91 research outputs found

    Chatbots for Modelling, Modelling of Chatbots

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    Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Escuela Politécnica Superior, Departamento de Ingeniería Informática. Fecha de Lectura: 28-03-202

    High Throughput Computational Methods for Immuno-oncology: Precise Patient Stratification Based on Neoantigen Profile Analyses

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    Computational prediction of binding between neoantigen peptides and major histocompatibility complex (MHC) proteins can be used to predict patient response to cancer immunotherapy for immune-checkpoint blockade (ICB) therapies. Current neoantigen predictors focus on in silico estimation of MHC binding affinity and are limited by low predictive value (PPV) for actual peptide presentation, inadequate support for rare MHC alleles, and poor scalability to high-throughput data sets. To address these limitations, I developed MHCnuggets, a deep neural network method that predicts peptide-MHC binding. MHCnuggets can predict binding for common or rare alleles of MHC class I or II with a single network. Using a long short-term memory (LSTM) network, MHCnuggets accepts peptides of variable length and is faster than other methods. MHCnuggets yields a 4-fold PPV improvement when tested with MHC-bound peptide (HLAp) data. MHCnuggets’ was next used to explore ICB-treated patients’ mutation-associated neoantigen (MANA) and immunogenic mutation (IMM) profiles. I found that responding tumors harbored a significantly higher HLA class II IMM burden for both melanoma and Non-Small Cell Lung Cancer (NSCLC) (P≤9.6e-3). HLA class II IMM burden was correlated with longer survival. HLA class I and II IMMs were largely distinct, suggesting a complementary role for class II IMMs in tumor rejection. A higher HLA class II IMM burden was associated with CD4+ T-cell infiltration. In addition, I found distinct sex-based immunogenomic landscapes in NSCLC: TMB, class I IMM load, class II IMM load, and mutational smoking signature were significantly higher in female responding tumors as compared to female non-responding tumors (P≤0.005). In contrast, among males, there was no significant association between durable-clinical benefit and any of these features. When IMM was considered in the context of HLA zygosity, high MHC-II restricted IMM load and high HLA class II diversity was significantly associated with overall survival in males (p=0.017). Such results indicated that inherent sex-driven differences in immune surveillance affect the immunogenomic determinants of response to ICB and likely mediate the dimorphic outcomes with ICB therapy. Taken together, my thesis work used computational methods to provide more precise patient stratification in immune oncology based on patients’ genomic and neoantigen profiles

    Inspecting Java Program States with Semantic Web Technologies

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    Semantic debugging, as introduced by Kamburjan et al., refers to the practice of applying technologies of the semantic web to query the run-time state of a program and combine it with external domain knowledge. This master thesis aims to take the first step toward making the benefits of semantic debugging available for real-world application development. For this purpose, we implement a semantic debugging tool for the Java programming language, called the Semantic Java Debugger or sjdb. The sjdb tool provides an interactive, command line-based user interface through which users can (1) run Java programs and suspend their execution at user-defined breakpoints, (2) automatically extract RDF knowledge bases with description logic semantics that describe the current state of the program, (3) optionally supplement the knowledge base with external domain knowledge formalized in OWL, (4) run (semantic) queries on this extended knowledge base, and resolve the query results back to Java objects. As part of this debugging tool, the development of an extraction mechanism for knowledge bases from the states of suspended Java programs is one of the main contributions of this thesis. For this purpose, we also devise an OWL formalization of Java runtime states to structure this extraction process and give meaning to the resulting knowledge base. Moreover, case studies are conducted to demonstrate the capabilities of sjdb, but also to identify its limitations, as well as its response times and memory requirements

    Software Engineering 2021 : Fachtagung vom 22.-26. Februar 2021 Braunschweig/virtuell

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    Conceptual framework for closed-loop inspection based on the coordinate measurement technology adherent to STEP-NC

