Library

Description: Consolidation of commodities and coordination of vehicle routes are fundamental features of supply chain management problems. While locations for consolidation and coordination are typically known a priori, in adaptive transportation networks this is not the case. The identification of such consolidation locations forms part of the decision making process. Supply chain management problems integrating the designation of consolidation locations with the coordination of long haul and local vehicle routing is not only challenging to solve, but also very difficult to formulate mathematically. In this paper, the first mathematical model integrating location clustering with long haul and local vehicle routing is proposed. This mathematical formulation is used to develop algorithms to find high quality solutions. A novel parallel framework is developed that combines exact and heuristic methods to improve the search for high quality solutions and provide valid bounds. The results demonstrate that using exact methods to guide heuristic search is an effective approach to find high quality solutions for difficult supply chain management problems.

Description: We performed a citation analysis on the Web of Science publications consisting of more than 63 million articles and 1.45 billion citations on 254 subjects from 1981 to 2020. We proposed the Article’s Scientific Prestige (ASP) metric and compared this metric to number of citations (#Cit) and journal grade in measuring the scientific impact of individual articles in the large-scale hierarchical and multi-disciplined citation network. In contrast to #Cit, ASP, that is computed based on the eigenvector centrality, considers both direct and indirect citations, and provides steady-state evaluation cross different disciplines. We found that ASP and #Cit are not aligned for most articles, with a growing mismatch amongst the less cited articles. While both metrics are reliable for evaluating the prestige of articles such as Nobel Prize winning articles, ASP tends to provide more persuasive rankings than #Cit when the articles are not highly cited. The journal grade, that is eventually determined by a few highly cited articles, is unable to properly reflect the scientific impact of individual articles. The number of references and coauthors are less relevant to scientific impact, but subjects do make a difference.

Description: Reaction coordinates (RCs) are indicators of hidden, low-dimensional mechanisms that govern the long-term behavior of high-dimensional stochastic processes. We present a novel and general variational characterization of optimal RCs and provide conditions for their existence. Optimal RCs are minimizers of a certain loss function, and reduced models based on them guarantee a good approximation of the statistical long-term properties of the original high-dimensional process. We show that for slow-fast systems, metastable systems, and other systems with known good RCs, the novel theory reproduces previous insight. Remarkably, for reversible systems, the numerical effort required to evaluate the loss function scales only with the variability of the underlying, low-dimensional mechanism, and not with that of the full system. The theory provided lays the foundation for an efficient and data-sparse computation of RCs via modern machine learning techniques.

Description: Tackling societal challenges relating to sustainability requires both an understanding of the underlying complex socio-ecological systems and participation of scientists as well as relevant stakeholders, such as practice experts, decision makers, and citizens. This paper introduces the Decision Theatre Triangle, a method which combines empirical information, mathematical modelling and simulation, and a format for dialogue between scientists and stakeholders. While it builds on previous Decision Theatre work, the new structuring into these three elements emphasizes what is needed for setting up a Decision Theatre for a given challenge. Based on experience with a specific example – sustainable mobility in Germany – it is argued that agent-based models are particularly suitable for Decision Theatres and that the method is useful not only for decision support but also for science communication and co-creation of a deeper knowledge of the system under discussion. As a step towards facilitating a broader use of the Decision Theatre Triangle method, the paper then sketches research needs for each of its three elements, with a focus on mathematical modelling and simulation.

Description: The remarkably complex skeletal systems of the sea stars (Echinodermata, Asteroidea), consisting of hundreds to thousands of individual elements (ossicles), have intrigued investigators for more than 150 years. While the general features and structural diversity of isolated asteroid ossicles have been well documented in the literature, the task of mapping the spatial organization of these constituent skeletal elements in a whole-animal context represents an incredibly laborious process, and as such, has remained largely unexplored. To address this unmet need, particularly in the context of understanding structure-function relationships in these complex skeletal systems, we present an integrated approach that combines micro-computed tomography, semi-automated ossicle segmentation, data visualization tools, and the production of additively manufactured tangible models to reveal biologically relevant structural data that can be rapidly analyzed in an intuitive manner. In the present study, we demonstrate this high-throughput workflow by segmenting and analyzing entire skeletal systems of the giant knobby star, Pisaster giganteus, at four different stages of growth. The in-depth analysis, presented herein, provides a fundamental understanding of the three-dimensional skeletal architecture of the sea star body wall, the process of skeletal maturation during growth, and the relationship between skeletal organization and morphological characteristics of individual ossicles. The widespread implementation of this approach for investigating other species, subspecies, and growth series has the potential to fundamentally improve our understanding of asteroid skeletal architecture and biodiversity in relation to mobility, feeding habits, and environmental specialization in this fascinating group of echinoderms.

Description: For over ten years, the constraint integer programming framework SCIP has been extended by capabilities for the solution of convex and nonconvex mixed-integer nonlinear programs (MINLPs). With the recently published version~8.0, these capabilities have been largely reworked and extended. This paper discusses the motivations for recent changes and provides an overview of features that are particular to MINLP solving in SCIP. Further, difficulties in benchmarking global MINLP solvers are discussed and a comparison with several state-of-the-art global MINLP solvers is provided.

Description: Existing planning approaches for onshore wind farm siting and network integration often do not meet minimum cost solutions or social and environmental considerations. In this paper, we develop an approach for the multi-objective optimization of turbine locations and their network connection using a Quota Steiner tree problem. Applying a novel transformation on a known directed cut formulation, reduction techniques, and heuristics, we design an exact solver that makes large problem instances solvable and outperforms generic MIP solvers. Although our case studies in selected regions of Germany show large trade-offs between the objective criteria of cost and landscape impact, small burdens on one criterion can significantly improve the other criteria. In addition, we demonstrate that contrary to many approaches for exclusive turbine siting, network integration must be simultaneously optimized in order to avoid excessive costs or landscape impacts in the course of a wind farm project. Our novel problem formulation and the developed solver can assist planners in decision making and help optimize wind farms in large regions in the future.

Description: This thesis considers the transient gas network control optimization problem for on-shore pipeline-based transmission networks with numerous gas routing options. As input, the problem is given the network's topology, its initial state, and future demands at the boundaries of the network, which prescribe the gas flow exchange and potentially the pressure values. The task is to find a set of future control measures for all the active, i.e., controllable, elements in the network that minimizes a combination of different penalty functions. The problem is examined in the context of a decision support tool for gas network dispatchers. This results in detailed models featuring a diverse set of constraints, large and challenging real-world instances, and demanding time limit requirements. All these factors further complicate the problem, which is already difficult to solve in theory due to the inherent combination of non-linear and combinatorial aspects. Our contributions concern different steps of the process of solving the problem. Regarding the model formulation, we investigate the validity of two common approximations of the gas flow description in transport pipes: neglecting the inertia term and assuming a friction term that linearly depends on the gas flow and the pressure. For both, we examine if they can be applied under real-world conditions by evaluating a large amount of historical state data of the network of our project partner, the gas network operator Open Grid Europe. While we can confirm that it is reasonable to ignore the influence of the inertia term, the friction term linearization leads to significant errors and, as a consequence, cannot be used for describing the general gas flow behavior in transport pipes. As another topic of this thesis, we introduce the target value concept as a more realistic approach to express control actions of dispatchers regarding regulators and compressor stations. Here, we derive the mechanisms defined for target values based on the gas flow principles in pipes and develop a mixed-integer programming model capturing their behavior. The accuracy of this model is demonstrated in comparison to a target-value-based industry-standard simulator. Furthermore, we present two heuristics for the transient gas network control optimization problem featuring target values that are based on approximative models for the target-value-based control and determine the final decisions in a post-processing step. To compare the performance of the two heuristics with the approach of directly solving the corresponding model, we evaluate them on a set of artificially created test instances. Finally, we develop problem-specific algorithms for two variants of the described problem. One considers the control optimization for a single network station, which represents a local operation site featuring a large number of active elements. The used transient model is very detailed and includes a sophisticated representation of the compressor stations. Based on the shortness of the pipes in the station, the corresponding algorithm finds valid solutions by solving a series of stationary model variants as well as a transient rolling horizon approach. As the second variant, we consider the problem on the entire network but assume an approximative model representing the control capabilities of network stations. Aside from a new description of the compression capabilities, we introduce an algorithm that uses a combination of sequential mixed-integer programming, two heuristics based on reduced time horizons, and a specialized dynamic branch-and-bound node limit to determine promising values for the binary variables of the model. Complete solutions for the problem are obtained by fixing the binary values and solving the remaining non-linear program. Both algorithms are investigated in extensive empirical studies based on real-world instances of the corresponding model variants.

