97 research outputs found

    Development and application of methodologies and infrastructures for cancer genome analysis within Personalized Medicine

    Full text link
    [eng] Next-generation sequencing (NGS) has revolutionized biomedical sciences, especially in the area of cancer. It has nourished genomic research with extensive collections of sequenced genomes that are investigated to untangle the molecular bases of disease, as well as to identify potential targets for the design of new treatments. To exploit all this information, several initiatives have emerged worldwide, among which the Pan-Cancer project of the ICGC (International Cancer Genome Consortium) stands out. This project has jointly analyzed thousands of tumor genomes of different cancer types in order to elucidate the molecular bases of the origin and progression of cancer. To accomplish this task, new emerging technologies, including virtualization systems such as virtual machines or software containers, were used and had to be adapted to various computing centers. The portability of this system to the supercomputing infrastructure of the BSC (Barcelona Supercomputing Center) has been carried out during the first phase of the thesis. In parallel, other projects promote the application of genomics discoveries into the clinics. This is the case of MedPerCan, a national initiative to design a pilot project for the implementation of personalized medicine in oncology in Catalonia. In this context, we have centered our efforts on the methodological side, focusing on the detection and characterization of somatic variants in tumors. This step is a challenging action, due to the heterogeneity of the different methods, and an essential part, as it lays at the basis of all downstream analyses. On top of the methodological section of the thesis, we got into the biological interpretation of the results to study the evolution of chronic lymphocytic leukemia (CLL) in a close collaboration with the group of Dr. Elías Campo from the Hospital Clínic/IDIBAPS. In the first study, we have focused on the Richter transformation (RT), a transformation of CLL into a high-grade lymphoma that leads to a very poor prognosis and with unmet clinical needs. We found that RT has greater genomic, epigenomic and transcriptomic complexity than CLL. Its genome may reflect the imprint of therapies that the patients received prior to RT, indicating the presence of cells exposed to these mutagenic treatments which later expand giving rise to the clinical manifestation of the disease. Multiple NGS- based techniques, including whole-genome sequencing and single-cell DNA and RNA sequencing, among others, confirmed the pre-existence of cells with the RT characteristics years before their manifestation, up to the time of CLL diagnosis. The transcriptomic profile of RT is remarkably different from that of CLL. Of particular importance is the overexpression of the OXPHOS pathway, which could be used as a therapeutic vulnerability. Finally, in a second study, the analysis of a case of CLL in a young adult, based on whole genome and single-cell sequencing at different times of the disease, revealed that the founder clone of CLL did not present any somatic driver mutations and was characterized by germline variants in ATM, suggesting its role in the origin of the disease, and highlighting the possible contribution of germline variants or other non-genetic mechanisms in the initiation of CLL

    Development and application of methodologies and infrastructures for cancer genome analysis within Personalized Medicine

    Get PDF
    Programa de Doctorat en Biomedicina / Tesi realitzada al Barcelona Supercomputing Cener (BSC)[eng] Next-generation sequencing (NGS) has revolutionized biomedical sciences, especially in the area of cancer. It has nourished genomic research with extensive collections of sequenced genomes that are investigated to untangle the molecular bases of disease, as well as to identify potential targets for the design of new treatments. To exploit all this information, several initiatives have emerged worldwide, among which the Pan-Cancer project of the ICGC (International Cancer Genome Consortium) stands out. This project has jointly analyzed thousands of tumor genomes of different cancer types in order to elucidate the molecular bases of the origin and progression of cancer. To accomplish this task, new emerging technologies, including virtualization systems such as virtual machines or software containers, were used and had to be adapted to various computing centers. The portability of this system to the supercomputing infrastructure of the BSC (Barcelona Supercomputing Center) has been carried out during the first phase of the thesis. In parallel, other projects promote the application of genomics discoveries into the clinics. This is the case of MedPerCan, a national initiative to design a pilot project for the implementation of personalized medicine in oncology in Catalonia. In this context, we have centered our efforts on the methodological side, focusing on the detection and characterization of somatic variants in tumors. This step is a challenging action, due to the heterogeneity of the different methods, and an essential part, as it lays at the basis of all downstream analyses. On top of the methodological section of the thesis, we got into the biological interpretation of the results to study the evolution of chronic lymphocytic leukemia (CLL) in a close collaboration with the group of Dr. Elías Campo from the Hospital Clínic/IDIBAPS. In the first study, we have focused on the Richter transformation (RT), a transformation of CLL into a high-grade lymphoma that leads to a very poor prognosis and with unmet clinical needs. We found that RT has greater genomic, epigenomic and transcriptomic complexity than CLL. Its genome may reflect the imprint of therapies that the patients received prior to RT, indicating the presence of cells exposed to these mutagenic treatments which later expand giving rise to the clinical manifestation of the disease. Multiple NGS- based techniques, including whole-genome sequencing and single-cell DNA and RNA sequencing, among others, confirmed the pre-existence of cells with the RT characteristics years before their manifestation, up to the time of CLL diagnosis. The transcriptomic profile of RT is remarkably different from that of CLL. Of particular importance is the overexpression of the OXPHOS pathway, which could be used as a therapeutic vulnerability. Finally, in a second study, the analysis of a case of CLL in a young adult, based on whole genome and single-cell sequencing at different times of the disease, revealed that the founder clone of CLL did not present any somatic driver mutations and was characterized by germline variants in ATM, suggesting its role in the origin of the disease, and highlighting the possible contribution of germline variants or other non-genetic mechanisms in the initiation of CLL

