Dissertations / Theses on the topic 'Marginal structure model'

L’objectif de cette thèse est de proposer un Alphabet Structural (AS) permettant une caractérisation fine et précise des structures tridimensionnelles (3D) des protéines, à l’aide des chaînes de Markov cachées (HMM) qui permettent de prendre en compte la logique issue de l’enchaînement des fragments structuraux en intégrant l’augmentation des conformations 3D des structures protéiques désormais disponibles dans la banque de données de la Protein Data Bank (PDB). Nous proposons dans cette thèse un nouvel alphabet, améliorant l’alphabet structural HMM-SA27,appelé SAFlex (Structural Alphabet Flexibility), dans le but de prendre en compte l’incertitude des données (données manquantes dans les fichiers PDB) et la redondance des structures protéiques. Le nouvel alphabet structural SAFlex obtenu propose donc un nouveau modèle d’encodage rigoureux et robuste. Cet encodage permet de prendre en compte l’incertitude des données en proposant trois options d’encodages : le Maximum a posteriori (MAP), la distribution marginale a posteriori (POST)et le nombre effectif de lettres à chaque position donnée (NEFF). SAFlex fournit également un encodage consensus à partir de différentes réplications (chaînes multiples, monomères et homomères) d’une même protéine. Il permet ainsi la détection de la variabilité structurale entre celles-ci. Les avancées méthodologiques ainsi que l’obtention de l’alphabet SAFlex constituent les contributions principales de ce travail de thèse. Nous présentons aussi le nouveau parser de la PDB (SAFlex-PDB) et nous démontrons que notre parser a un intérêt aussi bien sur le plan qualitatif (détection de diverses erreurs)que quantitatif (rapidité et parallélisation) en le comparant avec deux autres parsers très connus dans le domaine (Biopython et BioJava). Nous proposons également à la communauté scientifique un site web mettant en ligne ce nouvel alphabet structural SAFlex. Ce site web représente la contribution concrète de cette thèse alors que le parser SAFlex-PDB représente une contribution importante pour le fonctionnement du site web proposé. Cette caractérisation précise des conformations 3D et la prise en compte de la redondance des informations 3D disponibles, fournies par SAFlex, a en effet un impact très important pour la modélisation de la conformation et de la variabilité des structures 3D, des boucles protéiques et des régions d’interface avec différents partenaires, impliqués dans la fonction des protéines
The purpose of this PhD is to provide a Structural Alphabet (SA) for more accurate characterization of protein three-dimensional (3D) structures as well as integrating the increasing protein 3D structure information currently available in the Protein Data Bank (PDB). The SA also takes into consideration the logic behind the structural fragments sequence by using the hidden Markov Model (HMM). In this PhD, we describe a new structural alphabet, improving the existing HMM-SA27 structural alphabet, called SAFlex (Structural Alphabet Flexibility), in order to take into account the uncertainty of data (missing data in PDB files) and the redundancy of protein structures. The new SAFlex structural alphabet obtained therefore offers a new, rigorous and robust encoding model. This encoding takes into account the encoding uncertainty by providing three encoding options: the maximum a posteriori (MAP), the marginal posterior distribution (POST), and the effective number of letters at each given position (NEFF). SAFlex also provides and builds a consensus encoding from different replicates (multiple chains, monomers and several homomers) of a single protein. It thus allows the detection of structural variability between different chains. The methodological advances and the achievement of the SAFlex alphabet are the main contributions of this PhD. We also present the new PDB parser(SAFlex-PDB) and we demonstrate that our parser is therefore interesting both qualitative (detection of various errors) and quantitative terms (program optimization and parallelization) by comparing it with two other parsers well-known in the area of Bioinformatics (Biopython and BioJava). The SAFlex structural alphabet is being made available to the scientific community by providing a website. The SAFlex web server represents the concrete contribution of this PhD while the SAFlex-PDB parser represents an important contribution to the proper function of the proposed website. Here, we describe the functions and the interfaces of the SAFlex web server. The SAFlex can be used in various fashions for a protein tertiary structure of a given PDB format file; it can be used for encoding the 3D structure, identifying and predicting missing data. Hence, it is the only alphabet able to encode and predict the missing data in a 3D protein structure to date. Finally, these improvements; are promising to explore increasing protein redundancy data and obtain useful quantification of their flexibility

