<p>Population pharmacokinetic-pharmacodynamic (PK-PD) models can be fitted using nonlinear mixed effects modelling (NONMEM). This is an efficient way of learning about drugs and diseases from data collected in clinical trials. Identifying covariates which explain differences between patients is important to discover patient subpopulations at risk of sub-therapeutic or toxic effects and for treatment individualization. Stepwise covariate modelling (SCM) is commonly used to this end. The aim of the current thesis work was to evaluate SCM and to develop alternative approaches. A further aim was to develop a mechanistic PK-PD model describing fasting plasma glucose, fasting insulin, insulin sensitivity and beta-cell mass.</p><p>The lasso is a penalized estimation method performing covariate selection simultaneously to shrinkage estimation. The lasso was implemented within NONMEM as an alternative to SCM and is discussed in comparison with that method. Further, various ways of incorporating information and propagating knowledge from previous studies into an analysis were investigated. In order to compare the different approaches, investigations were made under varying, replicated conditions. In the course of the investigations, more than one million NONMEM analyses were performed on simulated data. Due to selection bias the use of SCM performed poorly when analysing small datasets or rare subgroups. In these situations, the lasso method in NONMEM performed better, was faster, and additionally validated the covariate model. Alternatively, the performance of SCM can be improved by propagating knowledge or incorporating information from previously analysed studies and by population optimal design.</p><p>A model was also developed on a physiological/mechanistic basis to fit data from three phase II/III studies on the investigational drug, tesaglitazar. This model described fasting glucose and insulin levels well, despite heterogeneous patient groups ranging from non-diabetic insulin resistant subjects to patients with advanced diabetes. The model predictions of beta-cell mass and insulin sensitivity were well in agreement with values in the literature.</p>

Population pharmacokinetic-pharmacodynamic (PK-PD) models can be fitted using nonlinear mixed effects modelling (NONMEM). This is an efficient way of learning about drugs and diseases from data collected in clinical trials. Identifying covariates which explain differences between patients is important to discover patient subpopulations at risk of sub-therapeutic or toxic effects and for treatment individualization. Stepwise covariate modelling (SCM) is commonly used to this end. The aim of the current thesis work was to evaluate SCM and to develop alternative approaches. A further aim was to develop a mechanistic PK-PD model describing fasting plasma glucose, fasting insulin, insulin sensitivity and beta-cell mass. The lasso is a penalized estimation method performing covariate selection simultaneously to shrinkage estimation. The lasso was implemented within NONMEM as an alternative to SCM and is discussed in comparison with that method. Further, various ways of incorporating information and propagating knowledge from previous studies into an analysis were investigated. In order to compare the different approaches, investigations were made under varying, replicated conditions. In the course of the investigations, more than one million NONMEM analyses were performed on simulated data. Due to selection bias the use of SCM performed poorly when analysing small datasets or rare subgroups. In these situations, the lasso method in NONMEM performed better, was faster, and additionally validated the covariate model. Alternatively, the performance of SCM can be improved by propagating knowledge or incorporating information from previously analysed studies and by population optimal design. A model was also developed on a physiological/mechanistic basis to fit data from three phase II/III studies on the investigational drug, tesaglitazar. This model described fasting glucose and insulin levels well, despite heterogeneous patient groups ranging from non-diabetic insulin resistant subjects to patients with advanced diabetes. The model predictions of beta-cell mass and insulin sensitivity were well in agreement with values in the literature.