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    Tese (doutorado) — Universidade de Brasília, Faculdade de Tecnologia, Departamento de Engenharia Mecânica, 2021.As demandas por qualidade e produtividade na fabricação de peças com especificações de projeto com- plexas representam novos desafios para os processos de fabricação e sistemas de inspeção de qualidade. Os desafios são coletar, processar, transmitir e armazenar dados do processo de fabricação e inspeção e refinar cada processo relacionado ao ciclo de vida do produto. Conceitos como integração e interoperabili- dade, relevantes no contexto digital, apresentam barreiras que impedem sua plena implementação no atual cenário de manufatura. A implementação de uma malha fechada de manufatura permite que os resulta- dos da inspeção sejam realimentados na cadeia digital e usados para tomar decisões nas fases de projeto, planejamento e fabricação que reduzem as incertezas na fabricação. A inspeção dimensional e geométrica permite a geração de dados contendo vestígios de fabricação. Esses dados processados corretamente podem fornecer conhecimento sobre as causas do desvio da peça fabricada e as condições de fabricação que podem ser melhoradas. Este trabalho de tese se enquadra nesta perspectiva e apresenta uma solução de integração de dados gerados nas diferentes fases do ciclo de vida de um produto. A integração de dados ocorre em uma arquitetura de manufatura em malha fechada por meio de uma linguagem neutra, extensível e sintaticamente homogênea que permite vincular informações de projeto, manufatura, resultados de medição e suportar o fluxo por meio de sistemas CAx (tecnologias assistidas por computador). Como resultado da pesquisa, a arquitetura de integração interoperável baseada no padrão ISO10303 e seus protocolos de aplicação é apresentada, cobrindo especificações de projeto, requisitos de fabricação e troca de informações de inspeção dimensional e geométrica. Uma implementação computacional é desenvolvida usando o ambiente Java para manipular esquemas EXPRESS, gerar bibliotecas com entidades, funções, métodos e desenvolver uma aplicação que permite ler, escrever e modificar arquivos neutros de troca STEP. A metodologia seguida por meio de uma estrutura conceitual prática é exposta para gerar novas aplicações baseadas na norma ISO 10303. Três estudos de caso são apresentados para verificar a integração e interoperabilidade dentro da arquitetura de manufatura em malha fechada. Os resultados revelam novas linhas de pesquisa que são propostas para trabalhos futuros.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).The demands for quality and productivity in manufacturing parts with complex design specifications pose new challenges for manufacturing processes and quality inspection systems. The challenges are collecting, processing, transmitting, and storing data from the manufacturing and inspection process and refining each process related to the product life cycle. Concepts such as integration and interoperability, relevant within the digital context, show barriers that prevent their full implementation within the current manufacturing scenario. Implementing a closed manufacturing loop allows inspection results to be fed back into the digital chain and used to make decisions in the design, planning, and manufacturing phases that reduce uncertainties in manufacturing. Dimensional and geometric inspection allows the generation of data containing traces of manufactur- ing. These correctly processed data can provide knowledge about causes of deviation of the manufactured part and manufacturing conditions that can be improved. This thesis work is framed within this perspective and presents a solution for integrating data generated in the different phases of the life cycle of a prod- uct. Data integration occurs within a closed-loop manufacturing architecture through a neutral, extensible, syntactically homogeneous language that allows both linking design information, manufacturing, measure- ment results, and supporting the flow through Computer-Aided Technologies (CAx) systems. As a result of the research, interoperable integration architecture based on the ISO10303 standard and its application protocols is presented, covering design specifications, manufacturing requirements, and dimensional and geometric inspection information exchange. A computational implementation is developed using the Java environment to manipulate EXPRESS schemas, generate libraries with entities, functions, methods and develop an application that allows read- ing, writing, and modifying neutral STandard for the Exchange of Product model data (STEP) exchange files. The methodology followed through a practical conceptual framework is exposed to generate new applications based on the International Standards Organization (ISO) 10303 standard. Three case studies are presented to verify integration and interoperability within the closed-loop manufacturing architecture. The results reveal new lines of research that are proposed for future work