In longitudinal studies, both treatments and covariates may vary throughout the follow-up period. Time-dependent (TD) Cox proportional hazards (PH) models can be used to model the effect of time-varying treatments on the hazard. However, two challenges exist in such modeling. First, accurate modeling of the effects of TD treatments on the hazard requires resolving the uncertainty about the etiological relevance of treatments taken in different time periods. The second challenge arises in the presence of TD confounders affected by prior treatments. By assuming the absence of the other challenge, two different methodologies, weighted cumulative exposure (WCE) and marginal structural models (MSM), have been recently proposed to separately address each challenge, respectively. In this thesis, I proposed the combination of these methodologies so as to address both challenges simultaneously, as both may commonly arise in combination in longitudinal studies.In the first manuscript, I proposed and validated a novel approach to implement the marginal structural Cox proportional hazards model (referred to as Cox MSM) with inverse-probability-of-treatment weighting (IPTW) directly via a weighted time-dependent Cox PH model, rather than via a pooled logistic regression approximation. The simulations show that the IPTW estimator yields consistent estimates of the causal effect of treatment, but it may suffer from large variability, due to some extremely high IPT weights. The precision of the IPTW estimator could be improved by normalizing the stabilized IPT weights.Simple weight truncation has been proposed and commonly used in practice as another solution to reduce the large variability of IPTW estimators. However, truncation levels are typically chosen based on ad hoc criteria which have not been systematically evaluated. Thus, in the second manuscript, I proposed a systematic data-adaptive approach to select the optimal truncation level which minimizes the estimated expected MSE of the IPTW estimates. In simulation, the new approach exhibited the performance that was as good as the approaches that simply truncate the stabilized weights at high percentiles such as the 99th or 99.5th of their distribution, in terms of reducing the variance and improving the MSE of the estimatesIn the third manuscript, I proposed a new, flexible model to estimate the cumulative effect of time-varying treatment in the presence of the time-dependent confounders/mediators. The model incorporated weighted cumulative exposure modeling in a marginal structural Cox model. Specifically, weighted cumulative exposure was used to summarize the treatment history, which was defined as the weighted sum of the past treatments. The function that assigns different weights to treatments received at different times was modeled with cubic regression splines. The stabilized IPT weights for each person at each visit were calculated to account for the time-varying confounding and mediation. The weighted Cox MSM, using stabilized IPT weights, was fitted to estimate the total causal cumulative effect of the treatments on the hazard. Simulations demonstrate that the proposed new model can estimate the total causal cumulative effect, i.e. to capture both the direct and the indirect (mediated by the TD confounder) treatment effects. Bootstrap-based 95% confidence bounds for the estimated weight function were constructed and the impact of some extreme IPT weights on the estimates of the causal cumulative effect was explored.In the last manuscript, I applied the WCE MSM to the Swiss HIV Cohort Study (SHCS) to re-assess whether the cumulative exposure to abacavir therapy may increase the potential risk of cardiovascular events, such as myocardial infarction or the cardiovascular-related death.