Description: Diese Arbeit behandelt das Optimierungsproblem der transienten Gasnetzwerksteuerung von Fernleitungsnetzen auf dem Festland mit einer großen Anzahl möglicher Gastransportrouten. Die Eingabedaten bestehen aus der Netzwerktopologie, dem Anfangszustand des Netzes und zukünftigen Vorgaben an den Randknoten des Netzes, welche den Gaseinfluss und Gasausfluss sowie eine potenzielle Vorgabe von Druckwerten umfassen. Gegeben diese Daten besteht die Aufgabe besteht darin, eine Menge an zukünftigen Steuerungsentscheidungen für alle aktiven, also steuerbaren, Elemente des Netzes zu finden, sodass eine Kombination von Straffunktionen minimiert wird. Das Problem wird in dieser Arbeit im Rahmen der Erstellung eines entscheidungsunterstützenden Systems für Dispatcher betrachtet, welche das Gasnetz steuern. Dies resultiert in einer detaillierten Modellierung mit einer Vielzahl von Nebenbedingungen, großen und herausfordernden realistischen Instanzen sowie anspruchsvollen Vorgaben zur maximalen Laufzeit. Diese Eigenschaften erhöhen die Komplexität des Problems, welches bereits in der Theorie auf Grund der inhärenten Kombination von nichtlinearen und kombinatorischen Aspekten schwierig zu lösen ist. Die Beiträge dieser Arbeit betreffen verschiedene Schritte des Prozesses zur Lösung des Problems. Bezüglich der Modellformulierung werden zwei übliche Approximationen der Gasflussbeschreibung in Fernleitungsrohren auf Validität überprüft: die Vernachlässigung des Trägheitsterms und die Annahme einer linearisierten Beschreibung des Reibungsterms. Für beide Approximationen wird untersucht, ob sie für reale Gasflussbedingungen zulässig sind. Dazu wird eine große Anzahl historischer Netzzustandsdaten des Gasnetzbetreibers Open Grid Europe ausgewertet. Während bestätigt werden kann, dass eine Vernachlässigung des Trägheitsterms unter Realbedingungen angemessen ist, führt die Linearisierung des Reibungsterms zu signifikanten Fehlern und kann daher nicht für die allgemeine Beschreibung des Gasflusses in Fernleitungsrohren verwendet werden. In einem weiteren Teil dieser Arbeit wird das Konzept der Sollwerte eingeführt. Mit diesen ist eine realistischere Beschreibung der Steuerungsbefehle möglich, welche den Dispatchern für Regler und Verdichterstationen zur Verfügung stehen. Der Sollwertmechanismus wird basierend auf den Gasflussprinzipien in Rohrleitungen hergeleitet, um anschließend ein gemischt-ganzzahliges Programm zu entwickeln, welches das entsprechende Verhalten erzeugt. Die Präzision dieses Modells wird durch einen Vergleich mit einem Simulator von Industriestandard sichergestellt, welcher auf Sollwerten basiert. Außerdem werden zwei Heuristiken für das Optimierungsproblem der transienten Gasnetzwerksteuerung mit Sollwertmodellierung vorgestellt. Diese basieren auf approximativen Modellen für die Sollwertsteuerung und ermitteln die letztendlichen Steuerungsentscheidungen in einer nachgelagerten Routine. Basierend auf künstlich erzeugten Testinstanzen werden die Heuristiken schließlich mit dem direkten Lösen des entsprechenden Modells verglichen. Zudem werden in dieser Arbeit problemspezifische Algorithmen für zwei Varianten des beschriebenen Optimierungsproblems entwickelt. Die erste Variante betrachtet das Gasnetzwerksteuerungsproblem beschränkt auf eine einzelne Netzstation, die lokale Betriebsstellen darstellen und über eine Vielzahl an aktiven Steuerungselementen verfügen. Das entsprechende transiente Modell ist sehr detailliert und beinhaltet eine differenzierte Beschreibung der Verdichterstationen. Der problemspezifische Algorithmus basiert auf der Kürze der Rohre innerhalb der Station und findet zulässige Lösungen durch das Lösen von stationären Varianten des Modells sowie der Nutzung eines transienten Rolling-Horizon Ansatzes. In der zweiten Problemvariante wird das gesamte Gasnetz betrachtet, wobei eine vereinfachte Modellierung der Steuerungsmöglichkeiten innerhalb von Netzstationen angenommen wird. Neben einer neuen Beschreibung der Verdichtungsmöglichkeiten einer Station wird ebenfalls ein problemspezifischer Algorithmus entwickelt. Dieser erstellt aussichtsreiche Werte für die Binärvariablen und nutzt dafür eine Kombination aus sequenzieller gemischt-ganzzahliger Programmierung, zwei auf verkürzten Zeithorizonten basierenden Heuristiken und eine spezialisierte dynamische Obergrenze für die Anzahl der Branch-and-Bound-Knoten. Diese Teillösungen werden durch eine Fixierung der binären Variablen und das anschließende Lösen des restlichen nichtlinearen Programms komplettiert. Die Güte beider Algorithmen wird in umfangreichen empirischen Experimenten untersucht, welche reale Instanzen der jeweiligen Problemvarianten betrachten.

Description: The concept of shape correspondence describes a relation between two or more shapes of the same class. It often consists of a mapping between points on semantically similar locations of all shapes. One possible application for shape correspondence in medicine is the automatic location of anatomical landmarks. Another popular application is the construction of statistical shape models. These models are an established way to represent geometric variation of anatomical shapes in a compact way. Possible applications range from the generation of shapes and reconstruction tasks to disease classification. This thesis aims to investigate unsupervised methods that can be used to estimate such a correspondence on anatomical shapes. While most methods used in the medical domain focus on classical optimization algorithms to establish correspondence, the broader computer vision domain developed a versatile field of data-driven methods. Recently, the new shape model FlowSSM was introduced, which does not require predefined correspondences for training as it generates them itself. As the performance of the shape model is quite competitive, it is natural to assume that the generated correspondences are of high quality as well. For this reason, we evaluate the quality of the correspondences generated by FlowSSM within this thesis. Furthermore, we modify the method by adding a second loss term that minimizes geodesic distortions. This is done to favor isometric deformations which can lead to better correspondences. We compare the results with two established methods from the medical domain, LDDMM and Meshmonk. Furthermore, we investigate the performance of a fourth method called Neuromoph. This data-driven method comes from the wider computer vision field and was not tested on anatomical data yet. All methods are evaluated with a set of different metrics. This includes metrics to assess the quality of the resulting meshes, a sparse correspondence error on anatomical landmarks, and metrics to measure the quality of the resulting shape models. Furthermore, we test all methods on three datasets with different degrees of geometric variation, namely liver, distal femur and face. We show that FlowSSM produces correspondences with state-of-the-art quality. Moreover, our modification further improved the quality of correspondences at a global level. Nevertheless, there is no clear ranking between all methods, as the results differ between metrics and datasets. Thereby, we can show that there are different qualities to a proper correspondence which are reflected in the different metrics. It is therefore strongly recommendable to choose a correspondence estimation method specifically for the problem at hand.

Description: Das Konzept der Formkorrespondenz zwischen 3D-Objekten einer Klasse beschreibt eine Beziehung zwischen den Instanzen (oft Punkten) der unterschiedlichen Objekten. Hierbei werden Punkte, die an semantisch gleichwertigen Orten liegen, miteinander in Verbindung gebracht. Eine mögliche Anwednung der Formkorrespondenz im medizinischen Bereich ist daher die automatisierte Lokalisierung von anatomischen Landmarken. Eine weitere Anwendung ist das Erstellen von statistischen Formmodellen. Mit diesen kann die geometrische Variation anatomischer Formen kompakt abgebildet werden. Medizinische Anwendungen reichen dabei von der einfachen Formgenerierung zu komplexeren Rekonstruktionsaufgaben und der Klassifizierung von gesunden und pathologischen Formen. In dieser Arbeit werden unterschiedliche Methoden zur Erzeugung von Formkorrespondenzen untersucht. Die entsprechende Literatur im medizinischen Bereich verwendet hierzu meist Methoden, die das klassische Optimierungsproblem einer nichtrigiden Transformation lösen. Im Computer Vision Bereich wurden in den letzten Jahren auch einige datengetriebene Methoden zur Korrespondenzgenerierung veröffentlicht. Im letzten Jahr wurde außerdem die Methode FlowSSM zur Erstellung statistischer Formmodelle vorgestellt, die nicht auf korrespondierenden Oberflächen basiert, sondern diese selbst erzeugt. Da FlowSSM trotzdem konkurenzfähige Ergebnisse erzielt, ist naheliegend, dass auch die zugrundeliegenden, selbst generierten Korrespondenzen von hoher Qualität sind. Innerhalb dieser Arbeit wird daher die Qualität der von FlowSSM erzeugten Korrespondenzen evaluiert. Außerdem wird die Methode um eine zusätzliche Kostenfunktion erweitert, die geod#tische Verzerrungen verhindern soll. Dadurch sollen nichtisometrische Deformationen vermieden werden, wodurch die Qualität der resultierenden Korrenspondenzen gesteigert werden kann. Die Ergebnisse von FlowSSM werden mit zwei etablierten Methoden aus dem medizinischen Bereich, LDDMM und Meshmonk, verglichen. Außerdem wird NeuroMorph, eine aktuelle, datengetriebene Methode aus dem Bereich des maschinellen Sehens getestet. Letztere wurde bisher noch nicht auf medizinischen Daten evaluiert. Die Bewertung aller generierten Korrespondenzen basiert auf ausgewählten indirekten Metriken. Hierzu gehört auch die Performance bei konkreten Anwendungsfällen wie der Lokalisierung von Landmarken und dem Erstellen von statistischen Formmodellen. Im Rahmen der Arbeit wird gezeigt, dass FlowSSM Korrespondenzen produziert, deren Qualität dem aktuellen State-of-the-art entspricht. Durch das Hinzufügen der zweiten Kostenfunktion wird die Qualität der Korrespondenzen auf einem globalen Level noch weiter gesteigert. Prinzipiell lässt sich jedoch keine Hierarchie zwischen den Methoden ableiten, da die Performance stark innerhalb der untersuchten Metriken und Datensätzen schwankt. Die Auswahl einer passenden Methode sollte sich daher vor allem am Anwendungsfall orientieren.

Description: The Periodic Event Scheduling Problem (PESP) is the central mathematical tool for periodic timetable optimization in public transport. PESP can be formulated in several ways as a mixed-integer linear program with typically general integer variables. We investigate the split closure of these formulations and show that split inequalities are identical with the recently introduced flip inequalities. While split inequalities are a general mixed-integer programming technique, flip inequalities are defined in purely combinatorial terms, namely cycles and arc sets of the digraph underlying the PESP instance. It is known that flip inequalities can be separated in pseudo-polynomial time. We prove that this is best possible unless P $=$ NP, but also observe that the complexity becomes linear-time if the cycle defining the flip inequality is fixed. Moreover, introducing mixed-integer-compatible maps, we compare the split closures of different formulations, and show that reformulation or binarization by subdivision do not lead to stronger split closures. Finally, we estimate computationally how much of the optimality gap of the instances of the benchmark library PESPlib can be closed exclusively by split cuts, and provide better dual bounds for five instances.

Description: Solving high-dimensional partial differential equations is a recurrent challenge in economics, science and engineering. In recent years, a great number of computational approaches have been developed, most of them relying on a combination of Monte Carlo sampling and deep learning based approximation. For elliptic and parabolic problems, existing methods can broadly be classified into those resting on reformulations in terms of backward stochastic differential equations (BSDEs) and those aiming to minimize a regression-type L2-error (physics-informed neural networks, PINNs). In this paper, we review the literature and suggest a methodology based on the novel diffusion loss that interpolates between BSDEs and PINNs. Our contribution opens the door towards a unified understanding of numerical approaches for high-dimensional PDEs, as well as for implementations that combine the strengths of BSDEs and PINNs. The diffusion loss furthermore bears close similarities to (least squares) temporal difference objectives found in reinforcement learning. We also discuss eigenvalue problems and perform extensive numerical studies, including calculations of the ground state for nonlinear Schr ¨odinger operators and committor functions relevant in molecular dynamics.

Description: Using the recently proposed maximal quadratic-free sets and the well-known monoidal strengthening procedure, we show how to improve inter- section cuts for quadratically-constrained optimization problems by exploiting integrality requirements. We provide an explicit construction that allows an efficient implementation of the strengthened cuts along with computational results showing their improvements over the standard intersection cuts. We also show that, in our setting, there is unique lifting which implies that our strengthening procedure is generating the best possible cut coefficients for the integer variables.

Description: In this article, we propose a deep learning-based algorithm for the classification of crop types from Sentinel-1 and Sentinel-2 time series data which is based on the celebrated transformer architecture. Crucially, we enable our algorithm to do early classification, i.e., predict crop types at arbitrary time points early in the year with a single trained model (progressive intra-season classification). Such early season predictions are of practical relevance for instance for yield forecasts or the modeling of agricultural water balances, therefore being important for the public as well as the private sector. Furthermore, we improve the mechanism of combining different data sources for the prediction task, allowing for both optical and radar data as inputs (multi-modal data fusion) without the need for temporal interpolation. We can demonstrate the effectiveness of our approach on an extensive data set from three federal states of Germany reaching an average F1 score of 0.92 using data of a complete growing season to predict the eight most important crop types and an F1 score above 0.8 when doing early classification at least one month before harvest time. In carefully chosen experiments, we can show that our model generalizes well in time and space.