    From Word Models to World Models: Translating from Natural Language to the Probabilistic Language of Thought

    Full text link
    How does language inform our downstream thinking? In particular, how do humans make meaning from language -- and how can we leverage a theory of linguistic meaning to build machines that think in more human-like ways? In this paper, we propose \textit{rational meaning construction}, a computational framework for language-informed thinking that combines neural models of language with probabilistic models for rational inference. We frame linguistic meaning as a context-sensitive mapping from natural language into a \textit{probabilistic language of thought} (PLoT) -- a general-purpose symbolic substrate for probabilistic, generative world modeling. Our architecture integrates two powerful computational tools that have not previously come together: we model thinking with \textit{probabilistic programs}, an expressive representation for flexible commonsense reasoning; and we model meaning construction with \textit{large language models} (LLMs), which support broad-coverage translation from natural language utterances to code expressions in a probabilistic programming language. We illustrate our framework in action through examples covering four core domains from cognitive science: probabilistic reasoning, logical and relational reasoning, visual and physical reasoning, and social reasoning about agents and their plans. In each, we show that LLMs can generate context-sensitive translations that capture pragmatically-appropriate linguistic meanings, while Bayesian inference with the generated programs supports coherent and robust commonsense reasoning. We extend our framework to integrate cognitively-motivated symbolic modules to provide a unified commonsense thinking interface from language. Finally, we explore how language can drive the construction of world models themselves

    Wissensintegration von generischem und fallbasiertem Wissen, uniforme Repräsentation, Verwendung relationaler Datenbanksysteme sowie Problemlösen mit Concept Based und Case Based Reasoning sowie Bayesschen Netzen in medizinischen wissensbasierten Systemen

