Topics in Genomic Signal Processing

Genomic information is digital in its nature and admits mathematical modeling in order to gain biological knowledge. This dissertation focuses on the development and application of detection and estimation theories for solving problems in genomics by describing biological problems in mathematical terms and proposing a solution in this domain. More specifically, a novel framework for hypothesis testing is presented, where it is desired to decide among multiple hypotheses and where each hypothesis involves unknown parameters. Within this framework, a test is developed to perform both detection and estimation jointly in an optimal sense. The proposed test is then applied to the problem of detecting and estimating periodicities in DNA sequences. Moreover, the problem of motif discovery in DNA sequences is presented, where a set of sequences is observed and it is needed to determine which sequences contain instances (if any) of an unknown motif and estimate their positions. A statistical description of the problem is used and a sequential Monte Carlo method is applied for the inference. Finally, the phasing of haplotypes for diploid organisms is introduced, where a novel mathematical model is proposed. The haplotypes that are used to reconstruct the observed genotypes of a group of unrelated individuals are detected and the haplotype pair for each individual in the group is estimated. The model translates a biological principle, the maximum parsimony principle, to a sparseness condition

Interpretable Machine Learning for Electro-encephalography

While behavioral, genetic and psychological markers can provide important information about brain health, research in that area over the last decades has much focused on imaging devices such as magnetic resonance tomography (MRI) to provide non-invasive information about cognitive processes. Unfortunately, MRI based approaches, able to capture the slow changes in blood oxygenation levels, cannot capture electrical brain activity which plays out on a time scale up to three orders of magnitude faster. Electroencephalography (EEG), which has been available in clinical settings for over 60 years, is able to measure brain activity based on rapidly changing electrical potentials measured non-invasively on the scalp. Compared to MRI based research into neurodegeneration, EEG based research has, over the last decade, received much less interest from the machine learning community. But generally, EEG in combination with sophisticated machine learning offers great potential such that neglecting this source of information, compared to MRI or genetics, is not warranted. In collaborating with clinical experts, the ability to link any results provided by machine learning to the existing body of research is especially important as it ultimately provides an intuitive or interpretable understanding. Here, interpretable means the possibility for medical experts to translate the insights provided by a statistical model into a working hypothesis relating to brain function. To this end, we propose in our first contribution a method allowing for ultra-sparse regression which is applied on EEG data in order to identify a small subset of important diagnostic markers highlighting the main differences between healthy brains and brains affected by Parkinson's disease. Our second contribution builds on the idea that in Parkinson's disease impaired functioning of the thalamus causes changes in the complexity of the EEG waveforms. The thalamus is a small region in the center of the brain affected early in the course of the disease. Furthermore, it is believed that the thalamus functions as a pacemaker - akin to a conductor of an orchestra - such that changes in complexity are expressed and quantifiable based on EEG. We use these changes in complexity to show their association with future cognitive decline. In our third contribution we propose an extension of archetypal analysis embedded into a deep neural network. This generative version of archetypal analysis allows to learn an appropriate representation where every sample of a data set can be decomposed into a weighted sum of extreme representatives, the so-called archetypes. This opens up an interesting possibility of interpreting a data set relative to its most extreme representatives. In contrast, clustering algorithms describe a data set relative to its most average representatives. For Parkinson's disease, we show based on deep archetypal analysis, that healthy brains produce archetypes which are different from those produced by brains affected by neurodegeneration

A precise bare simulation approach to the minimization of some distances. Foundations

In information theory -- as well as in the adjacent fields of statistics, machine learning, artificial intelligence, signal processing and pattern recognition -- many flexibilizations of the omnipresent Kullback-Leibler information distance (relative entropy) and of the closely related Shannon entropy have become frequently used tools. To tackle corresponding constrained minimization (respectively maximization) problems by a newly developed dimension-free bare (pure) simulation method, is the main goal of this paper. Almost no assumptions (like convexity) on the set of constraints are needed, within our discrete setup of arbitrary dimension, and our method is precise (i.e., converges in the limit). As a side effect, we also derive an innovative way of constructing new useful distances/divergences. To illustrate the core of our approach, we present numerous examples. The potential for widespread applicability is indicated, too; in particular, we deliver many recent references for uses of the involved distances/divergences and entropies in various different research fields (which may also serve as an interdisciplinary interface)