Description: Recently, a series of papers proposed deep learning-based approaches to sample from unnormalized target densities using controlled diffusion processes. In this work, we identify these approaches as special cases of the Schrödinger bridge problem, seeking the most likely stochastic evolution between a given prior distribution and the specified target. We further generalize this framework by introducing a variational formulation based on divergences between path space measures of time-reversed diffusion processes. This abstract perspective leads to practical losses that can be optimized by gradient-based algorithms and includes previous objectives as special cases. At the same time, it allows us to consider divergences other than the reverse Kullback-Leibler divergence that is known to suffer from mode collapse. In particular, we propose the so-called log-variance loss, which exhibits favorable numerical properties and leads to significantly improved performance across all considered approaches.

Description: This Package implements a variation of the Voronoi Graph Traversal algorithm by Polianskii and Pokorny [1]. It constructs a Voronoi Diagram from a set of points by performing a random walk on the graph of the vertices of the diagram. Unlike many other Voronoi implementations this algorithm is not limited to 2 or 3 dimensions and promises good performance even in higher dimensions.

Description: The optical inspection of the surfaces of diode lasers, especially the p-sides and facets, is an essential part of the quality control in the laser fabrication procedure. With reliable, fast, and flexible optical inspection processes, it is possible to identify and eliminate defects, accelerate device selection, reduce production costs, and shorten the cycle time for product development. Due to a vast range of rapidly changing designs, structures, and coatings, however, it is impossible to realize a practical inspection with conventional software. In this work, we therefore suggest a deep learning based defect detection algorithm that builds on a Faster Regional Convolutional Neural Network (Faster R-CNN) as a core component. While for related, more general object detection problems, the application of such models is straightforward, it turns out that our task exhibits some additional challenges. On the one hand, a sophisticated pre- and postprocessing of the data has to be deployed to make the application of the deep learning model feasible. On the other hand, we find that creating labeled training data is not a trivial task in our scenario, and one has to be extra careful with model evaluation. We can demonstrate in multiple empirical assessments that our algorithm can detect defects in diode lasers accurately and reliably in most cases. We analyze the results of our production-ready pipeline in detail, discuss its limitations and provide some proposals for further improvements.

Description: The Feasibility Pump (FP) is one of the best-known primal heuristics for mixed-integer programming (MIP): more than 15 papers suggested various modifications of all of its steps. So far, no variant considered information across multiple iterations, but all instead maintained the principle to optimize towards a single reference integer point. In this paper, we evaluate the usage of multiple reference vectors in all stages of the FP algorithm. In particular, we use LP-feasible vectors obtained during the main loop to tighten the variable domains before entering the computationally expensive enumeration stage. Moreover, we consider multiple integer reference vectors to explore further optimizing directions and introduce alternative objective scaling terms to balance the contributions of the distance functions and the original MIP objective. Our computational experiments demonstrate that the new method can improve performance on general MIP test sets. In detail, our modifications provide a 29.3% solution quality improvement and 4.0% running time improvement in an embedded setting, needing 16.0% fewer iterations over a large test set of MIP instances. In addition, the method’s success rate increases considerably within the first few iterations. In a standalone setting, we also observe a moderate performance improvement, which makes our version of FP suitable for the two main use-cases of the algorithm.

Description: We present a fully computer-assisted proof system for solving a particular family of problems in Extremal Combinatorics. Existing techniques using Flag Algebras have proven powerful in the past, but have so far lacked a computational counterpart to derive matching constructive bounds. We demonstrate that common search heuristics are capable of finding constructions far beyond the reach of human intuition. Additionally, the most obvious downside of such heuristics, namely a missing guarantee of global optimality, can often be fully eliminated in this case through lower bounds and stability results coming from the Flag Algebra approach. To illustrate the potential of this approach, we study two related and well-known problems in Extremal Graph Theory that go back to questions of Erdős from the 60s. Most notably, we present the first major improvement in the upper bound of the Ramsey multiplicity of the complete graph on 4 vertices in 25 years, precisely determine the first off-diagonal Ramsey multiplicity number, and settle the minimum number of independent sets of size four in graphs with clique number strictly less than five.

Description: Fibrotic tissue is one of the main risk factors for cardiac arrhythmias. It is therefore a key component in computational studies. In this work, we compare the monodomain equation to two eikonal models for cardiac electrophysiology in the presence of fibrosis. We show that discontinuities in the conductivity field, due to the presence of fibrosis, introduce a delay in the activation times. The monodomain equation and eikonal-diffusion model correctly capture these delays, contrarily to the classical eikonal equation. Importantly, a coarse space discretization of the monodomain equation amplifies these delays, even after accounting for numerical error in conduction velocity. The numerical discretization may also introduce artificial conduction blocks and hence increase propagation complexity. Therefore, some care is required when comparing eikonal models to the discretized monodomain equation.

Description: The maximum-cut problem is one of the fundamental problems in combinatorial optimization. With the advent of quantum computers, both the maximum-cut and the equivalent quadratic unconstrained binary optimization problem have experienced much interest in recent years. This article aims to advance the state of the art in the exact solution of both problems—by using mathematical programming techniques. The main focus lies on sparse problem instances, although also dense ones can be solved. We enhance several algorithmic components such as reduction techniques and cutting-plane separation algorithms, and combine them in an exact branch-and-cut solver. Furthermore, we provide a parallel implementation. The new solver is shown to significantly outperform existing state-of-the-art software for sparse maximum-cut and quadratic unconstrained binary optimization instances. Furthermore, we improve the best known bounds for several instances from the 7th DIMACS Challenge and the QPLIB, and solve some of them (for the first time) to optimality.

Description: Cutting plane selection is a subroutine used in all modern mixed-integer linear programming solvers with the goal of selecting a subset of generated cuts that induce optimal solver performance. These solvers have millions of parameter combinations, and so are excellent candidates for parameter tuning. Cut selection scoring rules are usually weighted sums of different measurements, where the weights are parameters. We present a parametric family of mixed-integer linear programs together with infinitely many family-wide valid cuts. Some of these cuts can induce integer optimal solutions directly after being applied, while others fail to do so even if an infinite amount are applied. We show for a specific cut selection rule, that any finite grid search of the parameter space will always miss all parameter values, which select integer optimal inducing cuts in an infinite amount of our problems. We propose a variation on the design of existing graph convolutional neural networks, adapting them to learn cut selection rule parameters. We present a reinforcement learning framework for selecting cuts, and train our design using said framework over MIPLIB 2017 and a neural network verification data set. Our framework and design show that adaptive cut selection does substantially improve performance over a diverse set of instances, but that finding a single function describing such a rule is difficult. Code for reproducing all experiments is available at https://github.com/Opt-Mucca/Adaptive-Cutsel-MILP.

Description: Concrete plays a central role as the standard building material in civil engineering. Experimental characterization of the concrete microstructure and a description of failure mechanisms are important to understand the concrete’s mechanical properties. Computed tomography is a powerful source of information as it yields 3d images of concrete specimens. However, complete visual inspection is often infeasible due to very large image sizes. Hence, automatic methods for crack detection and segmentation are needed. A region-growing algorithm and a 3d U-Net showed promising results in a previous study. Cracks in normal concrete and high-performance concrete that were initiated via tensile tests were investigated. Here, the methods are validated on a more diverse set of concrete types and crack characteristics. Adequate adaptions of the methods are necessary to deal with the complex crack structures. The segmentation results are assessed qualitatively and compared to those of a template matching algorithm which is well-established in industry.

Description: Data are often subject to some degree of uncertainty, whether aleatory or epistemic. This applies both to experimental data acquired with sensors as well as to simulation data. Displaying these data and their uncertainty faithfully is crucial for gaining knowledge. Specifically, the effective communication of the uncertainty can influence the interpretation of the data and the user’s trust in the visualization. However, uncertainty-aware visualization has gotten little attention in molecular visualization. When using the established molecular representations, the physicochemical attributes of the molecular data usually already occupy the common visual channels like shape, size, and color. Consequently, to encode uncertainty information, we need to open up another channel by using feature lines. Even though various line variables have been proposed for uncertainty visualizations, they have so far been primarily used for two-dimensional data and there has been little perceptual evaluation. Thus, we conducted two perceptual studies to determine the suitability of the line variables blur, dashing, grayscale, sketchiness, and width for distinguishing several values in molecular visualizations. While our work was motivated by uncertainty visualization, our techniques and study results also apply to other types of scalar data.

Description: Mixed-integer linear programming (MILP) plays a crucial role in the field of mathematical optimization and is especially relevant for practical applications due to the broad range of problems that can be modeled in that fashion. The vast majority of MILP solvers employ the LP-based branch-and-cut approach. As the name suggests, the linear programming (LP) subproblems that need to be solved therein influence their behavior and performance significantly. This thesis explores the impact of various LP solvers as well as LP solving techniques on the constraint integer programming framework SCIP Optimization Suite. SCIP allows for comparisons between academic and open-source LP solvers like Clp and SoPlex, as well as commercially developed, high-end codes like CPLEX, Gurobi, and Xpress. We investigate how the overall performance and stability of an MILP solver can be improved by new algorithmic enhancements like LP solution polishing and persistent scaling that we have implemented in the LP solver SoPlex. The former decreases the fractionality of LP solutions by selecting another vertex on the optimal hyperplane of the LP relaxation, exploiting degeneracy. The latter provides better numerical properties for the LP solver throughout the MILP solving process by preserving and extending the initial scaling factors, effectively also improving the overall performance of SCIP. Both enhancement techniques are activated by default in the SCIP Optimization Suite. Additionally, we provide an analysis of numerical conditions in SCIP through the lens of the LP solver by comparing different measures and how these evolve during the different stages of the solving process. A side effect of our work on this topic was the development of TreeD: a new and convenient way of presenting the search tree interactively and animated in the three-dimensional space. This visualization technique facilitates a better understanding of the MILP solving process of SCIP. Furthermore, this thesis presents the various algorithmic techniques like the row representation and iterative refinement that are implemented in SoPlex and that distinguish the solver from other simplex-based codes. Although it is often not as performant as its competitors, SoPlex demonstrates the ongoing research efforts in the field of linear programming with the simplex method. Aside from that, we demonstrate the rapid prototyping of algorithmic ideas and modeling approaches via PySCIPOpt, the Python interface to the SCIP Optimization Suite. This tool allows for convenient access to SCIP's internal data structures from the user-friendly Python programming language to implement custom algorithms and extensions without any prior knowledge of SCIP's programming language C. TreeD is one such example, demonstrating the use of several Python libraries on top of SCIP. PySCIPOpt also provides an intuitive modeling layer to formulate problems directly in the code without having to utilize another modeling language or framework. All contributions presented in this thesis are readily accessible in source code in SCIP Optimization Suite or as separate projects on the public code-sharing platform GitHub.