    Get PDF
    Ein wissensbasiertes System soll den Mediziner im Rahmen der Diagnosestellung unterstützen, indem relevante Informationen bereitgestellt werden. Aus komplexen Symptomkonstellationen soll eine zuverlässige Diagnose und damit verbundene medizinische Maßnahmen abgeleitet werden. Grundlage dafür bildet das im System adäquat repräsentierte Wissen, das effizient verarbeitet wird. Dieses Wissen ist in der medizinischen Domäne sehr heterogen und häufig nicht gut strukturiert. In der Arbeit wird eine Methodik entwickelt, die die begriffliche Erfassung und Strukturierung der Anwendungsdomäne über Begriffe, Begriffshierarchien, multiaxiale Komposition von Begriffen sowie Konzeptdeklarationen ermöglicht. Komplexe Begriffe können so vollständig, eindeutig und praxisrelevant abgebildet werden. Darüber hinaus werden mit der zugrunde liegenden Repräsentation Dialogsysteme, fallbasierte und generische Problemlösungsmethoden sowie ihr Zusammenspiel mit relationalen Datenbanken in einem System vorgestellt. Dies ist vor allem im medizinischen Diskursbereich von Bedeutung, da zur Problemlösung generisches Wissen (Lehrbuchwissen) und Erfahrungswissen (behandelte Fälle) notwendig ist. Die Wissensbestände können auf relationalen Datenbanken uniform gespeichert werden. Um das vorliegende Wissen effizient verarbeiten zu können, wird eine Methode zur semantischen Indizierung vorgestellt und deren Anwendung im Bereich der Wissensrepräsentation beschrieben. Ausgangspunkt der semantischen Indizierung ist das durch Konzepthierarchien repräsentierte Wissen. Ziel ist es, den Knoten (Konzepten) Schlüssel zuzuordnen, die hierarchisch geordnet und syntaktisch sowie semantisch korrekt sind. Mit dem Indizierungsalgorithmus werden die Schlüssel so berechnet, dass die Konzepte mit den spezifischeren Konzepten unifizierbar sind und nur semantisch korrekte Konzepte zur Wissensbasis hinzugefügt werden dürfen. Die Korrektheit und Vollständigkeit des Indizierungsalgorithmus wird bewiesen. Zur Wissensverarbeitung wird ein integrativer Ansatz der Problemlösungsmethoden des Concept Based und Case Based Reasoning vorgestellt. Concept Based Reasoning kann für die Diagnose-, Therapie- und Medikationsempfehlung und -evaluierung über generisches Wissen verwendet werden. Mit Hilfe von Case Based Reasoning kann Erfahrungswissen von Patientenfällen verarbeitet werden. Weiterhin werden zwei neue Ähnlichkeitsmaße (Kompromissmengen für Ähnlichkeitsmaße und multiaxiale Ähnlichkeit) für das Retrieval ähnlicher Patientenfälle entwickelt, die den semantischen Kontext adäquat berücksichtigen. Einem ausschließlichen deterministischen konzeptbasiertem Schließen sind im medizinischen Diskursbereich Grenzen gesetzt. Für die diagnostische Inferenz unter Unsicherheit, Unschärfe und Unvollständigkeit werden Bayessche Netze untersucht. Es können so die gültigen allgemeinen Konzepte nach deren Wahrscheinlichkeit ausgegeben werden. Dazu werden verschiedene Inferenzmechanismen vorgestellt und anschließend im Rahmen der Entwicklung eines Prototypen evaluiert. Mit Hilfe von Tests wird die Klassifizierung von Diagnosen durch das Netz bewertet.:1 Einleitung 2 Medizinische wissensbasierte Systeme 3 Medizinischer Behandlungsablauf und erweiterter wissensbasierter Agent 4 Methoden zur Wissensrepräsentation 5 Uniforme Repräsentation mit Begriffshierachien, Konzepten, generischem und fallbasierten Schließen 6 Semantische Indizierung 7 Medizinisches System als Beispielanwendung 8 Ähnlichkeitsmaße, Kompromissmengen, multiaxiale Ähnlichkeit 9 Inferenzen mittels Bayesscher Netze 10 Zusammenfassung und Ausblick A Ausgewählte medizinische wissensbasierte Systeme zur Entscheidungsunterstützung aus der Literatur B Realisierung mit Softwarewerkzeugen C Causal statistic modeling and calculation of distribution functions of classification featuresA knowledge-based system is designed to support the medical professionals in the diagnostic process by providing relevant information. A reliable diagnosis and associated medical measures are to be derived from complex symptom constellations. It is based on the knowledge adequately represented in the system, which is processed efficiently. This knowledge is very heterogeneous in the medical domain and often not well structured. In this work, a methodology is developed that enables the conceptual capture and structuring of the application domain via concepts, conecpt hierarchies, multiaxial composition of concepts as well as concept declarations. Complex concepts can thus be mapped completely, clearly and with practical relevance. Furthermore, the underlying representation introduces dialogue systems, \acrlong{abk:CBR} and generic problem solving methods as well as their interaction with relational databases in one system. This is particularly important in the field of medical discourse, since generic knowledge (textbook knowledge) and experiential knowledge (treated cases) are necessary for problem solving. The knowledge can be stored uniformly on relational databases. In order to be able to process the available knowledge efficiently, a method for semantic indexing is presented and its application in the field of knowledge representation is described. The starting point of semantic indexing is the knowledge represented by concept hierarchies. The goal is to assign keys to the nodes (concepts) that are hierarchically ordered and syntactically and semantically correct. With the indexing algorithm, the keys are calculated in such a way that the concepts are unifiable with the more specific concepts and only semantically correct concepts may be added to the knowledge base. The correctness and completeness of the indexing algorithm is proven. An integrative approach of the problem-solving methods of Concept Based and \acrlong{abk:CBR} is presented for knowledge processing. Concept Based Reasoning can be used for diagnosis, therapy and medication recommendation and evaluation via generic knowledge. Case Based Reasoning can be used to process experiential knowledge of patient cases. Furthermore, two new similarity measures (compromise sets for similarity measures and multiaxial similarity) are developed for the retrieval of similar patient cases that adequately consider the semantic context. There are limits to an exclusively deterministic Concept Based Reasoning in the medical domain. For diagnostic inference under uncertainty, vagueness and incompleteness Bayesian networks are investigated. The method is based on an adequate uniform representation of the necessary knowledge. Thus, the valid general concepts can be issued according to their probability. To this end, various inference mechanisms are introduced and subsequently evaluated within the context of a developed prototype. Tests are employed to assess the classification of diagnoses by the network.:1 Einleitung 2 Medizinische wissensbasierte Systeme 3 Medizinischer Behandlungsablauf und erweiterter wissensbasierter Agent 4 Methoden zur Wissensrepräsentation 5 Uniforme Repräsentation mit Begriffshierachien, Konzepten, generischem und fallbasierten Schließen 6 Semantische Indizierung 7 Medizinisches System als Beispielanwendung 8 Ähnlichkeitsmaße, Kompromissmengen, multiaxiale Ähnlichkeit 9 Inferenzen mittels Bayesscher Netze 10 Zusammenfassung und Ausblick A Ausgewählte medizinische wissensbasierte Systeme zur Entscheidungsunterstützung aus der Literatur B Realisierung mit Softwarewerkzeugen C Causal statistic modeling and calculation of distribution functions of classification feature