    A viabilidade de Dart em desenvolvimento full stack: um estudo de caso

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    In 2012, Google released the Dart language which, more recently, due to Flutter, has received a boost in popularity and is being often referred to as a full-stack language / ecosystem suitable for developing front-end and back-end solutions. However, aside from Flutter for mobile, Dart usage is still quite low when it comes to developing enterprise level solutions. In this dissertation, we tried to investigate the adequacy of using Dart to develop a full-stack solution with special focus on its back-end support. With that in mind, a typical scenario involving both a mobile and a web-supported front end, where both communicate with a back-end server via a REST endpoint, was established. For performance comparison, we deployed an equivalent back-end server developed using Spring Boot, a popular Java-based solution, which was used as reference. The main result was that a full-stack system can be developed with just a Dart / Flutter ecosystem and, in our scenario, this system’s performance surpassed Spring Boot’s. From a developer’s perspective, off-the-shelf Dart embedded asynchronous solutions (e.g., streams, Futures, etc.) are clearly an improvement over similar mechanisms in Java / Spring Boot due to avoiding typical Java solutions, namely asynchronous configurations, and annotations. However, despite some interesting projects arising, when excluding Google’s own developed packages/resources, most third-party packages are either using out-of-date dependencies due to compatibility issues or have been abandoned entirely – this had an impact during the development stage as it led to unplanned constraints when choosing packages and / or frameworks used.Em 2012, Google lançou a linguagem Dart que, mais recentemente, devido ao Flutter, recebeu um impulso em popularidade e é muitas vezes referida como uma linguagem / ecossistema full stack adequado para o desenvolvimento de soluções front end e back end. No entanto, além do Flutter para dispositivos móveis, o uso de Dart ainda é muito baixo quando se trata de desenvolver soluções de nível corporativo. Nesta dissertação, tentamos investigar a adequação do uso de Dart para desenvolver uma solução full stack com foco especial no seu suporte de back end. Com isso em mente, foi estabelecido um cenário típico envolvendo um front end móvel e um compatível com web, em que ambos comunicam com um servidor back end por meio de um endpoint REST. Para comparação de desempenho, implementamos um servidor back end equivalente desenvolvido usando Spring Boot, uma solução popular baseada em Java, que foi usada como referência. O resultado principal foi que um sistema full stack pode ser desenvolvido com apenas um ecossistema Dart / Flutter e, no nosso cenário, o desempenho desse sistema ultrapassou o Spring Boot. Do ponto de vista do programador, soluções assíncronas incorporadas Dart prontas para uso (por exemplo, streams, Futures, etc.) são claramente uma melhoria em relação a mecanismos semelhantes em Java / Spring Boot devido a evitarem soluções Java típicas, nomeadamente configurações assíncronas e anotações. No entanto, apesar de alguns projetos interessantes surgirem, ao excluir os pacotes / recursos desenvolvidos pela própria Google, a maioria dos pacotes desenvolvidos por terceiros usam dependências desatualizadas devido a problemas de compatibilidade ou foram abandonados inteiramente - isso teve um impacto durante a fase de desenvolvimento, pois levou a restrições não planeadas na escolha de pacotes e / ou frameworks usados.Mestrado em Engenharia de Computadores e Telemátic