Description: It has recently been shown that ISTA, an unaccelerated optimization method, presents sparse updates for the ℓ1-regularized undirected personalized PageRank problem (Fountoulakis et al., 2019), leading to cheap iteration complexity and providing the same guarantees as the approximate personalized PageRank algorithm (APPR) (Andersen et al., 2006). In this work, we design an accelerated optimization algorithm for this problem that also performs sparse updates, providing an affirmative answer to the COLT 2022 open question of Fountoulakis and Yang (2022). Acceleration provides a reduced dependence on the condition number, while the dependence on the sparsity in our updates differs from the ISTA approach. Further, we design another algorithm by using conjugate directions to achieve an exact solution while exploiting sparsity. Both algorithms lead to faster convergence for certain parameter regimes. Our findings apply beyond PageRank and work for any quadratic objective whose Hessian is a positive-definite 푀-matrix.

Description: Small ring nitrogen heterocycles, azabicyclobutanes and azirines, were investigated by computational methods in order to address the discrepancy between their regioisomers 1- and 2-azabicyclobutane and 1H- and 2H-azirines. Both 1-azabicyclobutane and 2H-azirine are well known synthetic starting points to larger nitrogen heterocycles whereas 2-azabicyclobutane and 1H-azirine and their derivatives have yet to be reported as isolable compounds. Calculated parameters such as structure, base strength (proton affinities), NICS values and enthalpies of formation from which strain energies are derived are reported. The destabilization of the less stable regioisomers is attributed to homoantiaromaticity in 2-azabicyclobutane and antiaromaticity in 1H-azirine. Two stereoisomers exist for 2-azabicyclobutane with the endo- stereoisomer being more stable. This phenomenon is indicative of the hydrogen bond acceptor properties of the neighboring cyclpropane and the π-bond character of the central bond in 2-azabicyclobutane.

Description: It is important to design multi-energy supply systems optimally in consideration of their operations for variations in energy demands. An approach for efficiently solving such an optimal design problem with a large number of periods for variations in energy demands is to derive an approximate optimal design solution by time series aggregation. However, such an approach does not provide any information on the accuracy for the optimal value of the objective function. In this paper, an effective approach for time series aggregation is proposed to derive an approximate optimal design solution and evaluate a proper gap between the upper and lower bounds for the optimal value of the objective function based on a mixed-integer linear model. In accordance with aggregation, energy demands are relaxed to uncertain parameters and the problem for deriving an approximate optimal design solution and evaluating it is transformed to a three-level optimization problem, and it is solved by applying both the robust and hierarchical optimization methods. A case study is conducted on a cogeneration system with a practical configuration, and it turns out that the proposed approach enables one to derive much smaller gaps as compared with those obtained by a conventional approach.

Description: We propose a globally-accelerated, first-order method for the optimization of smooth and (strongly or not) geodesically-convex functions in a wide class of Hadamard manifolds. We achieve the same convergence rates as Nesterov’s accelerated gradient descent, up to a multiplicative geometric penalty and log factors. Crucially, we can enforce our method to stay within a compact set we define. Prior fully accelerated works \emph{resort to assuming} that the iterates of their algorithms stay in some pre-specified compact set, except for two previous methods of limited applicability. For our manifolds, this solves the open question in (Kim and Yang, 2022) about obtaining global general acceleration without iterates assumptively staying in the feasible set.In our solution, we design an accelerated Riemannian inexact proximal point algorithm, which is a result that was unknown even with exact access to the proximal operator, and is of independent interest. For smooth functions, we show we can implement the prox step inexactly with first-order methods in Riemannian balls of certain diameter that is enough for global accelerated optimization.

Description: Due to the current and foreseeable shifts towards carbon dioxide neutral energy production, which will likely result in balancing fluctuating renewable energy generation by transforming power-to-gas-to-power as well as building a large-scale hydrogen transport infrastructure, the trading and transport operations of gas will become more dynamic, volatile, and hence also less predictable. Therefore, computer-aided support in terms of rapid simulation and control optimization will further broaden its importance for gas network dispatching. In this paper, we aim to contribute and openly publish two new mathematical models for regulators, also referred to as control valves, which together with compressors make up the most complex and involved types of active elements in gas network infrastructures. They provide direct control over gas networks but are in turn controlled via target values, also known as set-point values, themselves. Our models incorporate up to six dynamical target values to define desired transient states for the elements' local vicinity within the network. That is, each pair of every two target values defines a bounding box for the inlet pressure, outlet pressure as well as the passing mass flow of gas. In the proposed models, those target values are prioritized differently and are constantly in competition with each other, which can only be resolved dynamically at run-time of either a simulation or optimization process. Besides careful derivation, we compare simulation and optimization results with predictions of the widely adopted commercial simulation tool SIMONE, serving as our substitute for actual real-world transport operations.

Description: Tooth enamel is the hardest tissue in human organism, formed by prism layers in regularly alternating directions. These prisms form the Hunter-Schreger Bands (HSB) pattern when under side illumination, which is composed of light and dark stripes resembling fingerprints. We have shown in previous works that HSB pattern is highly variable, seems to be unique for each tooth and can be used as a biometric method for human identification. Since this pattern cannot be acquired with sensors, the HSB region in the digital photograph must be identified and correctly segmented from the rest of the tooth and background. Although these areas can be manually removed, this process is not reliable as excluded areas can vary according to the individual‘s subjective impression. Therefore, the aim of this work was to develop an algorithm that automatically selects the region of interest (ROI), thus, making the entire biometric process straightforward. We used two different approaches: a classical image processing method which we called anisotropy-based segmentation (ABS) and a machine learning method known as U-Net, a fully convolutional neural network. Both approaches were applied to a set of extracted tooth images. U-Net with some post processing outperformed ABS in the segmentation task with an Intersection Over Union (IOU) of 0.837 against 0.766. Even with a small dataset, U-Net proved to be a potential candidate for fully automated in-mouth application. However, the ABS technique has several parameters which allow a more flexible segmentation with interactive adjustments specific to image properties.

Description: Classic models to derive a timetable for public transport often face a chicken-and-egg situation: A good timetable should offer passengers routes with small travel times, but the route choice of passengers depends on the timetable. While models that fix passenger routes were frequently considered in the literature, integrated models that simultaneously optimize timetables and passenger routes have seen increasing attention lately. This creates a growing need for a set of instances that allows to test and compare new algorithmic developments for the integrated problem. Our paper addresses this requirement by presenting TimPassLib, a new benchmark library of instances for integrated periodic timetabling and passenger routing.

Description: Manual processing of tomographic data volumes, such as interactive image segmentation in medicine or paleontology, is considered a time-consuming and cumbersome endeavor. Immersive volume sculpting stands as a potential solution to improve its efficiency and intuitiveness. However, current open-source software solutions do not yield the required performance and functionalities. We address this issue by contributing a novel open-source game engine voxel library that supports real-time immersive volume sculpting. Our design leverages GPU instancing, parallel computing, and a chunk-based data structure to optimize collision detection and rendering. We have implemented features that enable fast voxel interaction and improve precision. Our benchmark evaluation indicates that our implementation offers a significant improvement over the state-of-the-art and can render and modify millions of visible voxels while maintaining stable performance for real-time interaction in virtual reality.

Description: We consider maintenance sites for urban rail systems, where unavailable tracks typically require changes to the regular timetable, and often even to the line plan. In this paper, we present an integrated mixed-integer linear optimization model to compute an optimal line plan that makes best use of the available tracks, together with a periodic timetable, including its detailed routing on the tracks within the stations. The key component is a flexible, turn-sensitive event-activity network that allows to integrate line planning and train routing using a track choice extension of the Periodic Event Scheduling Problem (PESP). Major goals are to maintain as much of the regular service as possible, and to keep the necessary changes rather local. Moreover, we present computational results on real construction site scenarios on the S-Bahn Berlin network. We demonstrate that this integrated problem is indeed solvable on practically relevant instances.

Description: Periodic timetabling for highly utilized railway networks is a demanding challenge. We formulate an infrastructure-aware extension of the Periodic Event Scheduling Problem (PESP) by requiring that not only events, but also activities using the same infrastructure must be separated by a minimum headway time. This extended problem can be modeled as a mixed-integer program by adding constraints on the sum of periodic tensions along certain cycles, so that it shares some structural properties with standard PESP. We further refine this problem by fixing cyclic orders at each infrastructure element. Although the computational complexity remains unchanged, the mixed-integer programming model then becomes much smaller. Furthermore, we also discuss how to find a minimal subset of infrastructure elements whose cyclic order already prescribes the order for the remaining parts of the network, and how cyclic order information can be modeled in a mixed-integer programming context. In practice, we evaluate the impact of cyclic orders on a real-world instance on the S-Bahn Berlin network, which turns out to be computationally fruitful.

Description: The ongoing electrification of logistics systems and vehicle fleets increases the complexity of associated vehicle routing or scheduling problems. Battery-powered vehicles have to be scheduled to recharge in-service, and the relationship between charging time and replenished driving range is non-linear. In order to access the powerful toolkit offered by mixed-integer and linear programming techniques, this battery behavior has to be linearized. Moreover, as electric fleets grow, power draw peaks have to be avoided to save on electricity costs or to adhere to hard grid capacity limits, such that it becomes desirable to keep recharge rates dynamic. We suggest a novel linearization approach of battery charging behavior for vehicle scheduling problems, in which the recharge rates are optimization variables and not model parameters.

Description: In optical nano metrology numerical models are used widely for parameter reconstructions. Using the Bayesian target vector optimization method we fit a finite element numerical model to a Grazing Incidence x-ray fluorescence data set in order to obtain the geometrical parameters of a nano structured line grating. Gaussian process, stochastic machine learning surrogate models, were trained during the reconstruction and afterwards sampled with a Markov chain Monte Carlo sampler to determine the distribution of the reconstructed model parameters. The numerical discretization parameters of the used finite element model impact the numerical discretization error of the forward model. We investigated the impact of the polynomial order of the finite element ansatz functions on the reconstructed parameters as well as on the model parameter distributions. We showed that such a convergence study allows to determine numerical parameters which allows for efficient and accurate reconstruction results.

