systems

We provide a tutorial introduction to reachability computation, a class of computational techniques that exports verification technology toward continuous and hybrid systems. For open under-determined systems, this technique can sometimes replace an infinite number of simulations.Comment: In Proceedings INFINITY 2013, arXiv:1402.661

Efficient Syntax-Driven Lumping of Differential Equations

We present an algorithm to compute exact aggregations of a class of systems of ordinary differential equations (ODEs). Our approach consists in an extension of Paige and Tarjan’s seminal solution to the coarsest refinement problem by encoding an ODE system into a suitable discrete-state representation. In particular, we consider a simple extension of the syntax of elementary chemical reaction networks because (i) it can express ODEs with derivatives given by polynomials of degree at most two, which are relevant in many applications in natural sciences and engineering; and (ii) we can build on two recently introduced bisimulations, which yield two complementary notions of ODE lumping. Our algorithm computes the largest bisimulations in O(r⋅s⋅logs)O(r⋅s⋅log⁡s) time, where r is the number of monomials and s is the number of variables in the ODEs. Numerical experiments on real-world models from biochemistry, electrical engineering, and structural mechanics show that our prototype is able to handle ODEs with millions of variables and monomials, providing significant model reductions

Robustness Analysis and Behavior Discrimination in Enzymatic Reaction Networks

Characterizing the behavior and robustness of enzymatic networks with numerous variables and unknown parameter values is a major challenge in biology, especially when some enzymes have counter-intuitive properties or switch-like behavior between activation and inhibition. In this paper, we propose new methodological and tool-supported contributions, based on the intuitive formalism of temporal logic, to express in a rigorous manner arbitrarily complex dynamical properties. Our multi-step analysis allows efficient sampling of the parameter space in order to define feasible regions in which the model exhibits imposed or experimentally observed behaviors. In a first step, an algorithmic methodology involving sensitivity analysis is conducted to determine bifurcation thresholds for a limited number of model parameters or initial conditions. In a second step, this boundary detection is supplemented by a global robustness analysis, based on quasi-Monte Carlo approach that takes into account all model parameters. We apply this method to a well-documented enzymatic reaction network describing collagen proteolysis by matrix metalloproteinase MMP2 and membrane type 1 metalloproteinase (MT1-MMP) in the presence of tissue inhibitor of metalloproteinase TIMP2. For this model, our method provides an extended analysis and quantification of network robustness toward paradoxical TIMP2 switching activity between activation or inhibition of MMP2 production. Further implication of our approach is illustrated by demonstrating and analyzing the possible existence of oscillatory behaviors when considering an extended open configuration of the enzymatic network. Notably, we construct bifurcation diagrams that specify key parameters values controlling the co-existence of stable steady and non-steady oscillatory proteolytic dynamics

Evidence-based Development of Trustworthy Mobile Medical Apps

abstract: Widespread adoption of smartphone based Mobile Medical Apps (MMAs) is opening new avenues for innovation, bringing MMAs to the forefront of low cost healthcare delivery. These apps often control human physiology and work on sensitive data. Thus it is necessary to have evidences of their trustworthiness i.e. maintaining privacy of health data, long term operation of wearable sensors and ensuring no harm to the user before actual marketing. Traditionally, clinical studies are used to validate the trustworthiness of medical systems. However, they can take long time and could potentially harm the user. Such evidences can be generated using simulations and mathematical analysis. These methods involve estimating the MMA interactions with human physiology. However, the nonlinear nature of human physiology makes the estimation challenging. This research analyzes and develops MMA software while considering its interactions with human physiology to assure trustworthiness. A novel app development methodology is used to objectively evaluate trustworthiness of a MMA by generating evidences using automatic techniques. It involves developing the Health-Dev β tool to generate a) evidences of trustworthiness of MMAs and b) requirements assured code generation for vulnerable components of the MMA without hindering the app development process. In this method, all requests from MMAs pass through a trustworthy entity, Trustworthy Data Manager which checks if the app request satisfies the MMA requirements. This method is intended to expedite the design to marketing process of MMAs. The objectives of this research is to develop models, tools and theory for evidence generation and can be divided into the following themes: • Sustainable design configuration estimation of MMAs: Developing an optimization framework which can generate sustainable and safe sensor configuration while considering interactions of the MMA with the environment. • Evidence generation using simulation and formal methods: Developing models and tools to verify safety properties of the MMA design to ensure no harm to the human physiology. • Automatic code generation for MMAs: Investigating methods for automatically • Performance analysis of trustworthy data manager: Evaluating response time generating trustworthy software for vulnerable components of a MMA and evidences.performance of trustworthy data manager under interactions from non-MMA smartphone apps.Dissertation/ThesisDoctoral Dissertation Computer Science 201