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Software for designing structural frameworks in civil engineering is getting more and more complex. By offering reliable and efficient calculation methods, economic goals can be reached as well as the civil engineer's demands. Furthermore, opportunities for special developments are created and acceptance of new building systems is increased. The work presented here introduces a method for the physically nonlinear analysis of different composite beam designs for building and bridge structures which are subjected mainly to bending stresses under quasi-static, long-term loading. In addition, the utilization of these methods, including materials and modelling concepts, are shown in a newly developed software package. Present developments for composite construction and civil engineering requirements are the basis for the materials and modelling possibilities discussed. Particular attention is given to a realistic description of time and load dependent variables characterizing the state of the composite structures and their interactions. The selection of material models is based on experimental results. The main points of interest are concrete properties like creep, shrinkage, effluent hydration heat, cracking and boundary behaviour between different materials. Material behaviour under load and reload conditions was taken into account as well. The static solution is based on the incremental iterative application of the deformation method. Each iteration starts with the numerical integration of the beam system of differential equations. Based on the effects at the beam boundaries, the consideration of load and system modifications, as well as time dependent and independent constraint processes, is shown. An essential extension of the composite beam structure model is obtained using the system of differential equations for the flexible bond. Several detailed models are linked to a time dependent simulation for the entire system, which has been incorporated into a software package visualizing the time dependent variables. Finally, some practical application examples are presented. The validation of the implemented approach is demonstrated by correlating the calculated results with real life measurements. / Softwareentwicklungen für die Tragwerksplanung im Bauwesen werden zunehmend komplexer. Mit der Bereitstellung zuverlässiger und effizienter Berechnungsmethoden, welche sowohl ingenieurgemäße Ansprüche als auch wirtschaftliche Zielsetzungen erfüllen, werden neue Möglichkeiten für eine zielgerichtete Entwicklung oder verstärkte Etablierung von neueren Bauweisen geschaffen. Die vorliegende Arbeit beschreibt ein Verfahren zur physikalisch nichtlinearen Analyse vorwiegend biegebeanspruchter Verbund-Stabtragwerke des Hoch- und Brückenbaues unter quasi-statischer Langzeitbeanspruchung. Die zugehörige programmtechnische Umsetzung wird veranschaulicht. Die Modellierungsmöglichkeiten bezüglich der Werkstoffe orientieren sich an baupraktisch relevanten Erfordernissen sowie an den Besonderheiten und aktuellen Entwicklungen der Verbundbauweise. Besonderes Augenmerk wird zunächst auf eine realitätsnahe Darstellung der den Gebrauchs¬zustand von Verbundtragwerken charakterisierenden zeit- und lastabhängigen Einflussgrößen sowie ihrer Wechselwirkungen gelegt. Zur objektiven Beurteilung möglicher Materialmodelle wird zuerst auf das prinzipielle Verhalten im Experiment eingegangen, danach erfolgt eine Auswahl geeigneter Modelle. Schwerpunkte stellen dabei insbesondere die Betoneigenschaften Kriechen, Schwinden, abfließende Hydratationswärme und die Rissbildung sowie das Verbundverhalten zwischen den Werkstoffen dar. Diese Betrachtungen schließen das Werk¬stoffverhalten unter Be- und Entlastung ein. Die statische Lösung basiert auf einer inkrementell-iterativen Anwendung der Deformations¬methode. Ausgangspunkt der Berechnungen in einem Iterationsschritt ist die numerische Integration des Stab-Differentialgleichungssystems. Ausgehend von der Formulierung der Wirkungsgrößen an einem Stabrändern wird die Berücksichtigung von Belastungs- und Systemmodifikationen sowie zeitabhängigen und -unabhängigen Zwangsprozessen aufgezeigt. Eine wesentliche Erweiterung der Anwendungen im Stahl-Beton-Verbundbau stellt die Herleitung des Stab-Differentialgleichungssystems für den nachgiebigen Verbund dar. Mit der Verknüpfung einzelner Detailmodelle zu einem zeitabhängigen Lösungsverfahren und deren Integration in einen entsprechenden Softwareentwurf wird die programmtechnische Basis für eine modellhafte, zeitvariante Erfassung der beschreibenden Kenngrößen bereitgestellt. Ausgewählte praktische Beispiele demonstrieren abschließend die Anwendungsmöglichkeiten des Verfahrens und stellen die Verifikation der Simulationsergebnisse anhand von Messungen dar.