Description: Purpose: To investigate the influence of teeth and dental restorations on the facial skeleton's gray value distributions in cone-beam computed tomography (CBCT). Methods: Gray value selection for the upper and lower jaw segmentation was performed in 40 patients. In total, CBCT data of 20 maxillae and 20 mandibles, ten partial edentulous and ten fully edentulous in each jaw, respectively, were evaluated using two different gray value selection procedures: manual lower threshold selection and automated lower threshold selection. Two sample t tests, linear regression models, linear mixed models, and Pearson's correlation coefficients were computed to evaluate the influence of teeth, dental restorations, and threshold selection procedures on gray value distributions. Results: Manual threshold selection resulted in significantly different gray values in the fully and partially edentulous mandible. (p = 0.015, difference 123). In automated threshold selection, only tendencies to different gray values in fully edentulous compared to partially edentulous jaws were observed (difference: 58–75). Significantly different gray values were evaluated for threshold selection approaches, independent of the dental situation of the analyzed jaw. No significant correlation between the number of teeth and gray values was assessed, but a trend towards higher gray values in patients with more teeth was noted. Conclusions: Standard gray values derived from CT imaging do not apply for threshold-based bone segmentation in CBCT. Teeth influence gray values and segmentation results. Inaccurate bone segmentation may result in ill-fitting surgical guides produced on CBCT data and misinterpreting bone density, which is crucial for selecting surgical protocols.

Description: Testing for significant differences in quantities at the protein level is a common goal of many LFQ-based mass spectrometry proteomics experiments. Starting from a table of protein and/or peptide quantities from a given proteomics quantification software, many tools and R packages exist to perform the final tasks of imputation, summarization, normalization, and statistical testing. To evaluate the effects of packages and settings in their substeps on the final list of significant proteins, we studied several packages on three public data sets with known expected protein fold changes. We found that the results between packages and even across different parameters of the same package can vary significantly. In addition to usability aspects and feature/compatibility lists of different packages, this paper highlights sensitivity and specificity trade-offs that come with specific packages and settings.

Description: Modern Deep Neural Networks are getting wider and deeper in their architecture design. However, with an increasing number of parameters the decision mechanisms becomes more opaque. Therefore, there is a need for understanding the structures arising in the hidden layers of deep neural networks. In this work, we present a new mathematical framework for describing the canonical polyhedral decomposition in the input space, and in addition, we introduce the notions of collapsing- and preserving patches, pertinent to understanding the forward map and the activation space they induce. The activation space can be seen as the output of a layer and, in the particular case of ReLU activations, we prove that this output has the structure of a polyhedral complex.

Description: The optimization of periodic timetables is an indispensable planning task in public transport. Although the periodic event scheduling problem (PESP) provides an elegant mathematical formulation of the periodic timetabling problem that led to many insights for primal heuristics, it is notoriously hard to solve to optimality. One reason is that for the standard mixed-integer linear programming formulations, linear programming relaxations are weak, and the integer variables are of pure technical nature and in general do not correlate with the objective value. While the first problem has been addressed by developing several families of cutting planes, we focus on the second aspect. We discuss integral forward cycle bases as a concept to compute improved dual bounds for PESP instances. To this end, we develop the theory of forward cycle bases on general digraphs. Specifically for the application of timetabling, we devise a generic procedure to construct line-based event-activity networks and give a simple recipe for an integral forward cycle basis on such networks. Finally, we analyze the 16 railway instances of the benchmark library PESPlib, match them to the line-based structure, and use forward cycle bases to compute better dual bounds for 14 out of the 16 instances.

Description: Since the beginning of this millennium, the advent of high-throughput methods in numerous fields of the life sciences led to a shift in paradigms. A broad variety of technologies emerged that allow comprehensive quantification of molecules involved in biological processes. Simultaneously, a major increase in data volume has been recorded with these techniques through enhanced instrumentation and other technical advances. By supplying computational methods that automatically process raw data to obtain biological information, the field of bioinformatics plays an increasingly important role in the analysis of the ever-growing mass of data. Computational mass spectrometry in particular, is a bioinformatics field of research which provides means to gather, analyze and visualize data from high-throughput mass spectrometric experiments. For the study of the entirety of proteins in a cell or an environmental sample, even current techniques reach limitations that need to be circumvented by simplifying the samples subjected to the mass spectrometer. These pre-digested (so-called bottom-up) proteomics experiments then pose an even bigger computational burden during analysis since complex ambiguities need to be resolved during protein inference, grouping and quantification. In this thesis, we present several developments in the pursuit of our goal to provide means for a fully automated analysis of complex and large-scale bottom-up proteomics experiments. Firstly, due to prohibitive computational complexities in state-of-the-art Bayesian protein inference techniques, a refined, more stable technique for performing inference on sums of random variables was developed to enable a variation of standard Bayesian inference for the problem. nextflow and part of a set of standardized, well-tested, and community-maintained workflows by the nf-core collective. Our workflow runs on large-scale data with complex experimental designs and allows a one-command analysis of local and publicly available data sets with state-of-the-art accuracy on various high-performance computing environments or the cloud.

Description: Metabolomics experiments generate highly complex datasets, which are time and work-intensive, sometimes even error-prone if inspected manually. Therefore, new methods for automated, fast, reproducible, and accurate data processing and dereplication are required. Here, we present UmetaFlow, a computational workflow for untargeted metabolomics that combines algorithms for data pre-processing, spectral matching, molecular formula and structural predictions, and an integration to the GNPS workflows Feature-Based Molecular Networking and Ion Identity Molecular Networking for downstream analysis. UmetaFlow is implemented as a Snakemake workflow, making it easy to use, scalable, and reproducible. For more interactive computing, visualization, as well as development, the workflow is also implemented in Jupyter notebooks using the Python programming language and a set of Python bindings to the OpenMS algorithms (pyOpenMS). Finally, UmetaFlow is also offered as a web-based Graphical User Interface for parameter optimization and processing of smaller-sized datasets. UmetaFlow was validated with in-house LC–MS/MS datasets of actinomycetes producing known secondary metabolites, as well as commercial standards, and it detected all expected features and accurately annotated 76% of the molecular formulas and 65% of the structures. As a more generic validation, the publicly available MTBLS733 and MTBLS736 datasets were used for benchmarking, and UmetaFlow detected more than 90% of all ground truth features and performed exceptionally well in quantification and discriminating marker selection.

Description: The optimization of periodic timetables is an indispensable planning task in public transport. Although the periodic event scheduling problem (PESP) provides an elegant mathematical formulation of the periodic timetabling problem that led to many insights for primal heuristics, it is notoriously hard to solve to optimality. One reason is that for the standard mixed-integer linear programming formulations, linear programming relaxations are weak and the integer variables are of pure technical nature and in general do not correlate with the objective value. While the first problem has been addressed by developing several families of cutting planes, we focus on the second aspect. We discuss integral forward cycle bases as a concept to compute improved dual bounds for PESP instances. To this end, we develop the theory of forward cycle bases on general digraphs. Specifically for the application of timetabling, we devise a generic procedure to construct line-based event-activity networks, and give a simple recipe for an integral forward cycle basis on such networks. Finally, we analyze the 16 railway instances of the benchmark library PESPlib, match them to the line-based structure and use forward cycle bases to compute better dual bounds for 14 out of the 16 instances.

Description: Sampling rare events in metastable dynamical systems is often a computationally expensive task and one needs to resort to enhanced sampling methods such as importance sampling. Since we can formulate the problem of finding optimal importance sampling controls as a stochastic optimization problem, this then brings additional numerical challenges and the convergence of corresponding algorithms might as well suffer from metastabilty. In this article we address this issue by combining systematic control approaches with the heuristic adaptive metadynamics method. Crucially, we approximate the importance sampling control by a neural network, which makes the algorithm in principle feasible for high dimensional applications. We can numerically demonstrate in relevant metastable problems that our algorithm is more effective than previous attempts and that only the combination of the two approaches leads to a satisfying convergence and therefore to an efficient sampling in certain metastable settings.

Description: Classic models to derive a timetable for public transport often face a chicken-and-egg situation: A good timetable should offer passengers routes with small travel times, but the route choice of passengers depends on the timetable. While models that fix passenger routes were frequently considered in the literature, integrated models that simultaneously optimize timetables and passenger routes have seen increasing attention lately. This creates a growing need for a set of instances that allows to test and compare new algorithmic developments for the integrated problem. Our paper addresses this requirement by presenting TimPassLib, a new benchmark library of instances for integrated periodic timetabling and passenger routing.

Description: The goal of this study was to explore and define the thermodynamic properties of one of the subspaces of ‘chemical space’ using a mixture of graph theory and theoretical chemistry tools. Therefore, all possible mo- lecular structures with C4H8O2 stoichiometry were generated, considering constitutional isomers and molecular complexes. The thermodynamic properties of the obtained isomers have been obtained by G3MP2B3 protocol. The classification of the obtained isomers was simplified by using thermodynamic maps, which is an effective method for the comparison of thermodynamic stability for entities of complex molecular systems. Modern computational methods can be used to understand larger systems, which has made it possible to characterize a chemical subspace not only by selecting individual entities, but also as a whole. With this pro- cedure one can catch a glimpse into the diversity of a molecular system and predict further uses of newly discovered molecules or design molecules with predefined properties.

Description: The currently most popular approach to handle non-linear battery behavior for electric vehicle scheduling is to use a linear spline interpolation of the charge curve. We show that this can lead to approximate models that underestimate the charge duration and overestimate the state of charge, which is not desirable. While the error is of second order with respect to the interpolation step size, the associated mixed-integer linear programs do not scale well with the number of spline segments. It is therefore recommendable to use coarse interpolation grids adapted to the curvature of the charge curve, and to include sufficient safety margins to ensure solutions of approximate models remain feasible subjected to the exact charge curve.

Description: Three-dimensional (3D) imaging, such as micro-computed tomography (micro-CT), is increasingly being used by organismal biologists for precise and comprehensive anatomical characterization. However, the segmentation of anatomical structures remains a bottleneck in research, often requiring tedious manual work. Here, we propose a pipeline for the fully-automated segmentation of anatomical structures in micro-CT images utilizing state-of-the-art deep learning methods, selecting the ant brain as a test case. We implemented the U-Net architecture for 2D image segmentation for our convolutional neural network (CNN), combined with pixel-island detection. For training and validation of the network, we assembled a dataset of semi-manually segmented brain images of 76 ant species. The trained network predicted the brain area in ant images fast and accurately; its performance tested on validation sets showed good agreement between the prediction and the target, scoring 80% Intersection over Union (IoU) and 90% Dice Coefficient (F1) accuracy. While manual segmentation usually takes many hours for each brain, the trained network takes only a few minutes. Furthermore, our network is generalizable for segmenting the whole neural system in full-body scans, and works in tests on distantly related and morphologically divergent insects (e.g., fruit flies). The latter suggests that methods like the one presented here generally apply across diverse taxa. Our method makes the construction of segmented maps and the morphological quantification of different species more efficient and scalable to large datasets, a step toward a big data approach to organismal anatomy.