Mass spectral imaging of clinical samples using deep learning

A better interpretation of tumour heterogeneity and variability is vital for the improvement of novel diagnostic techniques and personalized cancer treatments. Tumour tissue heterogeneity is characterized by biochemical heterogeneity, which can be investigated by unsupervised metabolomics. Mass Spectrometry Imaging (MSI) combined with Machine Learning techniques have generated increasing interest as analytical and diagnostic tools for the analysis of spatial molecular patterns in tissue samples. Considering the high complexity of data produced by the application of MSI, which can consist of many thousands of spectral peaks, statistical analysis and in particular machine learning and deep learning have been investigated as novel approaches to deduce the relationships between the measured molecular patterns and the local structural and biological properties of the tissues. Machine learning have historically been divided into two main categories: Supervised and Unsupervised learning. In MSI, supervised learning methods may be used to segment tissues into histologically relevant areas e.g. the classification of tissue regions in H&E (Haemotoxylin and Eosin) stained samples. Initial classification by an expert histopathologist, through visual inspection enables the development of univariate or multivariate models, based on tissue regions that have significantly up/down-regulated ions. However, complex data may result in underdetermined models, and alternative methods that can cope with high dimensionality and noisy data are required. Here, we describe, apply, and test a novel diagnostic procedure built using a combination of MSI and deep learning with the objective of delineating and identifying biochemical differences between cancerous and non-cancerous tissue in metastatic liver cancer and epithelial ovarian cancer. The workflow investigates the robustness of single (1D) to multidimensional (3D) tumour analyses and also highlights possible biomarkers which are not accessible from classical visual analysis of the H&E images. The identification of key molecular markers may provide a deeper understanding of tumour heterogeneity and potential targets for intervention.Open Acces

Méthodes logico-numériques pour la vérification des systèmes discrets et hybrides

Cette thèse étudie la vérification automatique de propriétés de sûreté de systèmes logico-numériques discrets ou hybrides. Ce sont des systèmes ayant des variables booléennes et numériques et des comportements discrets et continus. Notre approche est fondée sur l'analyse statique par interprétation abstraite. Nous adressons les problèmes suivants : les méthodes d'interprétation abstraite numériques exigent l'énumération des états booléens, et par conséquent, ils souffrent du probléme d'explosion d'espace d'états. En outre, il y a une perte de précision due à l'utilisation d'un opérateur d'élargissement afin de garantir la terminaison de l'analyse. Par ailleurs, nous voulons rendre les méthodes d'interprétation abstraite accessibles à des langages de simulation hybrides. Dans cette thèse, nous généralisons d'abord l'accélération abstraite, une méthode qui améliore la précision des invariants numériques inférés. Ensuite, nous montrons comment étendre l'accélération abstraite et l'itération de max-stratégies à des programmes logico-numériques, ce qui aide à améliorer le compromis entre l'efficacité et la précision. En ce qui concerne les systèmes hybrides, nous traduisons le langage de programmation synchrone et hybride Zelus vers les automates hybrides logico-numériques, et nous étendons les méthodes d'analyse logico-numérique aux systèmes hybrides. Enfin, nous avons mis en oeuvre les méthodes proposées dans un outil nommé ReaVer et nous fournissons des résultats expérimentaux. En conclusion, cette thèse propose une approche unifiée à la vérification de systèmes logico-numériques discrets et hybrides fondée sur l'interprétation abstraite qui est capable d'intégrer des méthodes d'interprétation abstraite numériques sophistiquées tout en améliorant le compromis entre l'efficacité et la précision.This thesis studies the automatic verification of safety properties of logico-numerical discrete and hybrid systems. These systems have Boolean and numerical variables and exhibit discrete and continuous behavior. Our approach is based on static analysis using abstract interpretation. We address the following issues: Numerical abstract interpretation methods require the enumeration of the Boolean states, and hence, they suffer from the state space explosion problem. Moreover, there is a precision loss due to widening operators used to guarantee termination of the analysis. Furthermore, we want to make abstract interpretation-based analysis methods accessible to simulation languages for hybrid systems. In this thesis, we first generalize abstract acceleration, a method that improves the precision of the inferred numerical invariants. Then, we show how to extend abstract acceleration and max-strategy iteration to logico-numerical programs while improving the trade-off between efficiency and precision. Concerning hybrid systems, we translate the Zelus hybrid synchronous programming language to logico-numerical hybrid automata and extend logico-numerical analysis methods to hybrid systems. Finally, we implemented the proposed methods in ReaVer, a REActive System VERification tool, and provide experimental results. Concluding, this thesis proposes a unified approach to the verification of discrete and hybrid logico-numerical systems based on abstract interpretation, which is capable of integrating sophisticated numerical abstract interpretation methods while successfully trading precision for efficiency.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF