Institut für Mathematik
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Model-informed precision dosing (MIPD) is a quantitative dosing framework that combines prior knowledge on the drug-disease-patient system with patient data from therapeutic drug/ biomarker monitoring (TDM) to support individualized dosing in ongoing treatment. Structural models and prior parameter distributions used in MIPD approaches typically build on prior clinical trials that involve only a limited number of patients selected according to some exclusion/inclusion criteria. Compared to the prior clinical trial population, the patient population in clinical practice can be expected to also include altered behavior and/or increased interindividual variability, the extent of which, however, is typically unknown. Here, we address the question of how to adapt and refine models on the level of the model parameters to better reflect this real-world diversity. We propose an approach for continued learning across patients during MIPD using a sequential hierarchical Bayesian framework. The approach builds on two stages to separate the update of the individual patient parameters from updating the population parameters. Consequently, it enables continued learning across hospitals or study centers, because only summary patient data (on the level of model parameters) need to be shared, but no individual TDM data. We illustrate this continued learning approach with neutrophil-guided dosing of paclitaxel. The present study constitutes an important step toward building confidence in MIPD and eventually establishing MIPD increasingly in everyday therapeutic use.
We discuss Neumann problems for self-adjoint Laplacians on (possibly infinite) graphs. Under the assumption that the heat semigroup is ultracontractive we discuss the unique solvability for non-empty subgraphs with respect to the vertex boundary and provide analytic and probabilistic representations for Neumann solutions. A second result deals with Neumann problems on canonically compactifiable graphs with respect to the Royden boundary and provides conditions for unique solvability and analytic and probabilistic representations.
Extreme value statistics is a popular and frequently used tool to model the occurrence of large earthquakes. The problem of poor statistics arising from rare events is addressed by taking advantage of the validity of general statistical properties in asymptotic regimes. In this note, I argue that the use of extreme value statistics for the purpose of practically modeling the tail of the frequency-magnitude distribution of earthquakes can produce biased and thus misleading results because it is unknown to what degree the tail of the true distribution is sampled by data. Using synthetic data allows to quantify this bias in detail. The implicit assumption that the true M-max is close to the maximum observed magnitude M-max,M-observed restricts the class of the potential models a priori to those with M-max = M-max,M-observed + Delta M with an increment Delta M approximate to 0.5... 1.2. This corresponds to the simple heuristic method suggested by Wheeler (2009) and labeled :M-max equals M-obs plus an increment." The incomplete consideration of the entire model family for the frequency-magnitude distribution neglects, however, the scenario of a large so far unobserved earthquake.
A rigorous construction of the supersymmetric path integral associated to a compact spin manifold
(2022)
We give a rigorous construction of the path integral in N = 1/2 supersymmetry as an integral map for differential forms on the loop space of a compact spin manifold. It is defined on the space of differential forms which can be represented by extended iterated integrals in the sense of Chen and Getzler-Jones-Petrack. Via the iterated integral map, we compare our path integral to the non-commutative loop space Chern character of Guneysu and the second author. Our theory provides a rigorous background to various formal proofs of the Atiyah-Singer index theorem for twisted Dirac operators using supersymmetric path integrals, as investigated by Alvarez-Gaume, Atiyah, Bismut and Witten.
An explicit Dobrushin uniqueness region for Gibbs point processes with repulsive interactions
(2022)
We present a uniqueness result for Gibbs point processes with interactions that come from a non-negative pair potential; in particular, we provide an explicit uniqueness region in terms of activity z and inverse temperature beta. The technique used relies on applying to the continuous setting the classical Dobrushin criterion. We also present a comparison to the two other uniqueness methods of cluster expansion and disagreement percolation, which can also be applied for this type of interaction.
We propose a global geomagnetic field model for the last 14 thousand years, based on thermoremanent records. We call the model ArchKalmag14k. ArchKalmag14k is constructed by modifying recently proposed algorithms, based on space-time correlations. Due to the amount of data and complexity of the model, the full Bayesian posterior is numerically intractable. To tackle this, we sequentialize the inversion by implementing a Kalman-filter with a fixed time step. Every step consists of a prediction, based on a degree dependent temporal covariance, and a correction via Gaussian process regression. Dating errors are treated via a noisy input formulation. Cross correlations are reintroduced by a smoothing algorithm and model parameters are inferred from the data. Due to the specific statistical nature of the proposed algorithms, the model comes with space and time-dependent uncertainty estimates. The new model ArchKalmag14k shows less variation in the large-scale degrees than comparable models. Local predictions represent the underlying data and agree with comparable models, if the location is sampled well. Uncertainties are bigger for earlier times and in regions of sparse data coverage. We also use ArchKalmag14k to analyze the appearance and evolution of the South Atlantic anomaly together with reverse flux patches at the core-mantle boundary, considering the model uncertainties. While we find good agreement with earlier models for recent times, our model suggests a different evolution of intensity minima prior to 1650 CE. In general, our results suggest that prior to 6000 BCE the data is not sufficient to support global models.