Description: Rectal temperature measurement (RTM) from crime scenes is an important parameter for temperature-based time of death estimation (TDE). Various influential variables exist in TDE methods like the uncertainty in thermal and environmental parameters. Although RTM depends in particular on the location of measurement position, this relationship has never been investigated separately. The presented study fills this gap using Finite Element (FE) simulations of body cooling. A manually meshed coarse human FE model and an FE geometry model developed from the CT scan of a male corpse are used for TDE sensitivity analysis. The coarse model is considered with and without a support structure of moist soil. As there is no clear definition of ideal rectal temperature measurement location for TDE, possible variations in RTM location (RTML) are considered based on anatomy and forensic practice. The maximum variation of TDE caused by RTML changes is investigated via FE simulation. Moreover, the influence of ambient temperature, of FE model change and of the models positioning on a wet soil underground are also discussed. As a general outcome, we notice that maximum TDE deviations of up to ca. 2-3 h due to RTML deviations have to be expected. The direction of maximum influence of RTML change on TDE generally was on the line caudal to cranial.

Description: We describe a machine learning approach to approximate reaction energy barriers (E), requiring as input only estimates of geometry and energies of reactants and products. Using the dataset of Grambow, Pattanaik, and Green [Sci. Data 7 (1 3 7) (2020)] for reactions involving seven or fewer non-hydrogen atoms, 300 reaction features are computed, and an estimate of E is obtained by fitting a Kernel Ridge Regression (KRR) model with Laplacian kernel to a subset of Density Functional Theory reaction barriers. Our main interest is small energy barriers with the goal of modeling reactions in the interstellar medium and circumstellar envelope. We omitted reactions with E 〉 40 kcal mol−1 to obtain a subset of 5,276 reactions for 5-fold cross-validation. For this set, the KRR model predicts E with a mean absolute error of 4.13 kcal mol−1 and a root-mean square error of 6.02 kcal mol−1.

Description: Crystallization is a complex phenomenon with far-reaching implications for the production and formulation of active pharmaceutical ingredients. Understanding this process is critical for achieving control over key physicochemical properties that can affect, for example, the bioavailability and stability of a drug. In this study, we were able to reveal intricate and diverse dynamics of the formation of metastable intermediates of paracetamol crystallization varying with the choice of solvent. We demonstrate the efficacy of our novel approach utilizing an objective function-based non-negative matrix factorization technique for the analysis of time-resolved Raman spectroscopy data, in conjunction with time-lapse photography. Furthermore, we emphasize the crucial importance of integrating Raman spectroscopy with supplementary experimental instrumentation for the mathematical analysis of the obtained spectra.

Description: The elephant trunk operates as a muscular hydrostat and is actuated by the most complex musculature known in animals. Because the number of trunk muscles is unclear, we performed dense reconstructions of trunk muscle fascicles, elementary muscle units, from microCT scans of an Asian baby elephant trunk. Muscle architecture changes markedly across the trunk. Trunk tip and finger consist of about 8,000 extraordinarily filigree fascicles. The dexterous finger consists exclusively of microscopic radial fascicles pointing to a role of muscle miniaturization in elephant dexterity. Radial fascicles also predominate (at 82% volume) the remainder of the trunk tip and we wonder if radial muscle fascicles are of particular significance for fine motor control of the dexterous trunk tip. By volume, trunk-shaft muscles comprise one-third of the numerous, small radial muscle fascicles, two-thirds of the three subtypes of large longitudinal fascicles (dorsal longitudinals, ventral outer obliques, and ventral inner obliques), and a small fraction of transversal fascicles. Shaft musculature is laterally, but not radially, symmetric. A predominance of dorsal over ventral radial muscles and of ventral over dorsal longitudinal muscles may result in a larger ability of the shaft to extend dorsally than ventrally and to bend inward rather than outward. There are around 90,000 trunk muscle fascicles. While primate hand control is based on fine control of contraction by the convergence of many motor neurons on a small set of relatively large muscles, evolution of elephant grasping has led to thousands of microscopic fascicles, which probably outnumber facial motor neurons.

Description: The kinetics of the urethane forming reactions of hexamethylene diisocyanate (HDI), 4,4′-dicyclohexyl-methane-diisocyanate (HMDI) and isophorone diisocyanate (IPDI) with butan-1-ol were systematically studied by electrospray ionization mass spectrometry (ESI-MS) in the off-line mode. The reactions were performed in toluene solution in the temperature range of 50–80 °C and perdeuterated butan-1-ol was used for quenching the reaction. The butan-1-ol was employed in high excess to diisocyanates to obtain pseudo first-order rate coefficients. For rendering the kinetics, a simple A → B → C consecutive model was applied and found to adequately describe the observed kinetic behaviors. The corresponding rate coefficients were determined and reactivities of the diisocyanates were found to decrease in the order HDI 〉 IPDI 〉 HMDI. Furthermore, it was observed that the second isocyanate group in HDI, due to the ring formation by intramolecular hydrogen bonds, reacted faster with butan-1-ol after the first isocyanate moiety had reacted. The formation of hydrogen bonding rings was also confirmed by DFT calculations. However, the reactivity of the second isocyanate moiety (after the first one has reacted) did not change significantly in the case of HMDI. From the temperature dependences the apparent activation parameters such as the pre-exponential factors and activation energies were determined. In addition, the reactions were also studied at 80 °C in the presence of tin(II)-2-ethylhexanoate at different concentrations and a mechanism was proposed for the catalytic process.

Description: We propose a mixed-integer linear programming model to generate and optimize periodic timetables with integrated track choice in the context of railway construction sites. When a section of a railway network becomes unavailable, the nearby areas are typically operated close to their capacity limits, and hence carefully modeling headways and allowing flexible routings becomes vital. We therefore discuss first how to integrate headway constraints into the Periodic Event Scheduling Problem (PESP) that do not only prevent overtaking, but also guarantee conflict-free timetables in general and particularly inside stations. Secondly, we introduce a turn-sensitive event-activity network, which is able to integrate routing alternatives for turnarounds at stations, e.g., turning at a platform vs. at a pocket track for metro-like systems. We propose several model formulations to include track choice, and finally evaluate them on six real construction site scenarios on the S-Bahn Berlin network.

Description: Mixed Integer Programming (MIP) is NP-hard, and yet modern solvers often solve large real-world problems within minutes. This success can partially be attributed to heuristics. Since their behavior is highly instance-dependent, relying on hard-coded rules derived from empirical testing on a large heterogeneous corpora of benchmark instances might lead to sub-optimal performance. In this work, we propose an online learning approach that adapts the application of heuristics towards the single instance at hand. We replace the commonly used static heuristic handling with an adaptive framework exploiting past observations about the heuristic’s behavior to make future decisions. In particular, we model the problem of controlling Large Neighborhood Search and Diving – two broad and complex classes of heuristics – as a multi-armed bandit problem. Going beyond existing work in the literature, we control two different classes of heuristics simultaneously by a single learning agent. We verify our approach numerically and show consistent node reductions over the MIPLIB 2017 Benchmark set. For harder instances that take at least 1000 seconds to solve, we observe a speedup of 4%.

Description: This paper is concerned with the exact solution of mixed-integer programs (MIPs) over the rational numbers, i.e., without any roundoff errors and error tolerances. Here, one computational bottleneck that should be avoided whenever possible is to employ large-scale symbolic computations. Instead it is often possible to use safe directed rounding methods, e.g., to generate provably correct dual bounds. In this work, we continue to leverage this paradigm and extend an exact branch-and-bound framework by separation routines for safe cutting planes, based on the approach first introduced by Cook, Dash, Fukasawa, and Goycoolea in 2009. Constraints are aggregated safely using approximate dual multipliers from an LP solve, followed by mixed-integer rounding to generate provably valid, although slightly weaker inequalities. We generalize this approach to problem data that is not representable in floating-point arithmetic, add routines for controlling the encoding length of the resulting cutting planes, and show how these cutting planes can be verified according to the VIPR certificate standard. Furthermore, we analyze the performance impact of these cutting planes in the context of an exact MIP framework, showing that we can solve 21.5% more instances and reduce solving times by 26.8% on the MIPLIB 2017 benchmark test set.

Description: Nonnegativity certificates can be used to obtain tight dual bounds for polynomial optimization problems. Hierarchies of certificate-based relaxations ensure convergence to the global optimum, but higher levels of such hierarchies can become very computationally expensive, and the well-known sums of squares hierarchies scale poorly with the degree of the polynomials. This has motivated research into alternative certificates and approaches to global optimization. We consider sums of nonnegative circuit polynomials (SONC) certificates, which are well-suited for sparse problems since the computational cost depends on the number of terms in the polynomials and does not depend on the degrees of the polynomials. We propose a method that guarantees that given finite variable domains, a SONC relaxation will yield a finite dual bound. This method opens up a new approach to utilizing variable bounds in SONC-based methods, which is particularly crucial for integrating SONC relaxations into branch-and-bound algorithms. We report on computational experiments with incorporating SONC relaxations into the spatial branch-and-bound algorithm of the mixed-integer nonlinear programming framework SCIP. Applying our strengthening method increases the number of instances where the SONC relaxation of the root node yielded a finite dual bound from 9 to 330 out of 349 instances in the test set.

Description: Large-scale perturbations in the microbiome constitution are strongly correlated, whether as a driver or a consequence, with the health and functioning of human physiology. However, understanding the difference in the microbiome profiles of healthy and ill individuals can be complicated due to the large number of complex interactions among microbes. We propose to model these interactions as a time-evolving graph whose nodes are microbes and edges are interactions among them. Motivated by the need to analyse such complex interactions, we develop a method that learns a low-dimensional representation of the time-evolving graph and maintains the dynamics occurring in the high-dimensional space. Through our experiments, we show that we can extract graph features such as clusters of nodes or edges that have the highest impact on the model to learn the low-dimensional representation. This information can be crucial to identify microbes and interactions among them that are strongly correlated with clinical diseases. We conduct our experiments on both synthetic and real-world microbiome datasets.

Description: The security of lattice-based cryptography relies on the hardness of solving lattice problems. Lattice basis reduction is a strong tool for solving lattice problems, and the block Korkine–Zolotarev (BKZ) reduction algorithm is the de facto standard in cryptanalysis. We propose a parallel algorithm of BKZ-type reduction based on randomization. Randomized copies of an input lattice basis are independently reduced in parallel, while several basis vectors are shared asynchronously among all processes. There is a trade-off between randomization and information sharing; if a substantial amount of information is shared, all processes might work on the same problem, which diminishes the benefit of parallelization. To monitor the balance between randomness and sharing, we propose a new metric to quantify the variety of lattice bases, and we empirically find an optimal parameter of sharing for high-dimensional lattices. We also demonstrate the effectiveness of our parallel algorithm and metric through experiments from multiple perspectives.

