1,720,959 research outputs found
Statistische Ansätze zur Modellreduktion in der Systempharmakologie
No full textGiven the narrow therapeutic window and the large inter-individual variability (IIV) associated with certain drugs, employing a fixed dosing strategy may result in unsafe or ineffective therapy. Model-informed precision dosing (MIPD) can improve efficacy and safety for these drugs by individualising doses based on patient-specific data with a suitable model. Traditionally, pharmacokinetic (PK)/pharmacodynamic (PD) models developed from clinical data, thus depending on the study design and population, have been applied in MIPD. While quantitative systems pharmacology (QSP) models promise better extrapolation capabilities, their complexity often prevents straightforward parameter estimation within MIPD. Model reduction approaches can help develop mechanism-based PK/PD models suitable for MIPD that retain the clinically relevant dynamics from QSP
models. Yet, these methods often fail to achieve a level of reduction that renders the models as manageable as classical PK/PD models. Moreover, existing reduction approaches often rely on a single reference parameter set, neglecting that, to predict individual outcomes accurately, the reduced model should approximate the full model well across variability.
The objective of this thesis is to develop a model reduction method that allows the derivation of mechanism-based PK/PD models from QSP models in the presence of IIV. This involves (i) considerably reducing complexity while maintaining a physiological interpretation, (ii) efficiently accounting for IIV in the reduction, and (iii) evaluating reduced models to assess their suitability for MIPD. As a case study, we consider anticoagulant treatment with warfarin measured by the international normalised ratio (INR).
With the aim of reducing the model complexity to a degree suitable for clinical use, we extend a state variable reduction method to incorporate parameter reduction and simplification of the functional complexity of reaction rates. This combination of multiple reduction methods allows for a higher reduction degree than existing methods while preserving the interpretability. The approach enables us to develop a novel warfarin/INR model from a blood coagulation QSP model. This model considerably simplifies INR simulation under warfarin therapy and allows us to identify a promising biomarker for early INR prediction.
We account for IIV by simulating a virtual population with diverse parameter values and evaluating the approximation error across this population during model reduction. To enhance the efficiency of virtual population-based model reduction, we introduce a novel sampling method based on empirical observability Gramians. By identifying dominant parameter directions that govern the variability in responses, the high-dimensional parameter space can be covered efficiently. This approach allows for smaller sample sizes without compromising the robustness of reduced models under parameter variability.
Before applying a QSP-derived PK/PD model for MIPD, its predictive performance should be evaluated. We externally evaluate the clinical applicability of our reduced warfarin/INR model using a Bayesian approach, integrating the prior knowledge encoded in the model with individual patient data. Despite not being calibrated with clinical data from warfarin initiation, the accuracy and precision of predictions from our QSP-derived warfarin/INR model are comparable to the current gold-standard approach based on an empirical PK/PD model.
The proposed model reduction approach offers an improved rationale for developing mechanism-based PK/PD models for precision dosing by addressing IIV and facilitating biomarker identification. The approach enables improved dosing individualisation with the potential to advance patient safety and therapeutic efficacy, specifically in anticoagulant therapy.Angesichts von Arzneimitteln mit einem schmalen therapeutischen Fenster, in dem das Medikament sicher und effektiv ist, und großer interindividuellen Variabilität (IIV) kann die Anwendung einer festen Dosierungsstrategie zu einer unsicheren oder unwirksamen Therapie führen. Die modellinformierte Präzisionsdosierung (Model-Informed Precision Dosing, MIPD) kann die Wirksamkeit und Sicherheit dieser Arzneimittel verbessern, indem die Dosierung auf der Grundlage patientenspezifischer Daten mit einem geeigneten Modell individualisiert wird. Bisher wurden für die MIPD pharmakokinetische (PK)/pharmakodynamische (PD) Modelle verwendet, die aus klinischen Daten entwickelt wurden und somit vom Studiendesign und der betrachteten Population abhängen. Modelle der quantitativen Systempharmakologie (QSP) versprechen zwar bessere Extrapolationsmöglichkeiten, ihre Komplexität verhindert jedoch häufig eine einfache Parameterschätzung im Rahmen der MIPD. Ansätze zur Modellreduktion können helfen, mechanismusbasierte PK/PD-Modelle zu entwickeln, die für MIPD geeignet sind und die biologische Interpretierbarkeit von QSP-Modellen erhalten. Allerdings erreichen diese Methoden oft nicht den Grad der Reduktion, der die Modelle so handhabbar machen würde wie klassische PK/PD-Modelle. Darüber hinaus stützen sich die bestehenden Reduktionsansätze oft auf einen einzigen Referenzparametersatz und vernachlässigen, dass das reduzierte Modell das vollständige Modell über die Variabilität hinweg gut approximieren sollte, um individuelle Ergebnisse genau vorherzusagen.