Computational solutions for addressing heterogeneity in DNA methylation data

DNA methylation, a reversible epigenetic modification, has been implicated with various bi- ological processes including gene regulation. Due to the multitude of datasets available, it is a premier candidate for computational tool development, especially for investigating hetero- geneity within and across samples. We differentiate between three levels of heterogeneity in DNA methylation data: between-group, between-sample, and within-sample heterogeneity. Here, we separately address these three levels and present new computational approaches to quantify and systematically investigate heterogeneity. Epigenome-wide association studies relate a DNA methylation aberration to a phenotype and therefore address between-group heterogeneity. To facilitate such studies, which necessar- ily include data processing, exploratory data analysis, and differential analysis of DNA methy- lation, we extended the R-package RnBeads. We implemented novel methods for calculating the epigenetic age of individuals, novel imputation methods, and differential variability analysis. A use-case of the new features is presented using samples from Ewing sarcoma patients. As an important driver of epigenetic differences between phenotypes, we systematically investigated associations between donor genotypes and DNA methylation states in methylation quantitative trait loci (methQTL). To that end, we developed a novel computational framework –MAGAR– for determining statistically significant associations between genetic and epigenetic variations. We applied the new pipeline to samples obtained from sorted blood cells and complex bowel tissues of healthy individuals and found that tissue-specific and common methQTLs have dis- tinct genomic locations and biological properties. To investigate cell-type-specific DNA methylation profiles, which are the main drivers of within-group heterogeneity, computational deconvolution methods can be used to dissect DNA methylation patterns into latent methylation components. Deconvolution methods require pro- files of high technical quality and the identified components need to be biologically interpreted. We developed a computational pipeline to perform deconvolution of complex DNA methyla- tion data, which implements crucial data processing steps and facilitates result interpretation. We applied the protocol to lung adenocarcinoma samples and found indications of tumor in- filtration by immune cells and associations of the detected components with patient survival. Within-sample heterogeneity (WSH), i.e., heterogeneous DNA methylation patterns at a ge- nomic locus within a biological sample, is often neglected in epigenomic studies. We present the first systematic benchmark of scores quantifying WSH genome-wide using simulated and experimental data. Additionally, we created two novel scores that quantify DNA methyla- tion heterogeneity at single CpG resolution with improved robustness toward technical biases. WSH scores describe different types of WSH in simulated data, quantify differential hetero- geneity, and serve as a reliable estimator of tumor purity. Due to the broad availability of DNA methylation data, the levels of heterogeneity in DNA methylation data can be comprehensively investigated. We contribute novel computational frameworks for analyzing DNA methylation data with respect to different levels of hetero- geneity. We envision that this toolbox will be indispensible for understanding the functional implications of DNA methylation patterns in health and disease.DNA Methylierung ist eine reversible, epigenetische Modifikation, die mit verschiedenen biologischen Prozessen wie beispielsweise der Genregulation in Verbindung steht. Eine Vielzahl von DNA Methylierungsdatensätzen bildet die perfekte Grundlage zur Entwicklung von Softwareanwendungen, insbesondere um Heterogenität innerhalb und zwischen Proben zu beschreiben. Wir unterscheiden drei Ebenen von Heterogenität in DNA Methylierungsdaten: zwischen Gruppen, zwischen Proben und innerhalb einer Probe. Hier betrachten wir die drei Ebenen von Heterogenität in DNA Methylierungsdaten unabhängig voneinander und präsentieren neue Ansätze um die Heterogenität zu beschreiben und zu quantifizieren. Epigenomweite Assoziationsstudien verknüpfen eine DNA Methylierungsveränderung mit einem Phänotypen und beschreiben Heterogenität zwischen Gruppen. Um solche Studien, welche Datenprozessierung, sowie exploratorische und differentielle Datenanalyse beinhalten, zu vereinfachen haben wir die R-basierte Softwareanwendung RnBeads erweitert. Die Erweiterungen beinhalten neue Methoden, um das epigenetische Alter vorherzusagen, neue Schätzungsmethoden für fehlende Datenpunkte und eine differentielle Variabilitätsanalyse. Die Analyse von Ewing-Sarkom Patientendaten wurde als Anwendungsbeispiel für die neu entwickelten Methoden gewählt. Wir untersuchten Assoziationen zwischen Genotypen und DNA Methylierung von einzelnen CpGs, um sogenannte methylation quantitative trait loci (methQTL) zu definieren. Diese stellen einen wichtiger Faktor dar, der epigenetische Unterschiede zwischen Gruppen induziert. Hierzu entwickelten wir ein neues Softwarepaket (MAGAR), um statistisch signifikante Assoziationen zwischen genetischer und epigenetischer Variation zu identifizieren. Wir wendeten diese Pipeline auf Blutzelltypen und komplexe Biopsien von gesunden Individuen an und konnten gemeinsame und gewebespezifische methQTLs in verschiedenen Bereichen des Genoms lokalisieren, die mit unterschiedlichen biologischen Eigenschaften verknüpft sind. Die Hauptursache für Heterogenität innerhalb einer Gruppe sind zelltypspezifische DNA Methylierungsmuster. Um diese genauer zu untersuchen kann Dekonvolutionssoftware die DNA Methylierungsmatrix in unabhängige Variationskomponenten zerlegen. Dekonvolutionsmethoden auf Basis von DNA Methylierung benötigen technisch hochwertige Profile und die identifizierten Komponenten müssen biologisch interpretiert werden. In dieser Arbeit entwickelten wir eine computerbasierte Pipeline zur Durchführung von Dekonvolutionsexperimenten, welche die Datenprozessierung und Interpretation der Resultate beinhaltet. Wir wendeten das entwickelte Protokoll auf Lungenadenokarzinome an und fanden Anzeichen für eine Tumorinfiltration durch Immunzellen, sowie Verbindungen zum Überleben der Patienten. Heterogenität innerhalb einer Probe (within-sample heterogeneity, WSH), d.h. heterogene Methylierungsmuster innerhalb einer Probe an einer genomischen Position, wird in epigenomischen Studien meist vernachlässigt. Wir präsentieren den ersten Vergleich verschiedener, genomweiter WSH Maße auf simulierten und experimentellen Daten. Zusätzlich entwickelten wir zwei neue Maße um WSH für einzelne CpGs zu berechnen, welche eine verbesserte Robustheit gegenüber technischen Faktoren aufweisen. WSH Maße beschreiben verschiedene Arten von WSH, quantifizieren differentielle Heterogenität und sagen Tumorreinheit vorher. Aufgrund der breiten Verfügbarkeit von DNA Methylierungsdaten können die Ebenen der Heterogenität ganzheitlich beschrieben werden. In dieser Arbeit präsentieren wir neue Softwarelösungen zur Analyse von DNA Methylierungsdaten in Bezug auf die verschiedenen Ebenen der Heterogenität. Wir sind davon überzeugt, dass die vorgestellten Softwarewerkzeuge unverzichtbar für das Verständnis von DNA Methylierung im kranken und gesunden Stadium sein werden