Description: The benefits of cutting planes based on the perspective function are well known for many specific classes of mixed-integer nonlinear programs with on/off structures. However, we are not aware of any empirical studies that evaluate their applicability and computational impact over large, heterogeneous test sets in general-purpose solvers. This paper provides a detailed computational study of perspective cuts within a linear programming based branch-and-cut solver for general mixed-integer nonlinear programs. Within this study, we extend the applicability of perspective cuts from convex to nonconvex nonlinearities. This generalization is achieved by applying a perspective strengthening to valid linear inequalities which separate solutions of linear relaxations. The resulting method can be applied to any constraint where all variables appearing in nonlinear terms are semi-continuous and depend on at least one common indicator variable. Our computational experiments show that adding perspective cuts for convex constraints yields a consistent improvement of performance, and adding perspective cuts for nonconvex constraints reduces branch-and-bound tree sizes and strengthens the root node relaxation, but has no significant impact on the overall mean time.

Description: This paper is concerned with the exact solution of mixed-integer programs (MIPs) over the rational numbers, i.e., without any roundoff errors and error tolerances. Here, one computational bottleneck that should be avoided whenever possible is to employ large-scale symbolic computations. Instead it is often possible to use safe directed rounding methods, e.g., to generate provably correct dual bounds. In this work, we continue to leverage this paradigm and extend an exact branch-and-bound framework by separation routines for safe cutting planes, based on the approach first introduced by Cook, Dash, Fukasawa, and Goycoolea in 2009. Constraints are aggregated safely using approximate dual multipliers from an LP solve, followed by mixed-integer rounding to generate provably valid, although slightly weaker inequalities. We generalize this approach to problem data that is not representable in floating-point arithmetic, add routines for controlling the encoding length of the resulting cutting planes, and show how these cutting planes can be verified according to the VIPR certificate standard. Furthermore, we analyze the performance impact of these cutting planes in the context of an exact MIP framework, showing that we can solve 21.5% more instances and reduce solving times by 26.8% on the MIPLIB 2017 benchmark test set.

Description: The reformulation-linearization technique (RLT) is a prominent approach to constructing tight linear relaxations of non-convex continuous and mixed-integer optimization problems. The goal of this paper is to extend the applicability and improve the performance of RLT for bilinear product relations. First, a method for detecting bilinear product relations implicitly contained in mixed-integer linear programs is developed based on analyzing linear constraints with binary variables, thus enabling the application of bilinear RLT to a new class of problems. Our second contribution addresses the high computational cost of RLT cut separation, which presents one of the major difficulties in applying RLT efficiently in practice. We propose a new RLT cutting plane separation algorithm which identifies combinations of linear constraints and bound factors that are expected to yield an inequality that is violated by the current relaxation solution. A detailed computational study based on implementations in two solvers evaluates the performance impact of the proposed methods.

Description: Measurable levels of immunoglobulin G antibodies develop after infections with and vaccinations against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These antibody levels are dynamic: due to waning, antibody levels will drop over time. During the COVID-19 pandemic, multiple models predicting infection dynamics were used by policymakers to support the planning of public health policies. Explicitly integrating antibody and waning effects into the models is crucial for reliable calculations of individual infection risk. However, only few approaches have been suggested that explicitly treat these effects. This paper presents a methodology that explicitly models antibody levels and the resulting protection against infection for individuals within an agent-based model. The model was developed in response to the complexity of different immunization sequences and types and is based on neutralization titer studies. This approach allows complex population studies with explicit antibody and waning effects. We demonstrate the usefulness of our model in two use cases.

Description: WaveTrain is an open-source software for numerical simulations of chain-like quantum systems with nearest-neighbor (NN) interactions only. The Python package is centered around tensor train (TT, or matrix product) format representations of Hamiltonian operators and (stationary or time-evolving) state vectors. It builds on the Python tensor train toolbox Scikit_tt, which provides efficient construction methods and storage schemes for the TT format. Its solvers for eigenvalue problems and linear differential equations are used in WaveTrain for the time-independent and time-dependent Schrödinger equations, respectively. Employing efficient decompositions to construct low-rank representations, the tensor-train ranks of state vectors are often found to depend only marginally on the chain length N. This results in the computational effort growing only slightly more than linearly with N, thus mitigating the curse of dimensionality. As a complement to the classes for full quantum mechanics, WaveTrain also contains classes for fully classical and mixed quantum–classical (Ehrenfest or mean field) dynamics of bipartite systems. The graphical capabilities allow visualization of quantum dynamics “on the fly,” with a choice of several different representations based on reduced density matrices. Even though developed for treating quasi-one-dimensional excitonic energy transport in molecular solids or conjugated organic polymers, including coupling to phonons, WaveTrain can be used for any kind of chain-like quantum systems, with or without periodic boundary conditions and with NN interactions only. The present work describes version 1.0 of our WaveTrain software, based on version 1.2 of scikit_tt, both of which are freely available from the GitHub platform where they will also be further developed. Moreover, WaveTrain is mirrored at SourceForge, within the framework of the WavePacket project for numerical quantum dynamics. Worked-out demonstration examples with complete input and output, including animated graphics, are available.

Description: Implantable Cardiac Monitor (ICM) devices are demonstrating as of today, the fastest-growing market for implantable cardiac devices. As such, they are becoming increasingly common in patients for measuring heart electrical activity. ICMs constantly monitor and record a patient's heart rhythm and when triggered - send it to a secure server where health care professionals (denote HCPs from here on) can review it. These devices employ a relatively simplistic rule-based algorithm (due to energy consumption constraints) to alert for abnormal heart rhythms. This algorithm is usually parameterized to an over-sensitive mode in order to not miss a case (resulting in a relatively high false-positive rate) and this, combined with the device's nature of constantly monitoring the heart rhythm and its growing popularity, results in HCPs having to analyze and diagnose an increasingly growing amount of data. In order to reduce the load on the latter, automated methods for ECG analysis are nowadays becoming a great tool to assist HCPs in their analysis. While state-of-the-art algorithms are data-driven rather than rule-based, training data for ICMs often consist of specific characteristics that make its analysis unique and particularly challenging. This study presents the challenges and solutions in automatically analyzing ICM data and introduces a method for its classification that outperforms existing methods on such data. It does so by combining high-frequency noise detection (which often occurs in ICM data) with a semi-supervised learning pipeline that allows for re-labeling of training episodes, and by using segmentation and dimension reduction techniques that are robust to morphology variations of the sECG signal (which are typical to ICM data). As a result, it performs better than state-of-the-art techniques on such data with e.g. F1 score of 0.51 vs. 0.38 of our baseline state-of-the-art technique in correctly calling Atrial Fibrilation in ICM data. As such, it could be used in numerous ways such as aiding HCPs in the analysis of ECGs originating from ICMs by, e.g., suggesting a rhythm type.

Description: The Periodic Event Scheduling Problem (PESP) is a notoriously hard combinatorial optimization problem, essential for the design of periodic timetables in public transportation. The coefficients of the integer variables in the standard mixed integer linear programming formulations of PESP are the period time, e.g., 60 for a horizon of one hour with a resolution of one minute. In many application scenarios, lines with different frequencies have to be scheduled, leading to period times with many divisors. It then seems natural to consider derived instances, where the period time is a divisor of the original one, thereby smaller, and bounds are scaled and rounded accordingly. To this end, we identify two rounding schemes: wide and tight. We then discuss the approximation performance of both strategies, in theory and practice.

Description: We present incremental heuristics for the Periodic Event Scheduling Problem (PESP), the standard mathematical tool to optimize periodic timetables in public transport. The core of our method is to solve successively larger subinstances making use of previously found solutions. Introducing the technical notion of free stratifications, we formulate a general scheme for incremental heuristics for PESP. More practically, we use line and station information to create heuristics that add lines or stations one by one, and we evaluate these heuristics on instances of the benchmarking library PESPlib. This approach is indeed viable, and leads to new incumbent solutions for six PESPlib instances.

Description: One of the fundamental problems in neurobiological research is to understand how neural circuits generate behaviors in response to sensory stimuli. Elucidating such neural circuits requires anatomical and functional information about the neurons that are active during the processing of the sensory information and generation of the respective response, as well as an identification of the connections between these neurons. With modern imaging techniques, both morphological properties of individual neurons as well as functional information related to sensory processing, information integration and behavior can be obtained. Given the resulting information, neurobiologists are faced with the task of identifying the anatomical structures down to individual neurons that are linked to the studied behavior and the processing of the respective sensory stimuli. Here, we present a novel interactive tool that assists neurobiologists in the aforementioned task by allowing them to extract hypothetical neural circuits constrained by anatomical and functional data. Our approach is based on two types of structural data: brain regions that are anatomically or functionally defined, and morphologies of individual neurons. Both types of structural data are interlinked and augmented with additional information. The presented tool allows the expert user to identify neurons using Boolean queries. The interactive formulation of these queries is supported by linked views, using, among other things, two novel 2D abstractions of neural circuits. The approach was validated in two case studies investigating the neural basis of vision-based behavioral responses in zebrafish larvae. Despite this particular application, we believe that the presented tool will be of general interest for exploring hypotheses about neural circuits in other species, genera and taxa.

Description: The fact that the physical shapes of man-made objects are subject to overlapping influences—such as technological, economic, geographic, and stylistic progressions—holds great information potential. On the other hand, it is also a major analytical challenge to uncover these overlapping trends and to disentagle them in an unbiased way. This paper explores a novel mathematical approach to extract archaeological insights from ensembles of similar artifact shapes. We show that by considering all shape information in a find collection, it is possible to identify shape patterns that would be difficult to discern by considering the artifacts individually or by classifying shapes into predefined archaeological types and analyzing the associated distinguishing characteristics. Recently, series of high-resolution digital representations of artifacts have become available. Such data sets enable the application of extremely sensitive and flexible methods of shape analysis. We explore this potential on a set of 3D models of ancient Greek and Roman sundials, with the aim of providing alternatives to the traditional archaeological method of “trend extraction by ordination” (typology). In the proposed approach, each 3D shape is represented as a point in a shape space—a high-dimensional, curved, non-Euclidean space. Proper consideration of its mathematical properties reduces bias in data analysis and thus improves analytical power. By performing regression in shape space, we find that for Roman sundials, the bend of the shadow-receiving surface of the sundials changes with the latitude of the location. This suggests that, apart from the inscribed hour lines, also a sundial’s shape was adjusted to the place of installation. As an example of more advanced inference, we use the identified trend to infer the latitude at which a sundial, whose location of installation is unknown, was placed. We also derive a novel method for differentiated morphological trend assertion, building upon and extending the theory of geometric statistics and shape analysis. Specifically, we present a regression-based method for statistical normalization of shapes that serves as a means of disentangling parameter-dependent effects (trends) and unexplained variability. In addition, we show that this approach is robust to noise in the digital reconstructions of the artifact shapes.

