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Register a new userPersonalized Radiotherapy Design for Glioblastoma: Integrating Mathematical Tumor Models, Multimodal Scans and Bayesian Inference
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Added by
Jana Lipkova
Publication date
2018
fields
Informatics Engineering
and research's language is
English
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Glioblastoma is a highly invasive brain tumor, whose cells infiltrate surrounding normal brain tissue beyond the lesion outlines visible in the current medical scans. These infiltrative cells are treated mainly by radiotherapy. Existing radiotherapy plans for brain tumors derive from population studies and scarcely account for patient-specific conditions. Here we provide a Bayesian machine learning framework for the rational design of improved, personalized radiotherapy plans using mathematical modeling and patient multimodal medical scans. Our method, for the first time, integrates complementary information from high resolution MRI scans and highly specific FET-PET metabolic maps to infer tumor cell density in glioblastoma patients. The Bayesian framework quantifies imaging and modeling uncertainties and predicts patient-specific tumor cell density with confidence intervals. The proposed methodology relies only on data acquired at a single time point and thus is applicable to standard clinical settings. An initial clinical population study shows that the radiotherapy plans generated from the inferred tumor cell infiltration maps spare more healthy tissue thereby reducing radiation toxicity while yielding comparable accuracy with standard radiotherapy protocols. Moreover, the inferred regions of high tumor cell densities coincide with the tumor radioresistant areas, providing guidance for personalized dose-escalation. The proposed integration of multimodal scans and mathematical modeling provides a robust, non-invasive tool to assist personalized radiotherapy design.
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Modeling of brain tumor dynamics has the potential to advance therapeutic planning. Current modeling approaches resort to numerical solvers that simulate the tumor progression according to a given differential equation. Using highly-efficient numerical solvers, a single forward simulation takes up to a few minutes of compute. At the same time, clinical applications of tumor modeling often imply solving an inverse problem, requiring up to tens of thousands forward model evaluations when used for a Bayesian model personalization via sampling. This results in a total inference time prohibitively expensive for clinical translation. While recent data-driven approaches become capable of emulating physics simulation, they tend to fail in generalizing over the variability of the boundary conditions imposed by the patient-specific anatomy. In this paper, we propose a learnable surrogate for simulating tumor growth which maps the biophysical model parameters directly to simulation outputs, i.e. the local tumor cell densities, whilst respecting patient geometry. We test the neural solver on Bayesian tumor model personalization for a cohort of glioma patients. Bayesian inference using the proposed surrogate yields estimates analogous to those obtained by solving the forward model with a regular numerical solver. The near-real-time computation cost renders the proposed method suitable for clinical settings. The code is available at https://github.com/IvanEz/tumor-surrogate.
We consider Bayesian inference for stochastic differential equation mixed effects models (SDEMEMs) exemplifying tumor response to treatment and regrowth in mice. We produce an extensive study on how a SDEMEM can be fitted using both exact inference based on pseudo-marginal MCMC and approximate inference via Bayesian synthetic likelihoods (BSL). We investigate a two-compartments SDEMEM, these corresponding to the fractions of tumor cells killed by and survived to a treatment, respectively. Case study data considers a tumor xenography study with two treatment groups and one control, each containing 5-8 mice. Results from the case study and from simulations indicate that the SDEMEM is able to reproduce the observed growth patterns and that BSL is a robust tool for inference in SDEMEMs. Finally, we compare the fit of the SDEMEM to a similar ordinary differential equation model. Due to small sample sizes, strong prior information is needed to identify all model parameters in the SDEMEM and it cannot be determined which of the two models is the better in terms of predicting tumor growth curves. In a simulation study we find that with a sample of 17 mice per group BSL is able to identify all model parameters and distinguish treatment groups.
The performance of multimodal mobility systems relies on the seamless integration of conventional mass transit services and the advent of Mobility-on-Demand (MoD) services. Prior work is limited to individually improving various transport networks operations or linking a new mode to an existing system. In this work, we attempt to solve transit network design and pricing problems of multimodal mobility systems en masse. An operator (public transit agency or private transit operator) determines the frequency settings of the mass transit system, flows of the MoD service, and prices for each trip to optimize the overall welfare. A primal-dual approach, inspired by the market design literature, yields a compact mixed integer linear programming (MILP) formulation. However, a key computational challenge remains in allocating an exponential number of hybrid modes accessible to travelers. We provide a tractable solution approach through a decomposition scheme and approximation algorithm that accelerates the computation and enables optimization of large-scale problem instances. Using a case study in Nashville, Tennessee, we demonstrate the value of the proposed model. We also show that our algorithm reduces the average runtime by 60% compared to advanced MILP solvers. This result seeks to establish a generic and simple-to-implement way of revamping and redesigning regional mobility systems in order to meet the increase in travel demand and integrate traditional fixed-line mass transit systems with new demand-responsive services.
We use the theory of normal variance-mean mixtures to derive a data augmentation scheme for models that include gamma functions. Our methodology applies to many situations in statistics and machine learning, including Multinomial-Dirichlet distributions, Negative binomial regression, Poisson-Gamma hierarchical models, Extreme value models, to name but a few. All of those models include a gamma function which does not admit a natural conjugate prior distribution providing a significant challenge to inference and prediction. To provide a data augmentation strategy, we construct and develop the theory of the class of Exponential Reciprocal Gamma distributions. This allows scalable EM and MCMC algorithms to be developed. We illustrate our methodology on a number of examples, including gamma shape inference, negative binomial regression and Dirichlet allocation. Finally, we conclude with directions for future research.
The extremely regular, periodic radio emission from millisecond pulsars makes them useful tools for studying neutron star astrophysics, general relativity, and low-frequency gravitational waves. These studies require that the observed pulse times of arrival be fit to complex timing models that describe numerous effects such as the astrometry of the source, the evolution of the pulsars spin, the presence of a binary companion, and the propagation of the pulses through the interstellar medium. In this paper, we discuss the benefits of using Bayesian inference to obtain pulsar timing solutions. These benefits include the validation of linearized least-squares model fits when they are correct, and the proper characterization of parameter uncertainties when they are not; the incorporation of prior parameter information and of models of correlated noise; and the Bayesian comparison of alternative timing models. We describe our computational setup, which combines the timing models of Tempo2 with the nested-sampling integrator MultiNest. We compare the timing solutions generated using Bayesian inference and linearized least-squares for three pulsars: B1953+29, J2317+1439, and J1640+2224, which demonstrate a variety of the benefits that we posit.
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