Untangling hotel industry’s inefficiency: An SFA approach applied to a renowned Portuguese hotel chain

The present paper explores the technical efficiency of four hotels from Teixeira Duarte Group - a renowned Portuguese hotel chain. An efficiency ranking is established from these four hotel units located in Portugal using Stochastic Frontier Analysis. This methodology allows to discriminate between measurement error and systematic inefficiencies in the estimation process enabling to investigate the main inefficiency causes. Several suggestions concerning efficiency improvement are undertaken for each hotel studied.info:eu-repo/semantics/publishedVersio

An Initial Framework Assessing the Safety of Complex Systems

Trabajo presentado en la Conference on Complex Systems, celebrada online del 7 al 11 de diciembre de 2020.Atmospheric blocking events, that is large-scale nearly stationary atmospheric pressure patterns, are often associated with extreme weather in the mid-latitudes, such as heat waves and cold spells which have significant consequences on ecosystems, human health and economy. The high impact of blocking events has motivated numerous studies. However, there is not yet a comprehensive theory explaining their onset, maintenance and decay and their numerical prediction remains a challenge. In recent years, a number of studies have successfully employed complex network descriptions of fluid transport to characterize dynamical patterns in geophysical flows. The aim of the current work is to investigate the potential of so called Lagrangian flow networks for the detection and perhaps forecasting of atmospheric blocking events. The network is constructed by associating nodes to regions of the atmosphere and establishing links based on the flux of material between these nodes during a given time interval. One can then use effective tools and metrics developed in the context of graph theory to explore the atmospheric flow properties. In particular, Ser-Giacomi et al. [1] showed how optimal paths in a Lagrangian flow network highlight distinctive circulation patterns associated with atmospheric blocking events. We extend these results by studying the behavior of selected network measures (such as degree, entropy and harmonic closeness centrality)at the onset of and during blocking situations, demonstrating their ability to trace the spatio-temporal characteristics of these events.This research was conducted as part of the CAFE (Climate Advanced Forecasting of sub-seasonal Extremes) Innovative Training Network which has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 813844

Three Risky Decades: A Time for Econophysics?

Our Special Issue we publish at a turning point, which we have not dealt with since World War II. The interconnected long-term global shocks such as the coronavirus pandemic, the war in Ukraine, and catastrophic climate change have imposed significant humanitary, socio-economic, political, and environmental restrictions on the globalization process and all aspects of economic and social life including the existence of individual people. The planet is trapped—the current situation seems to be the prelude to an apocalypse whose long-term effects we will have for decades. Therefore, it urgently requires a concept of the planet's survival to be built—only on this basis can the conditions for its development be created. The Special Issue gives evidence of the state of econophysics before the current situation. Therefore, it can provide excellent econophysics or an inter-and cross-disciplinary starting point of a rational approach to a new era