Description: One of the main challenges in molecular dynamics is overcoming the ‘timescale barrier’: in many realistic molecular systems, biologically important rare transitions occur on timescales that are not accessible to direct numerical simulation, even on the largest or specifically dedicated supercomputers. This article discusses how to circumvent the timescale barrier by a collection of transfer operator-based techniques that have emerged from dynamical systems theory, numerical mathematics and machine learning over the last two decades. We will focus on how transfer operators can be used to approximate the dynamical behaviour on long timescales, review the introduction of this approach into molecular dynamics, and outline the respective theory, as well as the algorithmic development, from the early numerics-based methods, via variational reformulations, to modern data-based techniques utilizing and improving concepts from machine learning. Furthermore, its relation to rare event simulation techniques will be explained, revealing a broad equivalence of variational principles for long-time quantities in molecular dynamics. The article will mainly take a mathematical perspective and will leave the application to real-world molecular systems to the more than 1000 research articles already written on this subject.

Description: Visualization grammars are gaining popularity as they allow visualization specialists and experienced users to quickly create static and interactive views. Existing grammars, however, mostly focus on abstract views, ignoring three-dimensional (3D) views, which are very important in fields such as natural sciences. We propose a generalized interaction grammar for the problem of coordinating heterogeneous view types, such as standard charts (e.g., based on Vega-Lite) and 3D anatomical views. An important aspect of our web-based framework is that user interactions with data items at various levels of detail can be systematically integrated and used to control the overall layout of the application workspace. With the help of a concise JSON-based specification of the intended workflow, we can handle complex interactive visual analysis scenarios. This enables rapid prototyping and iterative refinement of the visual analysis tool in collaboration with domain experts. We illustrate the usefulness of our framework in two real-world case studies from the field of neuroscience. Since the logic of the presented grammar-based approach for handling interactions between heterogeneous web-based views is free of any application specifics, it can also serve as a template for applications beyond biological research.

Description: Recent advances in connectomics research enable the acquisition of increasing amounts of data about the connectivity patterns of neurons. How can we use this wealth of data to efficiently derive and test hypotheses about the principles underlying these patterns? A common approach is to simulate neural networks using a hypothesized wiring rule in a generative model and to compare the resulting synthetic data with empirical data. However, most wiring rules have at least some free parameters and identifying parameters that reproduce empirical data can be challenging as it often requires manual parameter tuning. Here, we propose to use simulation-based Bayesian inference (SBI) to address this challenge. Rather than optimizing a single rule to fit the empirical data, SBI considers many parametrizations of a wiring rule and performs Bayesian inference to identify the parameters that are compatible with the data. It uses simulated data from multiple candidate wiring rules and relies on machine learning methods to estimate a probability distribution (the `posterior distribution over rule parameters conditioned on the data') that characterizes all data-compatible rules. We demonstrate how to apply SBI in connectomics by inferring the parameters of wiring rules in an in silico model of the rat barrel cortex, given in vivo connectivity measurements. SBI identifies a wide range of wiring rule parameters that reproduce the measurements. We show how access to the posterior distribution over all data-compatible parameters allows us to analyze their relationship, revealing biologically plausible parameter interactions and enabling experimentally testable predictions. We further show how SBI can be applied to wiring rules at different spatial scales to quantitatively rule out invalid wiring hypotheses. Our approach is applicable to a wide range of generative models used in connectomics, providing a quantitative and efficient way to constrain model parameters with empirical connectivity data.

Description: Recent advances in connectomics research enable the acquisition of increasing amounts of data about the connectivity patterns of neurons. How can we use this wealth of data to efficiently derive and test hypotheses about the principles underlying these patterns? A common approach is to simulate neuronal networks using a hypothesized wiring rule in a generative model and to compare the resulting synthetic data with empirical data. However, most wiring rules have at least some free parameters, and identifying parameters that reproduce empirical data can be challenging as it often requires manual parameter tuning. Here, we propose to use simulation-based Bayesian inference (SBI) to address this challenge. Rather than optimizing a fixed wiring rule to fit the empirical data, SBI considers many parametrizations of a rule and performs Bayesian inference to identify the parameters that are compatible with the data. It uses simulated data from multiple candidate wiring rule parameters and relies on machine learning methods to estimate a probability distribution (the 'posterior distribution over parameters conditioned on the data') that characterizes all data-compatible parameters. We demonstrate how to apply SBI in computational connectomics by inferring the parameters of wiring rules in an in silico model of the rat barrel cortex, given in vivo connectivity measurements. SBI identifies a wide range of wiring rule parameters that reproduce the measurements. We show how access to the posterior distribution over all data-compatible parameters allows us to analyze their relationship, revealing biologically plausible parameter interactions and enabling experimentally testable predictions. We further show how SBI can be applied to wiring rules at different spatial scales to quantitatively rule out invalid wiring hypotheses. Our approach is applicable to a wide range of generative models used in connectomics, providing a quantitative and efficient way to constrain model parameters with empirical connectivity data.

Description: Predicting the future development of an anatomical shape from a single baseline observation is a challenging task. But it can be essential for clinical decision-making. Research has shown that it should be tackled in curved shape spaces, as (e.g., disease-related) shape changes frequently expose nonlinear characteristics. We thus propose a novel prediction method that encodes the whole shape in a Riemannian shape space. It then learns a simple prediction technique founded on hierarchical statistical modeling of longitudinal training data. When applied to predict the future development of the shape of the right hippocampus under Alzheimer's disease and to human body motion, it outperforms deep learning-supported variants as well as state-of-the-art.

Description: Data analysis has become fundamental to our society and comes in multiple facets and approaches. Nevertheless, in research and applications, the focus was primarily on data from Euclidean vector spaces. Consequently, the majority of methods that are applied today are not suited for more general data types. Driven by needs from fields like image processing, (medical) shape analysis, and network analysis, more and more attention has recently been given to data from non-Euclidean spaces---particularly (curved) manifolds. It has led to the field of geometric data analysis whose methods explicitly take the structure (for example, the topology and geometry) of the underlying space into account. This thesis contributes to the methodology of geometric data analysis by generalizing several fundamental notions from multivariate statistics to manifolds. We thereby focus on two different viewpoints. First, we use Riemannian structures to derive a novel regression scheme for general manifolds that relies on splines of generalized Bézier curves. It can accurately model non-geodesic relationships, for example, time-dependent trends with saturation effects or cyclic trends. Since Bézier curves can be evaluated with the constructive de Casteljau algorithm, working with data from manifolds of high dimensions (for example, a hundred thousand or more) is feasible. Relying on the regression, we further develop a hierarchical statistical model for an adequate analysis of longitudinal data in manifolds, and a method to control for confounding variables. We secondly focus on data that is not only manifold- but even Lie group-valued, which is frequently the case in applications. We can only achieve this by endowing the group with an affine connection structure that is generally not Riemannian. Utilizing it, we derive generalizations of several well-known dissimilarity measures between data distributions that can be used for various tasks, including hypothesis testing. Invariance under data translations is proven, and a connection to continuous distributions is given for one measure. A further central contribution of this thesis is that it shows use cases for all notions in real-world applications, particularly in problems from shape analysis in medical imaging and archaeology. We can replicate or further quantify several known findings for shape changes of the femur and the right hippocampus under osteoarthritis and Alzheimer's, respectively. Furthermore, in an archaeological application, we obtain new insights into the construction principles of ancient sundials. Last but not least, we use the geometric structure underlying human brain connectomes to predict cognitive scores. Utilizing a sample selection procedure, we obtain state-of-the-art results.

Description: The recent advances in machine learning in various fields of applications can be largely attributed to the rise of deep learning (DL) methods and architectures. Despite being a key technology behind autonomous cars, image processing, speech recognition, etc., a notorious problem remains the lack of theoretical understanding of DL and related interpretability and (adversarial) robustness issues. Understanding the specifics of DL, as compared to, say, other forms of nonlinear regression methods or statistical learning, is interesting from a mathematical perspective, but at the same time it is of crucial importance in practice: treating neural networks as mere black boxes might be sufficient in certain cases, but many applications require waterproof performance guarantees and a deeper understanding of what could go wrong and why it could go wrong. It is probably fair to say that, despite being mathematically well founded as a method to approximate complicated functions, DL is mostly still more like modern alchemy that is firmly in the hands of engineers and computer scientists. Nevertheless, it is evident that certain specifics of DL that could explain its success in applications demands systematic mathematical approaches. In this work, we review robustness issues of DL and particularly bridge concerns and attempts from approximation theory to statistical learning theory. Further, we review Bayesian Deep Learning as a means for uncertainty quantification and rigorous explainability.

Description: One of the fundamental problems in neurobiological research is to understand how neural circuits generate behaviors in response to sensory stimuli. Elucidating such neural circuits requires anatomical and functional information about the neurons that are active during the processing of the sensory information and generation of the respective response, as well as an identification of the connections between these neurons. With modern imaging techniques, both morphological properties of individual neurons as well as functional information related to sensory processing, information integration and behavior can be obtained. Given the resulting information, neurobiologists are faced with the task of identifying the anatomical structures down to individual neurons that are linked to the studied behavior and the processing of the respective sensory stimuli. Here, we present a novel interactive tool that assists neurobiologists in the aforementioned task by allowing them to extract hypothetical neural circuits constrained by anatomical and functional data. Our approach is based on two types of structural data: brain regions that are anatomically or functionally defined, and morphologies of individual neurons. Both types of structural data are interlinked and augmented with additional information. The presented tool allows the expert user to identify neurons using Boolean queries. The interactive formulation of these queries is supported by linked views, using, among other things, two novel 2D abstractions of neural circuits. The approach was validated in two case studies investigating the neural basis of vision-based behavioral responses in zebrafish larvae. Despite this particular application, we believe that the presented tool will be of general interest for exploring hypotheses about neural circuits in other species, genera and taxa.

Description: In this note, we apply Transition Path Theory (TPT) from Markov chains to shed light on the problem of Iceland-Scotland Overflow Water (ISOW) equatorward export. A recent analysis of observed trajectories of submerged floats demanded revision of the traditional abyssal circulation theory, which postulates that ISOW should steadily flow along a deep boundary current (DBC) around the subpolar North Atlantic prior to exiting it. The TPT analyses carried out here allow to focus the attention on the portions of flow from the origin of ISOW to the region where ISOW exits the subpolar North Atlantic and suggest that insufficient sampling may be biasing the aforementioned demand. The analyses, appropriately adapted to represent a continuous input of ISOW, are carried out on three time-homogeneous Markov chains modeling the ISOW flow. One is constructed using a high number of simulated trajectories homogeneously covering the flow domain. The other two use much fewer trajectories which heterogeneously cover the domain. The trajectories in the latter two chains are observed trajectories or simulated trajectories subsampled at the observed frequency. While the densely sampled chain supports a well-defined DBC, the more heterogeneously sampled chains do not, irrespective of whether observed or simulated trajectories are used. Studying the sampling sensitivity of the Markov chains, we can give recommendations for enlarging the existing float dataset to improve the significance of conclusions about time-asymptotic aspects of the ISOW circulation.