迴歸模式的變數選取是很重要的課題，Tibshirani於1996年提出最小絕對壓縮挑選機制（Least Absolute Shrinkage and Selection Operator；簡稱Lasso），主要特色是能在估計的過程中自動完成變數選取。但因為Lasso本身並沒有牽扯到統計推論的層面，因此2014年時Lockhart et al.所提出的Lasso顯著性檢定是重要的突破。由於Lasso顯著性檢定的建構過程與傳統向前逐步迴歸相近，本研究接續Lockhart et al.(2014)對兩種變數選取方法的比較，提出以Bootstrap來改良傳統向前逐步迴歸；最後並比較Lasso、Lasso顯著性檢定、傳統向前逐步迴歸、以AIC決定變數組合的向前逐步迴歸，以及以Bootstrap改良的向前逐步迴歸等五種方法變數選取之效果。最後發現Lasso顯著性檢定雖然不容易犯型一錯誤，選取變數時卻過於保守；而以Bootstrap改良的向前逐步迴歸跟Lasso顯著性檢定一樣不容易犯型一錯誤，而選取變數上又比起Lasso顯著性檢定更大膽，因此可算是理想的方法改良結果。 / Variable selection of a regression model is an essential topic. In 1996, Tibshirani proposed a method called Lasso (Least Absolute Shrinkage and Selection Operator), which completes the matter of selecting variable set while estimating the parameters. However, the original version of Lasso does not provide a way for making inference. Therefore, the significance test for lasso proposed by Lockhart et al. in 2014 is an important breakthrough. Based on the similarity of construction of statistics between Lasso significance test and forward selection method, continuing the comparisons between the two methods from Lockhart et al. (2014), we propose an improved version of forward selection method by bootstrap. And at the second half of our research, we compare the variable selection results of Lasso, Lasso significance test, forward selection, forward selection by AIC, and forward selection by bootstrap. We find that although the Type I error probability for Lasso Significance Test is small, the testing method is too conservative for including new variables. On the other hand, the Type I error probability for forward selection by bootstrap is also small, yet it is more aggressive in including new variables. Therefore, based on our simulation results, the bootstrap improving forward selection is rather an ideal variable selecting method.

Le panneau isolant sous vide, PIV est principalement constitué d’un matériau de cœur nano-poreux encapsulé sous vide par une enveloppe barrière multicouche polymère-métal. Dans l’objectif d’étendre le domaine d’emploi des PIV sur le marché de l’isolation thermique du bâtiment, il est nécessaire d’améliorer les performances d’étanchéités et la résistance en température et humidité des complexes barrières métallisés, ces derniers représentant le point faible des PIV. Ce travail a pour objectif d’identifier les différentes modifications subies par ces complexes au cours de leurs fonctionnement et de déterminer les mécanismes à l’origine de leur dégradation prématurée. Des vieillissements à 70 °C et 90 %RH (conditions maximales d’utilisations identifiées pour le bâtiment français) ont été réalisés à la fois sur les composants, sur les complexes et sur les PIV pour des temps compris entre 1 et 870 jours. A l’échelle microscopique, la dégradation chimique du polyéthylène téréphtalate (PET) et de l’adhésif polyuréthane (PU) ont été étudiées par spectroscopie IR. Des marqueurs de l’hydrolyse ont ainsi pu être identifiés et ont permis de mettre en évidence la dégradation de ces deux composants au sein du complexe. L’hydrolyse ayant des répercussions directes sur les propriétés mécaniques des polymères explique la fragilisation à long terme de l’enveloppe. L’action de l’eau entraine également un gonflement et une plastification du PET, mis en évidence par mesure gravimétrique. Ces derniers peuvent entrainer des modifications de microstructure ayant des répercussions directes sur les mécanismes de transports des molécules d’eau et ainsi participer à la fragilisation du complexe. A l’échelle macroscopique, des mesures fines de retrait des films polymères ont été réalisées. Ces dernières ont été corrélées aux différentes délaminations de l’enveloppe barrière. Des analyses aux interfaces ont permis de déterminer le mode de rupture, adhésif ou cohésif. / Vacuum Insulation Panels (VIPs) were already developed some time ago for low-temperature applications such as refrigerators. More recently, they have been used for the building application. They consist of a fine powder or fiber core material (fumed silica, glass fiber, PU foam) enveloped by a polymer-metal. The latter is responsible for preventing gas and water molecules from breaking the vacuum. Nevertheless, the use of VIPs for this application was limited for applications in severe conditions as for example: temperature, humidity and mechanical load. At high temperature and/or humidity, the most critical component of a VIP is the envelope: both for the tightness point of view and for its degradation. Consequently in these conditions, the vacuum was degraded and durability of the panel performance was decreased sharply.This work focuses on the degradation mechanisms of the polymer-metal envelope. The effect of hygrothermal ageing (70 °C and 90 %RH) on envelope was investigated at different scales: Microscopic: High humidity is at the origin of the hydrolysis of some components such as Polyethylene terephthalate (PET) and polyurethane adhesive (PU). Hydrolysis is directly at the origin of the changes mechanical properties, leading to embrittlement of the complex. An additional microstructural modifications was evidence in PET at high humidity and also contributes to embrittlement of the complex. Macroscopic: shrinkage of polymer film seems to be the origin of debonding in polymer-metal multilayer.