    2021-2022, University of Memphis bulletin

    Get PDF
    University of Memphis bulletin containing the graduate catalog for 2021-2022.https://digitalcommons.memphis.edu/speccoll-ua-pub-bulletins/1441/thumbnail.jp

    2019-2020, University of Memphis bulletin

    Get PDF
    University of Memphis bulletin containing the graduate catalog for 2019-2020.https://digitalcommons.memphis.edu/speccoll-ua-pub-bulletins/1439/thumbnail.jp

    The Convergence of Human and Artificial Intelligence on Clinical Care - Part I

    Get PDF
    This edited book contains twelve studies, large and pilots, in five main categories: (i) adaptive imputation to increase the density of clinical data for improving downstream modeling; (ii) machine-learning-empowered diagnosis models; (iii) machine learning models for outcome prediction; (iv) innovative use of AI to improve our understanding of the public view; and (v) understanding of the attitude of providers in trusting insights from AI for complex cases. This collection is an excellent example of how technology can add value in healthcare settings and hints at some of the pressing challenges in the field. Artificial intelligence is gradually becoming a go-to technology in clinical care; therefore, it is important to work collaboratively and to shift from performance-driven outcomes to risk-sensitive model optimization, improved transparency, and better patient representation, to ensure more equitable healthcare for all

    Understanding Quantum Technologies 2022

    Full text link
    Understanding Quantum Technologies 2022 is a creative-commons ebook that provides a unique 360 degrees overview of quantum technologies from science and technology to geopolitical and societal issues. It covers quantum physics history, quantum physics 101, gate-based quantum computing, quantum computing engineering (including quantum error corrections and quantum computing energetics), quantum computing hardware (all qubit types, including quantum annealing and quantum simulation paradigms, history, science, research, implementation and vendors), quantum enabling technologies (cryogenics, control electronics, photonics, components fabs, raw materials), quantum computing algorithms, software development tools and use cases, unconventional computing (potential alternatives to quantum and classical computing), quantum telecommunications and cryptography, quantum sensing, quantum technologies around the world, quantum technologies societal impact and even quantum fake sciences. The main audience are computer science engineers, developers and IT specialists as well as quantum scientists and students who want to acquire a global view of how quantum technologies work, and particularly quantum computing. This version is an extensive update to the 2021 edition published in October 2021.Comment: 1132 pages, 920 figures, Letter forma

    Knowledge Augmented Machine Learning with Applications in Autonomous Driving: A Survey

    Get PDF
    The existence of representative datasets is a prerequisite of many successful artificial intelligence and machine learning models. However, the subsequent application of these models often involves scenarios that are inadequately represented in the data used for training. The reasons for this are manifold and range from time and cost constraints to ethical considerations. As a consequence, the reliable use of these models, especially in safety-critical applications, is a huge challenge. Leveraging additional, already existing sources of knowledge is key to overcome the limitations of purely data-driven approaches, and eventually to increase the generalization capability of these models. Furthermore, predictions that conform with knowledge are crucial for making trustworthy and safe decisions even in underrepresented scenarios. This work provides an overview of existing techniques and methods in the literature that combine data-based models with existing knowledge. The identified approaches are structured according to the categories integration, extraction and conformity. Special attention is given to applications in the field of autonomous driving
    corecore