A description of numerical and analytical work pertaining to models that describe the growth and progression of glioblastoma multiforme (GBM), an aggressive form of primary brain cancer. Two reaction-diffusion models are used: the Fisher-Kolmogorov-Petrovsky-Piskunov equation and a 2-population model that divides the tumor into actively proliferating and quiescent (or necrotic) cells. The numerical portion of this work (chapter 2) focuses on simulating GBM expansion in patients undergoing treatment for recurrence of tumor following initial surgery. The models are simulated on 3-dimensional brain geometries derived from magnetic resonance imaging (MRI) scans provided by the Barrow Neurological Institute. The study consists of 17 clinical time intervals across 10 patients that have been followed in detail, each of whom shows significant progression of tumor over a period of 1 to 3 months on sequential follow up scans. A Taguchi sampling design is implemented to estimate the variability of the predicted tumors to using 144 different choices of model parameters. In 9 cases, model parameters can be identified such that the simulated tumor contains at least 40 percent of the volume of the observed tumor. In the analytical portion of the paper (chapters 3 and 4), a positively invariant region for our 2-population model is identified. Then, a rigorous derivation of the critical patch size associated with the model is performed. The critical patch (KISS) size is the minimum habitat size needed for a population to survive in a region. Habitats larger than the critical patch size allow a population to persist, while smaller habitats lead to extinction. The critical patch size of the 2-population model is consistent with that of the Fisher-Kolmogorov-Petrovsky-Piskunov equation, one of the first reaction-diffusion models proposed for GBM. The critical patch size may indicate that GBM tumors have a minimum size depending on the location in the brain. A theoretical relationship between the size of a GBM tumor at steady-state and its maximum cell density is also derived, which has potential applications for patient-specific parameter estimation based on magnetic resonance imaging data.

Autonomic closure is a recently-proposed subgrid closure methodology for large eddy simulation (LES) that replaces the prescribed subgrid models used in traditional LES closure with highly generalized representations of subgrid terms and solution of a local system identification problem that allows the simulation itself to determine the local relation between each subgrid term and the resolved variables at every point and time. The present study demonstrates, for the first time, practical LES based on fully dynamic implementation of autonomic closure for the subgrid stress and the subgrid scalar flux. It leverages the inherent computational efficiency of tensorally-correct generalized representations in terms of parametric quantities, and uses the fundamental representation theory of Smith (1971) to develop complete and minimal tensorally-correct representations for the subgrid stress and scalar flux. It then assesses the accuracy of these representations via a priori tests, and compares with the corresponding accuracy from nonparametric representations and from traditional prescribed subgrid models. It then assesses the computational stability of autonomic closure with these tensorally-correct parametric representations, via forward simulations with a high-order pseudo-spectral code, including the extent to which any added stabilization is needed to ensure computational stability, and compares with the added stabilization needed in traditional closure with prescribed subgrid models. Further, it conducts a posteriori tests based on forward simulations of turbulent conserved scalar mixing with the same pseudo-spectral code, in which velocity and scalar statistics from autonomic closure with these representations are compared with corresponding statistics from traditional closure using prescribed models, and with corresponding statistics of filtered fields from direct numerical simulation (DNS). These comparisons show substantially greater accuracy from autonomic closure than from traditional closure. This study demonstrates that fully dynamic autonomic closure is a practical approach for LES that requires accuracy even at the smallest resolved scales.

Cancer is a worldwide burden in every aspect: physically, emotionally, and financially. A need for innovation in cancer research has led to a vast interdisciplinary effort to search for the next breakthrough. Mathematical modeling allows for a unique look into the underlying cellular dynamics and allows for testing treatment strategies without the need for clinical trials. This dissertation explores several iterations of a dendritic cell (DC) therapy model and correspondingly investigates what each iteration teaches about response to treatment.

In Chapter 2, motivated by the work of de Pillis et al. (2013), a mathematical model employing six ordinary differential (ODEs) and delay differential equations (DDEs) is formulated to understand the effectiveness of DC vaccines, accounting for cell trafficking with a blood and tumor compartment. A preliminary analysis is performed, with numerical simulations used to show the existence of oscillatory behavior. The model is then reduced to a system of four ODEs. Both models are validated using experimental data from melanoma-induced mice. Conditions under which the model admits rich dynamics observed in a clinical setting, such as periodic solutions and bistability, are established. Mathematical analysis proves the existence of a backward bifurcation and establishes thresholds for R0 that ensure tumor elimination or existence. A sensitivity analysis determines which parameters most significantly impact the reproduction number R0. Identifiability analysis reveals parameters of interest for estimation. Results are framed in terms of treatment implications, including effective combination and monotherapy strategies.

In Chapter 3, a study of whether the observed complexity can be represented with a simplified model is conducted. The DC model of Chapter 2 is reduced to a non-dimensional system of two DDEs. Mathematical and numerical analysis explore the impact of immune response time on the stability and eradication of the tumor, including an analytical proof of conditions necessary for the existence of a Hopf bifurcation. In a limiting case, conditions for global stability of the tumor-free equilibrium are outlined.

Lastly, Chapter 4 discusses future directions to explore. There still remain open questions to investigate and much work to be done, particularly involving uncertainty analysis. An outline of these steps is provided for future undertakings.

Earth-system models describe the interacting components of the climate system and

technological systems that affect society, such as communication infrastructures. Data

assimilation addresses the challenge of state specification by incorporating system

observations into the model estimates. In this research, a particular data

assimilation technique called the Local Ensemble Transform Kalman Filter (LETKF) is

applied to the ionosphere, which is a domain of practical interest due to its effects

on infrastructures that depend on satellite communication and remote sensing. This

dissertation consists of three main studies that propose strategies to improve space-

weather specification during ionospheric extreme events, but are generally applicable

to Earth-system models:

Topic I applies the LETKF to estimate ion density with an idealized model of

the ionosphere, given noisy synthetic observations of varying sparsity. Results show

that the LETKF yields accurate estimates of the ion density field and unobserved

components of neutral winds even when the observation density is spatially sparse

(2% of grid points) and there is large levels (40%) of Gaussian observation noise.

Topic II proposes a targeted observing strategy for data assimilation, which uses

the influence matrix diagnostic to target errors in chosen state variables. This

strategy is applied in observing system experiments, in which synthetic electron density

observations are assimilated with the LETKF into the Thermosphere-Ionosphere-

Electrodynamics Global Circulation Model (TIEGCM) during a geomagnetic storm.

Results show that assimilating targeted electron density observations yields on

average about 60%–80% reduction in electron density error within a 600 km radius of

the observed location, compared to 15% reduction obtained with randomly placed

vertical profiles.

Topic III proposes a methodology to account for systematic model bias arising

ifrom errors in parametrized solar and magnetospheric inputs. This strategy is ap-

plied with the TIEGCM during a geomagnetic storm, and is used to estimate the

spatiotemporal variations of bias in electron density predictions during the

transitionary phases of the geomagnetic storm. Results show that this strategy reduces

error in 1-hour predictions of electron density by about 35% and 30% in polar regions

during the main and relaxation phases of the geomagnetic storm, respectively.