Dans le cadre de la recherche, nous nous intéressons à la pratique du projet urbain dans les villes en décroissance (ou ville rétrécissante), plus connues sous le terme anglophone de shrinking cities. Cet intérêt est né d’un questionnement plus large sur la pratique de l’architecte-urbaniste et la fabrique de la ville en ce début du XXIe siècle, où les débats se multiplient sur la ville résiliante, économe, autosuffisante face aux crises écologiques, socio- économiques et politiques actuelles. La ville en décroissance offre ainsi un cadre intéressant pour nous confronter à cette problématique où l’architecte-urbaniste se retrouve à devoir s’adapter et se réinventer face à de multiples contraintes. Par ailleurs, le programme allemand Shrinking Cities et les réflexions portées par l’architecte-chercheur allemand Philipp Oswalt ont été un élément déclencheur. Ce dernier revendiquait l’idée que la ville en décroissance était le nouveau terrain de jeu pour explorer de nouvelles pensées architecturales et urbanistiques. Il le démontre à partir d’un travail de collecte d’expériences à travers le monde. Aujourd’hui, nous proposons de poursuivre cette réflexion et de nous poser la question suivante: quels enseignements pouvons-nous tirer de ces expériences pour notre pratique et imaginer la ville de demain ? À partir de ce questionnement, nous faisons l’hypothèse que ces nouvelles pensées architecturales et urbaines (concepts, langages architecturaux, formes urbaines, etc.) participeraient à la formulation de nouvelles formes d’habiter les territoires (usages, modèles urbains, paysage, modes de vie, etc.), permettant d’envisager différemment la fabrique urbaine en ce début du XXIe. Ces démarches seraient par ailleurs actrices dans la reconnaissance de terrains favorables pour une gestion urbaine raisonnée et dans le développement de nouveaux outils et protocoles d’action imaginés par les architecte-urbanistes.Pour répondre à notre hypothèse de recherche, nous nous intéressons plus spécifiquement aux projets impulsant une mutation profonde du tissu urbain, dans sa forme comme dans ses usages que nous nommons ici par remodelage urbain. Notre analyse se base sur six démarches dites « innovantes », théoriques et réalisées, dont un cas est mis en œuvre par des habitants. Elles illustrent cette pratique dans différentes villes en décroissance depuis ces vingt dernières années.Ces cas d’étude sont situés dans des tissus urbains différents (habitat dense en centre-ville et dans les bourgs ruraux, grands ensembles, habitat pavillonnaire) pour montrer la diversité des terrains auxquels l’architecte-urbaniste peut être confronté. Parallèlement aux deux cas français (Saint-Étienne, Livradois-Forez), nous observerons d’autres expériences dans deux contextes étrangers, précurseurs en termes d’initiatives locales et de politiques urbaines : l’Allemagne (Halle- Neustadt, Dessau) et les États-Unis (Detroit). La diversité des approches et des échelles de réflexion de ces projets ne permet pas de conduire une étude comparative. Plus adaptée à notre démarche, nous proposons leur mise en discussion pour comprendre l’impact du cadre politique, socio-économique et de l’environnement urbain sur le processus de projet ainsi que la capacité de ces projets à amorcer une transformation du tissu urbain et de la ville.Notre objectif sera ainsi de comprendre l’originalité et les spécificités de ces démarches, mais aussi leurs apports potentiels dans les débats actuels sur la ville et ses évolutions. Cette démarche cherche à apporter une dimension prospective sur le sujet de la ville en décroissance. / Within the methodological framework of the academic research, this study focuses on the urban development specific to shrinking cities. This interest raised from a broader interrogation on the professional practice of urban architects and the making of the city ongoing in this early XXIth century, with regards to contemporary debates about cities that are resilient, economical, self sufficient toward ecological, socio-economical and political crises. The shrinking city offers thus an interesting framework to study architects-urban planners reactions to such contexts and constraints adaptation. Furthermore the German programm Shrinking Cities and the reflexions raised by the German architect and researcher Philipp Oswalt have been a trigger component. He claims that the shrinking city was a new playground to explore new architectural and planning thoughts. He demonstrates it from a gathering of experiences around the world. Today, we suggest to follow this reflexion and raise the following issue: which lessons are to be learned from those experiences for today’s professional practice and imagine the city of tomorrow ?From this initial questioning, we took for granted that those new ways of seeing architecture and urban project (concepts, architectural languages, urban shape, etc.) lead to new leaving standards territories (uses, urban patterns, landscape, leaving conditions, etc.), changing