Towards Cancer Hybrid Automata

This paper introduces Cancer Hybrid Automata (CHAs), a formalism to model the progression of cancers through discrete phenotypes. The classification of cancer progression using discrete states like stages and hallmarks has become common in the biology literature, but primarily as an organizing principle, and not as an executable formalism. The precise computational model developed here aims to exploit this untapped potential, namely, through automatic verification of progression models (e.g., consistency, causal connections, etc.), classification of unreachable or unstable states and computer-generated (individualized or universal) therapy plans. The paper builds on a phenomenological approach, and as such does not need to assume a model for the biochemistry of the underlying natural progression. Rather, it abstractly models transition timings between states as well as the effects of drugs and clinical tests, and thus allows formalization of temporal statements about the progression as well as notions of timed therapies. The model proposed here is ultimately based on hybrid automata, and we show how existing controller synthesis algorithms can be generalized to CHA models, so that therapies can be generated automatically. Throughout this paper we use cancer hallmarks to represent the discrete states through which cancer progresses, but other notions of discretely or continuously varying state formalisms could also be used to derive similar therapies.Comment: In Proceedings HSB 2012, arXiv:1208.315

Towards Personalized Prostate Cancer Therapy Using Delta-Reachability Analysis

Recent clinical studies suggest that the efficacy of hormone therapy for prostate cancer depends on the characteristics of individual patients. In this paper, we develop a computational framework for identifying patient-specific androgen ablation therapy schedules for postponing the potential cancer relapse. We model the population dynamics of heterogeneous prostate cancer cells in response to androgen suppression as a nonlinear hybrid automaton. We estimate personalized kinetic parameters to characterize patients and employ $\delta$-reachability analysis to predict patient-specific therapeutic strategies. The results show that our methods are promising and may lead to a prognostic tool for personalized cancer therapy.Comment: HSCC 201

Under-approximating Cut Sets for Reachability in Large Scale Automata Networks

In the scope of discrete finite-state models of interacting components, we present a novel algorithm for identifying sets of local states of components whose activity is necessary for the reachability of a given local state. If all the local states from such a set are disabled in the model, the concerned reachability is impossible. Those sets are referred to as cut sets and are computed from a particular abstract causality structure, so-called Graph of Local Causality, inspired from previous work and generalised here to finite automata networks. The extracted sets of local states form an under-approximation of the complete minimal cut sets of the dynamics: there may exist smaller or additional cut sets for the given reachability. Applied to qualitative models of biological systems, such cut sets provide potential therapeutic targets that are proven to prevent molecules of interest to become active, up to the correctness of the model. Our new method makes tractable the formal analysis of very large scale networks, as illustrated by the computation of cut sets within a Boolean model of biological pathways interactions gathering more than 9000 components

Statistical Model Checking for Stochastic Hybrid Systems

This paper presents novel extensions and applications of the UPPAAL-SMC model checker. The extensions allow for statistical model checking of stochastic hybrid systems. We show how our race-based stochastic semantics extends to networks of hybrid systems, and indicate the integration technique applied for implementing this semantics in the UPPAAL-SMC simulation engine. We report on two applications of the resulting tool-set coming from systems biology and energy aware buildings.Comment: In Proceedings HSB 2012, arXiv:1208.315

Programmable models of growth and mutation of cancer-cell populations

In this paper we propose a systematic approach to construct mathematical models describing populations of cancer-cells at different stages of disease development. The methodology we propose is based on stochastic Concurrent Constraint Programming, a flexible stochastic modelling language. The methodology is tested on (and partially motivated by) the study of prostate cancer. In particular, we prove how our method is suitable to systematically reconstruct different mathematical models of prostate cancer growth - together with interactions with different kinds of hormone therapy - at different levels of refinement.Comment: In Proceedings CompMod 2011, arXiv:1109.104

The detection and classification of blast cell in Leukaemia Acute Promyelocytic Leukaemia (AML M3) blood using simulated annealing and neural networks

This paper was delivered at AIME 2011: 13th Conference on Artifical Intelligence in Medicine.This paper presents a method for the detection and classification of blast cells in M3 with others sub-types using simulated annealing and neural networks. In this paper, we increased our test result from 10 images to 20 images. We performed Hill Climbing, Simulated Annealing and Genetic Algorithms for detecting the blast cells. As a result, simulated annealing is the “best” heuristic search for detecting the leukaemia cells. From the detection, we performed features extraction on the blast cells and we classifying based on M3 and other sub-types using neural networks. We received convincing result which has targeting around 97% in classifying of M3 with other sub-types. Our results are based on real world image data from a Haematology Department.Universiti Sains Islam Malaysia and the Ministry of Higher Education, Malaysi

Comparison of Timed Automata with Discrete Event Simulation for Modeling Personalized Treatment Decisions:the Case of Metastatic Castration Resistant Prostate Cancer

Objectives: The aim of this study is to compare the usefulness of two promising alternative modeling techniques, Timed Automata (TA) originating from informatics, and Discrete Event Simulation (DES) known in operations research, for modeling todays complex and personalized treatment decisions over time, involving multiple interactions and decision gates. Methods: The usefulness of both modeling techniques was assessed in a case study on the treatment of metastatic Castration Resistant Prostate Cancer (mCRPC) in which Circulating Tumor Cells (CTC) may be used as a response marker for switching first to second line treatment. Techniques were compared on user-friendliness, input requirements, input possibilities, model checking facilities, and results. Input parameters were similar for both models, consisting of costs, QoL, treatment effectiveness, diagnostic performance, physicians’ behavior and survival. Primary outcome measures were health outcomes, expressed in QALYs, and costs. Results: Modelling was considered easier using TA, as this approach allows independent modeling of the actors and elements comprising the treatment process, such as patients, physicians, tests and treatments, and their mutual interaction and communication. Furthermore, the statistical model checking feature in the TA software was found to be a powerful tool for validation. Input requirements and possibilities were similar for both modelling approaches in this case study. Both modelling approaches yield comparable results. Using TA, CTC reduced first and second line treatment by, on average, 108.9 and 107.6 days, respectively. Using DES, treatment was reduced by 83.6 and 85.0 days. CTC therefore reduced healthcare costs by €28,998 and €21,992 according to TA and DES, respectively. Conclusions: Both Timed Automata and Discrete Event Simulation seem to be suitable for modeling complex and personalized treatment processes like that of mCRPC. Timed Automata is a new and interesting alternative modeling technique, as it allows explicit separation of model components and supports statistical model checking to validate models

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