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Computational systems and methods are being applied to solve biological problems for many years. Incorporating methods of this kind in the research for cancer treatment and related drug discovery in particular, is shown to be challenging due to the complexity and the dynamic nature of the related factors. Usually, there are two objectives in such settings; first to calibrate the simulators so as to reproduce real-world cases, and second, to search for specific values of the parameter space concerning effective drug treatments. We combine a multi-scale simulator for tumor cell growth and a Genetic Algorithm (GA) as a heuristic search method for finding good parameter configurations in reasonable time. The two modules are integrated into a single workflow that can be executed in a parallel manner on high performance computing infrastructures, since large-scale computational and storage capabilities are necessary in this domain. After using the GA for calibration, our goal is to explore different drug delivery schemes. Among these schemes, we aim to find those that minimize tumor cell size and the probability of emergence of drug resistant cells in the future. Results from experiments on high performance computing infrastructure illustrate the effectiveness and timeliness of the approach.
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A significant challenge in Glioblastoma (GBM) management is identifying pseudo-progression (PsP), a benign radiation-induced effect, from tumor recurrence, on routine imaging following conventional treatment. Previous studies have linked tumor lobar presence and laterality to GBM outcomes, suggesting that disease etiology and progression in GBM may be impacted by tumor location. Hence, in this feasibility study, we seek to investigate the following question: Can tumor location on treatment-naive MRI provide early cues regarding likelihood of a patient developing pseudo-progression versus tumor recurrence? In this study, 74 pre-treatment Glioblastoma MRI scans with PsP (33) and tumor recurrence (41) were analyzed. First, enhancing lesion on Gd-T1w MRI and peri-lesional hyperintensities on T2w/FLAIR were segmented by experts and then registered to a brain atlas. Using patients from the two phenotypes, we construct two atlases by quantifying frequency of occurrence of enhancing lesion and peri-lesion hyperintensities, by averaging voxel intensities across the population. Analysis of differential involvement was then performed to compute voxel-wise significant differences (p-value<0.05) across the atlases. Statistically significant clusters were finally mapped to a structural atlas to provide anatomic localization of their location. Our results demonstrate that patients with tumor recurrence showed prominence of their initial tumor in the parietal lobe, while patients with PsP showed a multi-focal distribution of the initial tumor in the frontal and temporal lobes, insula, and putamen. These preliminary results suggest that lateralization of pre-treatment lesions towards certain anatomical areas of the brain may allow to provide early cues regarding assessing likelihood of occurrence of pseudo-progression from tumor recurrence on MRI scans.
The probability distribution describing the state of a Stochastic Reaction Network evolves according to the Chemical Master Equation (CME). It is common to estimated its solution using Monte Carlo methods such as the Stochastic Simulation Algorithm (SSA). In many cases these simulations can take an impractical amount of computational time. Therefore many methods have been developed that approximate the Stochastic Process underlying the Chemical Master Equation. Prominent strategies are Hybrid Models that regard the firing of some reaction channels as being continuous and applying the quasi-stationary assumption to approximate the dynamics of fast subnetworks. However as the dynamics of a Stochastic Reaction Network changes with time these approximations might have to be adapted during the simulation. We develop a method that approximates the solution of a CME by automatically partitioning the reaction dynamics into discrete/continuous components and applying the quasi-stationary assumption on identifiable fast subnetworks. Our method does not require user intervention and it adapts to exploit the changing timescale separation between reactions and/or changing magnitudes of copy numbers of constituent species. We demonstrate the efficiency of the proposed method by considering examples from Systems Biology and showing that very good approximations to the exact probability distributions can be achieved in significantly less computational time.
Understanding the dynamics of brain tumor progression is essential for optimal treatment planning. Cast in a mathematical formulation, it is typically viewed as evaluation of a system of partial differential equations, wherein the physiological processes that govern the growth of the tumor are considered. To personalize the model, i.e. find a relevant set of parameters, with respect to the tumor dynamics of a particular patient, the model is informed from empirical data, e.g., medical images obtained from diagnostic modalities, such as magnetic-resonance imaging. Existing model-observation coupling schemes require a large number of forward integrations of the biophysical model and rely on simplifying assumption on the functional form, linking the output of the model with the image information. In this work, we propose a learning-based technique for the estimation of tumor growth model parameters from medical scans. The technique allows for explicit evaluation of the posterior distribution of the parameters by sequentially training a mixture-density network, relaxing the constraint on the functional form and reducing the number of samples necessary to propagate through the forward model for the estimation. We test the method on synthetic and real scans of rats injected with brain tumors to calibrate the model and to predict tumor progression.
We study a simplified stochastic model for the vascularization of a growing tumor, incorporating the formation of new blood vessels at the tumor periphery as well as their regression in the tumor center. The resulting morphology of the tumor vasculature differs drastically from the original one. We demonstrate that the probabilistic vessel collapse has to be correlated with the blood shear force in order to yield percolating network structures. The resulting tumor vasculature displays fractal properties. Fractal dimension, microvascular density (MVD), blood flow and shear force has been computed for a wide range of parameters.
With the wealth of high-throughput sequencing data generated by recent large-scale consortia, predictive gene expression modelling has become an important tool for integrative analysis of transcriptomic and epigenetic data. However, sequencing data-sets are characteristically large, and previously modelling frameworks are typically inefficient and unable to leverage multi-core or distributed processing architectures. In this study, we detail an efficient and parallelised MapReduce implementation of gene expression modelling. We leverage the computational efficiency of this framework to provide an integrative analysis of over fifty histone modification data-sets across a variety of cancerous and non-cancerous cell-lines. Our results demonstrate that the genome-wide relationships between histone modifications and mRNA transcription are lineage, tissue and karyotype-invariant, and that models trained on matched epigenetic/transcriptomic data from non-cancerous cell-lines are able to predict cancerous expression with equivalent genome-wide fidelity.
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