thus the making of the city in this beginning of XXIth century. Indeed, those processes would be influential in the identification of favourable lands for a reasoned gestion of the city and the development of new tools and acting processes imagined by architects and urban planners.To answer to our hypothesis, we focus more specifically on projects initiating a deep mutation of the urban fabric, on its form and its uses that we would call here urban reshaping. Our analysis is based on six processes meant to be “innovative”, realized or no, one of them being built by inhabitants. They illustrate this practice in different shrinking cities since the 20 past years. Those case studies are located in different urban fabrics contexts to illustrate the diversity of situations that one can be facing. In parallel of two French case studies (Saint-Etienne, Livradois-Forez), we will observe other experiences in two foreign contexts, pioneers in terms of local initiatives and urban policy: Germany (Halle-Neustadt, Dessau) and the United states (Detroit). The diversity of projects, in terms of approach and scale does not constitute a comparative study. We suggest instead a more relevant approach consisting in questioning them to understand the political, socioeconomic and environment consequences on the process of project making and the capacity of those projects to initiate a transformation of urban fabric and of the city.Our goal will be to understand the originality and specifies of those initiatives, but also potential contributions to the contemporary debates on the city and its evolutions. This approach seeks bringing a prospective dimension about the shrinking city.

L'objectif dans cette recherche expérimentale est de contribuer à la compréhension des phénomènes de l'endommagement et de la fissuration dans les sols argileux saturés sous chargement hydrique (dessiccation) et mécanique (chemins de contrainte). L'étude mécanique est axée sur l'identification des propriétés élastiques du matériau endommagé sous chargement triaxial à différents niveaux et chemins de contrainte. Les principaux points traités étaient, l'influence de la contrainte de consolidation (p'ic), du degré de surconsolidation (OCR) et du chemin de contrainte sur la vitesse d'onde de compression. Les résultats montrent que les propriétés élastiques sont affectées et évoluent avec la déformation. La contractance semble augmenter la vitesse d'onde de compression à mesure que p'ic croît et densifie le matériau. En revanche, la dilatance semble plutôt diminuer la vitesse d'onde de compression. Par ailleurs, différents chemins triaxiaux conduits à un niveau de contrainte donné ont montré que les vitesses d'onde sont très proches si les chemins sont normalement consolidés. Les vitesses sont proches également si les chemins sont surconsolidés. En revanche, à un même état de contrainte, la vitesse d'onde est différente si on compare un chemin normalement consolidé avec un chemin surconsolidé. La deuxième partie de l'étude porte sur une analyse approfondie des mécanismes d'amorçage et de propagation des fissures sous dessiccation libre et contrôlée d'une argile initialement saturée. L'analyse via la corrélation d'images numériques (CIN) a permis, en premier lieu, une caractérisation multiéchelle du phénomène de retrait opéré au cours du séchage. Différents phénomènes ont été identifiés : le phénomène de relaxation, caractérisé par un changement de signe de la déformation locale extension / compression, le mécanisme de fissuration par extension (mode I), identifié par la cartographie des directions des déformations principales. L'étude a été complétée par des essais de traction indirecte par flexion 3 points réalisés sur des poutrelles de kaolin K13 initialement soumises à différentes succions. L'effet de la succion initiale sur la résistance à la traction a donc été observé. Les résultats montrent que plus la succion initiale est élevée, plus la pente de la courbe de variations de la résistance à la traction est élevée. D'autre part, la déformation de la zone tendue de la poutrelle atteint sa valeur critique lorsque la contrainte atteint la résistance maximale à la traction de l'argile / The objective of this experimental research is to contribute to understanding phenomena of damage and cracking in saturated clay soils under hydric loading (desiccation) and mechanical loading (stress paths). Mechanical study focuses on identifying the elastic properties of the damaged material under triaxial loading at different levels and stress paths. The main issues were the influence of; the consolidation stress (p'ic), the overconsolidation ratio (OCR) and the stress path on the compression wave velocity. The results show that the elastic properties are affected and evolve with strain. Contractancy appears to increase the compression wave velocity as p'ic increase and densifies the material. However, dilatancy seems rather decrease the compression wave velocity. Moreover, various triaxial