In these studies, we consider systems of equations describing flow in multiple, interacting fluid networks with different permeabilities. The resulting discrete systems of equations can easily become very large, and efficient solution techniques are key. In cases where the inter-network interactions dominate the intra-network permeabilities, we observed that the systems of equations became increasingly hard to solve. In particular, the number of solver iterations would increase with increasing discrete resolution and interaction parameters. However, by creating an algorithm for defining tailored changes of variables, we were able to define robust preconditioners with uniformly bounded iteration counts.
Personal favorite: The lovely trick for how to define parameter-tailored changes of variables via classical matrix analysis including simultaneous diagonalization by congruence.
Mathematical models in biology involve many parameters that are uncertain or in some cases unknown. Over the last years, increased computing power has expanded the complexity and increased the number of degrees of freedom of many such models. For this reason, efficient uncertainty quantification algorithms are now needed to explore the often large parameter space of a given model. Advanced Monte Carlo methods such as quasi Monte Carlo (QMC) and multilevel Monte Carlo (MLMC) have become very popular in the mathematical, engineering, and financial literature for the quantification of uncertainty in model predictions. However, applying these methods to physiologically relevant simulations is a difficult task given the typical complexity of the models and geometries involved. In this paper, we design and apply QMC and MLMC methods to quantify uncertainty in a convection-diffusion model for tracer transport within the brain. We show that QMC outperforms standard Monte Carlo simulations when the number of random inputs is small. MLMC considerably outperforms both QMC and standard Monte Carlo methods and should therefore be preferred for brain transport models.
Uncertainty in diffusion parameters substantially impact the amount of tracer in gray and white matter, and the average tracer concentration in gray and white subregions.
Even with an uncertainty in the diffusion coefficient of a factor three, and a resulting fourfold variation in white matter tracer enhancement, discrepancies between simulations of diffusion and experimental data are too large to be attributed to uncertainties in the diffusion coefficient alone.
A convective velocity field modelling the glymphatic theory did not increase tracer enhancement in the brain parenchyma compared to pure diffusion. However, when a large-scale directional structure was added to this glymphatic velocity field, tracer inflow increased.
Abstract: The usefulness of mechanistic models to disentangle complex multi-scale cancer processes such as treatment response has been widely acknowledged. However, a major barrier for multi-scale models to predict treatment outcomes in individual patients lies in their initialization and parametrization which need to reflect individual cancer characteristics accurately. In this study we use multi-type measurements acquired routinely on a single breast tumor, including histopathology, magnetic resonance imaging, and molecular profiling, to personalize parts of a complex multi-scale model of breast cancer treated with chemotherapeutic and anti-angiogenic agents. The model accounts for drug pharmacokinetics and pharmacodynamics. We developed an open-source computer program that simulates cross-sections of tumors under 12-week therapy regimens and use it to individually reproduce and elucidate treatment outcomes of four patients. Two of the tumors did not respond to therapy, and model simulations were used to suggest alternative regimens with improved outcomes dependent on the tumor’s individual characteristics. It was determined that more frequent and lower doses of chemotherapy reduce tumor burden in a low proliferative tumor while lower doses of anti-angiogenic agents improve drug penetration in a poorly perfused tumor. Furthermore, using this model we were able to predict correctly the outcome in another patient after 12 weeks of treatment. In summary, our model bridges multi-type clinical data to shed light on individual treatment outcomes.
Over the last decade, there has been a significant renewed interest in the waterscape of the brain; that is, the physiological mechanisms governing cerebrospinal fluid (CSF) and interstitial fluid (ISF) flow in (and around) the brain. A number of new theories have emerged, but a great deal of uncertainty relating to the roles of diffusion, convection and clearance within the brain remains. With this study, we aimed to rigorously quantify how the aforementioned uncertainties in the physiological parameters and in ISF flow affect the spread of a tracer into the brain. We assumed movement of tracer in the brain to occur by diffusion and/or convection. To account for uncertainty and variability, we circumvented the lack of precise parameter values by modelling velocity and diffusivity as Matérn stochastic fields. We then set up a PDE model with these stochastic (random) fields as coefficients and quantify the uncertainty in the model prediction via the Monte Carlo (MC) method.
How fluid moves during the cardiac cycle within a syrinx (a fluid-filled cyst in the spinal cord) may affect its development. We measured syrinx fluid velocities before and after craniovertebral decompression in a patient and simulated syrinx fluid velocities for different heart rates, syrinx sizes and cerebrospinal fluid (CSF) flow velocities in a model of syringomyelia. With phase-contrast magnetic resonance we measured CSF and syrinx fluid velocities in a Chiari patient before and after craniovertebral decompression. With an idealized two-dimensional model of the subarachnoid space (SAS), cord and syrinx, we simulated fluid movement in the SAS and syrinx with the Navier-Stokes equations for different heart rates, inlet velocities and syrinx diameters. In the patient, fluid oscillated in the syrinx at 200 to 210 cycles per minute before and after craniovertebral decompression. Velocities peaked at 3.6 and 2.0 cm per second respectively in the SAS and the syrinx before surgery and at 2.7 and 1.5 cm per second after surgery. In the model, syrinx velocity varied between 0.91 and 12.70 cm per second. Increasing CSF inlet velocities from 1.56 to 4.69 cm per second increased peak syrinx fluid velocities in the syrinx by 151% to 299% for the three cycle rates. Increasing cycle rates from 60 to 120 cpm increased peak syrinx velocities by 160% to 312% for the three inlet velocities. Peak velocities changed inconsistently with syrinx size. In conclusion, CSF velocity, heart rate and syrinx diameter affect syrinx fluid velocities, but not the frequency of syrinx fluid oscillation. Craniovertebral decompression decreases both CSF and syrinx fluid velocities.