    Quality and clinical utility of genomic variants in complex diseases

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    Continuous improvements in high-throughput genomic sequencing over the past two decades have made it exponentially faster and cheaper, enabling its routine use in the clinic and scientific research. Genomic prognostic tools make use of personalised genomic data to aid clinical decision making and inform patients of disease outcomes, allowing enhanced tailoring of treatment beyond traditional prognostic tools, which are insufficient for understanding the nuances of individual complex disease cases. This relies upon accurate sequencing data and effective quality control. We have developed improved genomic prognostic tools for use in the clinic and demonstrate a novel method for quality control of genomic sequencing data with broad applicability. Non-small-cell lung cancer (NSCLC) is the second most common cancer type in both males and females globally. Previous attempts to predict survival time for cancer patients have used genomic prognostic tools based on the burden of tumour mutations and neoantigens, but with limited success. We developed greatly improved classifiers of tumour mutation and neoantigenic burden showing strong 5-year survival differences between early-stage NSCLC patients. By using these together, we showed additional increases in prognostic efficacy, with the best survival group displaying a ~92% decreased risk of death in a 5-year period compared to the worst survival group. To improve the accuracy of sequencing data for uses such as this, we developed the first tool for automatically cataloguing systematic sequencing biases for a sequencing pipeline, and we demonstrated its value in human and SARS-CoV-2 sequencing quality control with Illumina and Oxford Nanopore sequencing. We discovered and blacklisted a range of false positive variants, and investigated the causes of these. Identifying these errors contributed to multiple studies, altering research conclusions. We share these tools to provide continued improvements to genomic prognostics and sequencing accuracy affecting a wide range of fields

    Tagungsband zum 21. Kolloquium Programmiersprachen und Grundlagen der Programmierung

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    Das 21. Kolloquium Programmiersprachen und Grundlagen der Programmierung (KPS 2021) setzt eine traditionelle Reihe von Arbeitstagungen fort, die 1980 von den Forschungsgruppen der Professoren Friedrich L. Bauer (TU München), Klaus Indermark (RWTH Aachen) und Hans Langmaack(CAU Kiel) ins Leben gerufen wurde.Die Veranstaltung ist ein offenes Forum für alle interessierten deutschsprachigen Wissenschaftlerinnen und Wissenschaftler zum zwanglosen Austausch neuer Ideen und Ergebnisse aus den Forschungsbereichen Entwurf und Implementierung von Programmiersprachen sowie Grundlagen und Methodik des Programmierens. Dieser Tagungsband enthält die wissenschaftlichen Beiträge,die bei dem 21. Kolloquium dieser Tagungsreihe präsentiert wurden, welches vom 27. bis 29. September 2021 in Kiel stattfand und von der Arbeitsgruppe Programmiersprachen und Übersetzerkonstruktion der Christian-Albrechts-Universität zu Kiel organisiert wurde

    Scalable Bayesian Hierarchical Modelling with application in genomics

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    Ph. D. Thesis.Hierarchical modelling can be applied to data organised in groups, for which we are interested in describing the within and between group variability. This type of model is very useful for a broad range of statistical problems. However, due to the complex nature of some data and the continuously increasing volume of datasets, using current methodologies for Bayesian hierarchical modelling can be challenging. The algorithms currently utilised, such as the Markov Chain Monte Carlo (MCMC) family, can be computationally intensive and difficult to parallelise, often leading to extended processing times, limiting exploration of different models, especially in cases of \Big Data" applications. These algorithms can be deployed using various programming paradigms, such as object-oriented, probabilistic and functional. The latter has been gaining ground in academia and industry over recent years. This thesis is concerned with examining an approach that will harness the benefits of functional programming and aims to provide valuable insights on whether MCMC algorithms, and in particular the Gibbs sampler, implemented in a functional style, can scale better whilst remaining accurate. More specifically, we implement a Gibbs sampler in Scala to t a Bayesian hierarchical two-way Anova model that includes interactions and accounts for various levels of asymmetry in the e ects. We incorporate variable selection on the interaction e ects through exploration of two techniques, an indicator variable approach, and the Horseshoe prior. In addition, we investigate under which model speci cations parallelism can a ect speed-up. After comparing the e ciency of the methods developed to the results deriving from some already existing libraries that automate and facilitate the modelling and inference processes, we explore their application on a yeast genome case study. The identi cation of gene complexes that genetically interact with telomere capping defects is of great importance in cell biology, as research has shown that telomeres can be related to ageing and various diseases. A Bayesian hierarchical model is developed to highlight and estimate the strength of potential epistatic relationships between genes of interest. However, the methodology developed has a wider range of applications and is not limited to the yeast genome case study.Engineering and Physical Sciences Research Counci
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