paths performed at a given stress level showed that the wave velocities are very close if the paths are normally consolidated. Velocities are also close if the paths are overconsolidated. However, at the same stress state, the wave velocity is different when comparing a normally consolidated path with an overconsolidated path. The second part of the study focuses on a thorough analysis of the cracks' initiation and propagation mechanisms under free and controlled desiccation on initial saturated clay. Analysis via the digital image correlation (DIC) allowed, first, a multi-scales characterization of the shrinkage phenomenon operated during drying. Different phenomena were identified; the relaxation phenomenon characterized by a change of the local strain's sign extension / compression, the cracking mechanism by extension (mode I) identified by the map of the directions of the principal strains. The study was completed with indirect tensile tests by bending performed on kaolin k13 beams initially submitted to different suctions. The effect of the initial suction on the tensile strength has been observed. The results show that more the initial suction is high, the greater the slope of the curve of changes in the tensile strength is high. On the other hand, strain of the tension zone of the beam reaches its critical value when the stress reaches the maximum tensile strength of the clay

I detta projekt har vi fördjupat oss i en glidlagerkonstruktion som befinner sig i en skruvpress. Skruvpressen kompakterar en okänd massa som är sekretessbelagd. Robustus har ett förslag på överdimensionering av det nuvarande glidlagret. Målet med projektet var att analysera och optimera några glidlager i förhållande till det befintliga glidlagret samt att ta hänsyn till materialval och den miljö som lagret kommer att befinner sig i. Det som analyserna och optimeringen visade var att det befintliga glidlagret hade den bästa geometrin bland alla lösningar men inte det optimala materialet. Projektet befinner sig i ett tidigt stadium och det behövs en del geometriska förändringar. Det viktigaste av allt är att problemet har identifierats med hjälp av det havererade glidlagret och med en excelmodell. / We have in this project become engrossed in a plain bearing design that is located in a screw press. The screw press compact an unknown mass that is confidential. Robustus have a suggestion to over dimensioning the present plain bearing. The aim of this project was to analyze and to do an optimization on some plain bearings and compare them to the present bearing and to take the choice of material and the environment where the bearing is located into account. The analysis and the optimizations showed that the current plain bearing had the best geometry but not the optimal material selection. The project is in an early state and it needs some geometrical changes. The most important of everything is that the problem has been identified with the help of the wrecked plain bearing and with an excel model.

The purpose of this study is to compare how the issue of new shipping opportunities in theArctic region is tackled and met by the governments of Sweden and Iceland when it comes tomaritime security regime building, and to set this into perspective by looking at the shippingindustry’s seemed aspirations and interests for Arctic shipping, the latter to see if policy and“reality” appear to be corresponding. By conducting a qualitative comparative analysisthrough studying previous research, government documents and through interviewingrepresentatives from the shipping industry; using the analytical framework of Regime Theoryfor International Relations; the following research questions have been answered: - In what ways do the governments of Sweden and Iceland contribute to developments of Arctic maritimesecurity regimes, due to new shipping opportunities in the High North? - Are these contributions in line with the shipping industry’s views of and aspirations for Arctic shipping? - (How) does this differ between the countries? - (How) does the shipping industry contribute to maritime security? Sweden and Iceland differ in many aspects, but the general aims at environmental protectionare visible in both countries. Iceland has a larger focus on crisis response due to its locationalexposure and do moreover have a chance on economically exploiting new shipping activitiesfor the same reason. Sweden can be said to have a more general approach to Arctic maritimesecurity, whereas Iceland rather focuses on its own proximity.Both countries’ responses to Arctic shipping are currently to be seen as in line with theshipping industry’s views and aspirations for Arctic shipping.The shipping industry contributes to maritime security by developing new methods andtechnology for addressing the Arctic ice; collectively and on shipping company individualbasis. The shipping industry furthermore contributes by educating ship commanders as well assharing experiences and knowledge with each other.