Ziel dieser Arbeit ist es, eine Modellreduktionsmethode zu entwickeln, die die Ableitung mechanismusbasierter PK/PD-Modelle aus QSP-Modellen in Gegenwart von IIV ermöglicht. Dies beinhaltet (i) eine beträchtliche Reduktion der Komplexität unter Beibehaltung einer physiologischen Interpretierbarkeit, (ii) eine effiziente Berücksichtigung von IIV bei der Reduktion und (iii) eine Bewertung der reduzierten Modelle, um ihre Eignung für MIPD zu beurteilen. Als Fallstudie betrachten wir die gerinnungshemmende Behandlung mit Warfarin, gemessen durch die internationale normalisierte Ratio (INR).
Mit dem Ziel, die Modellkomplexität auf ein für den klinischen Einsatz geeignetes Maß zu reduzieren, erweitern wir eine Methode zur Reduktion von Zustandsvariablen und kombinieren sie mit Parameterreduktion und einer Vereinfachung der funktionalen Komplexität der Reaktionsraten. Diese Kombination mehrerer Reduktionsmethoden ermöglicht einen höheren Reduktionsgrad als bestehende Methoden, wobei die Interpretierbarkeit erhalten bleibt. Dieser Ansatz ermöglicht es uns, ein Warfarin/INR-Modell aus einem QSP-Modell für die Blutgerinnung zu entwickeln. Dieses Modell vereinfacht die INR-Simulation unter Warfarin-Therapie erheblich und ermöglicht es uns, einen vielversprechenden Biomarker für die INR-Vorhersage zu identifizieren.
Wir berücksichtigen IIV, indem wir eine virtuelle Population mit verschiedenen Parameterwerten simulieren und während der Modellreduktion den Approximationsfehler über diese Population auswerten. Um die Effizienz der auf der virtuellen Population basierenden Modellreduktion zu verbessern, führen wir eine Sampling-Methode ein, die auf empirischen Beobachtbarkeits-Gramians basiert. Durch die Identifizierung dominanter Parameterrichtungen, die die Variabilität der Modellausgaben bestimmen, kann der hochdimensionale Parameterraum effizient abgedeckt werden. Dieser Ansatz ermöglicht eine kleinere Stichprobengröße, ohne die Robustheit der reduzierten Modelle unter Parametervariabilität zu beeinträchtigen.
Vor der Anwendung eines von QSP abgeleiteten PK/PD-Modells für MIPD sollte seine Vorhersageleistung bewertet werden. Wir evaluieren die klinische Anwendbarkeit unseres reduzierten Warfarin/INR-Modells mithilfe eines Bayes’schen Ansatzes, wobei wir das im Modell kodierte Vorwissen mit individuellen Patientendaten integrieren. Obwohl das Modell nicht mit INR-Daten aus der Warfarin-Einstellungsphase kalibriert wurde, sind die Genauigkeit und Präzision der Vorhersagen unseres Warfarin/INR-Modells vergleichbar mit dem derzeitigen Goldstandard-Ansatz, der auf einem empirischen PK/PD-Modell basiert.
Der vorgeschlagene Ansatz zur Modellreduktion bietet eine bessere Grundlage für die Entwicklung von mechanismusbasierten PK/PD-Modellen für die Präzisionsdosierung, indem er IIV berücksichtigt und die Identifizierung von Biomarkern erleichtert. Der Ansatz ermöglicht eine bessere Individualisierung der Dosierung mit dem Potenzial, die Sicherheit der Patienten und die therapeutische Wirksamkeit, insbesondere bei der Antikoagulanzientherapie, zu verbessern
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
- …