We study boundary value problems for first-order elliptic differential operators on manifolds with compact boundary. The adapted boundary operator need not be selfadjoint and the boundary condition need not be pseudo-local.We show the equivalence of various characterisations of elliptic boundary conditions and demonstrate how the boundary conditions traditionally considered in the literature fit in our framework. The regularity of the solutions up to the boundary is proven. We show that imposing elliptic boundary conditions yields a Fredholm operator if the manifold is compact. We provide examples which are conveniently treated by our methods.
The index theorem for elliptic operators on a closed Riemannian manifold by Atiyah and Singer has many applications in analysis, geometry and topology, but it is not suitable for a generalization to a Lorentzian setting.
In the case where a boundary is present Atiyah, Patodi and Singer provide an index theorem for compact Riemannian manifolds by introducing non-local boundary conditions obtained via the spectral decomposition of an induced boundary operator, so called APS boundary conditions. Bär and Strohmaier prove a Lorentzian version of this index theorem for the Dirac operator on a manifold with boundary by utilizing results from APS and the characterization of the spectral flow by Phillips. In their case the Lorentzian manifold is assumed to be globally hyperbolic and spatially compact, and the induced boundary operator is given by the Riemannian Dirac operator on a spacelike Cauchy hypersurface. Their results show that imposing APS boundary conditions for these boundary operator will yield a Fredholm operator with a smooth kernel and its index can be calculated by a formula similar to the Riemannian case.
Back in the Riemannian setting, Bär and Ballmann provide an analysis of the most general kind of boundary conditions that can be imposed on a first order elliptic differential operator that will still yield regularity for solutions as well as Fredholm property for the resulting operator. These boundary conditions can be thought of as deformations to the graph of a suitable operator mapping APS boundary conditions to their orthogonal complement.
This thesis aims at applying the boundary conditions found by Bär and Ballmann to a Lorentzian setting to understand more general types of boundary conditions for the Dirac operator, conserving Fredholm property as well as providing regularity results and relative index formulas for the resulting operators. As it turns out, there are some differences in applying these graph-type boundary conditions to the Lorentzian Dirac operator when compared to the Riemannian setting. It will be shown that in contrast to the Riemannian case, going from a Fredholm boundary condition to its orthogonal complement works out fine in the Lorentzian setting. On the other hand, in order to deduce Fredholm property and regularity of solutions for graph-type boundary conditions, additional assumptions for the deformation maps need to be made.
The thesis is organized as follows. In chapter 1 basic facts about Lorentzian and Riemannian spin manifolds, their spinor bundles and the Dirac operator are listed. These will serve as a foundation to define the setting and prove the results of later chapters.
Chapter 2 defines the general notion of boundary conditions for the Dirac operator used in this thesis and introduces the APS boundary conditions as well as their graph type deformations. Also the role of the wave evolution operator in finding Fredholm boundary conditions is analyzed and these boundary conditions are connected to notion of Fredholm pairs in a given Hilbert space.
Chapter 3 focuses on the principal symbol calculation of the wave evolution operator and the results are used to proof Fredholm property as well as regularity of solutions for suitable graph-type boundary conditions. Also sufficient conditions are derived for (pseudo-)local boundary conditions imposed on the Dirac operator to yield a Fredholm operator with a smooth solution space.
In the last chapter 4, a few examples of boundary conditions are calculated applying the results of previous chapters. Restricting to special geometries and/or boundary conditions, results can be obtained that are not covered by the more general statements, and it is shown that so-called transmission conditions behave very differently than in the Riemannian setting.
In this paper, we examine conditioning of the discretization of the Helmholtz problem. Although the discrete Helmholtz problem has been studied from different perspectives, to the best of our knowledge, there is no conditioning analysis for it. We aim to fill this gap in the literature. We propose a novel method in 1D to observe the near-zero eigenvalues of a symmetric indefinite matrix. Standard classification of ill-conditioning based on the matrix condition number is not true for the discrete Helmholtz problem. We relate the ill-conditioning of the discretization of the Helmholtz problem with the condition number of the matrix. We carry out analytical conditioning analysis in 1D and extend our observations to 2D with numerical observations. We examine several discretizations. We find different regions in which the condition number of the problem shows different characteristics. We also explain the general behavior of the solutions in these regions.