Dans les études longitudinales, aussi bien les covariables que les traitements peuvent varier au cours de la période de suivi. Les modèles de Cox à effets proportionnels avec variables dépendantes du temps peuvent être utilisés pour modéliser l'effet de traitement variant au cours du temps. Cependant, deux défis apparaissent pour ce type de modélisation. Tout d'abord, une modélisation précise des effets des traitements dépendants du temps sur le risque nécessite de résoudre l'incertitude quant à l'importance étiologique des traitements pris a différentes périodes de temps. Ensuite, un second défi se pose dans le cas de la présence d'une variable de confusion qui dépend du temps et qui est également un médiateur de l'effet du traitement sur le risque. Deux différentes méthodologies ont récemment été suggérées pour répondre, séparément, à chacun de ces deux défis, respectivement l'exposition cumulée pondérée et les modèles structuraux marginaux (MSM). Dans cette thèse, j'ai proposé la combinaison de ces méthodologies de façon à répondre aux deux défis simultanément, étant donné qu'ils peuvent tous les deux fréquemment se poser en même temps dans des études longitudinales. Dans le premier article, j'ai proposé et validé une nouvelle approche pour mettre en œuvre le Cox MSM avec la pondération par l'inverse de probabilité de traitement (PIPT) directement à partir d'un modèle de Cox a effets proportionnels pondéré et avec variables dépendantes du temps plutôt que par une approximation par régression logistique sur données agrégées. Les simulations montrent que l'estimateur PIPT donne des estimations consistantes de l'effet causal du traitement alors qu'il serait associé à une grande variabilité dans les estimations, à cause d'inverses de probabilités de traitement extrêmement élevés. La simple troncature de poids a été proposée et couramment utilisée dans la pratique comme une autre solution pour réduire la grande variabilité des estimateurs PIPT. Cependant, les niveaux de troncature sont généralement choisis en fonction de critères ad hoc, qui n'ont pas été systématiquement évalués. Ainsi, dans le deuxième article, j'ai proposé une approche systématique adaptative aux données systématique pour sélectionner le niveau de troncature optimal qui minimise l'erreur quadratique moyenne des estimations PIPT. Dans le troisième article, j'ai proposé un nouveau modèle flexible afin d'estimer l'effet cumulatif de traitements qui varient dans le temps en présence de facteurs de confusion/médiateurs dépendant du temps. Le modèle intègre la modélisation de l'exposition cumulative pondérée dans un Cox MSM. Plus précisément, l'exposition cumulée pondérée a été utilisée pour résumer l'histoire du traitement, qui a été définie comme la somme pondérée des traitements antérieurs. La fonction qui assigne des poids différents aux traitements reçus à différents moments a été modélisée avec des régressions par B-splines cubiques, en utilisant différentes covariables dépendantes du temps artificielles. Les poids IPT stabilisés pour chaque personne à chaque visite ont été calculés afin de tenir compte des variables de confusion et des médiateurs qui dépendent du temps. Le modèle structurel marginal de Cox à effets proportionnel et avec des covariables dépendantes du temps pondéré, qui utilise des poids stabilisés pondérés, a été ajusté pour estimer l'effet cumulatif causal total des traitements sur le risque. Les simulations montrent que le nouveau modèle proposé permet d'estimer l'effet cumulatif causal total, c'est à dire qu'il permet de capturer à la fois les effets direct et indirect.Dans le dernier article, j'ai appliqué le modèle structural marginal avec exposition cumulée pondérée à une étude de cohorte suisse sur le VIH afin de réévaluer si l'exposition cumulée à la thérapie abacavir augmentait le risque potentiel d'événements cardiovasculaires, tels que l'infarctus du myocarde ou le décès lié a un événement cardiovasculaire.

A marginal structural model parameterises the distribution of an outcome given a treatment intervention, where such a distribution is the fundamental probabilistic representation of the causal effect of treatment on the outcome. Causal inference methods are designed to consistently estimate aspects of these causal distributions, in the presence of interference from non-causal associations which typically occur in observational data. One such method, which involves the application of inverse probability of treatment weights, directly targets the parameters of marginal structural models. The asymptotic properties and practical applicability of this method are well established, but little attention has been paid to its finite-sample performance. This is because simulating data from known distributions which are entirely suitable for such investigations generally presents a significant challenge, especially in scenarios where the outcome is survival time. We illuminate these issues, and propose and implement certain solutions, considering separately the cases of static (pre-determined) and dynamic (tailored) treatment interventions. In so doing, we explore both theoretical and practical aspects of marginal structural models for survival outcomes, and the associated inference method.

Background: Inverse-probability-of-treatment-weighted estimation (IPTW) of marginal structural models was proposed to adjust for time-varying confounders that are influenced by prior treatment use. It is unknown whether pharmacoepidemiologic studies that applied IPTW conformed to the recommendations proposed by methodological studies. In addition, no previous study has compared the performance of different analytic strategies adopted in IPTW analyses. Objectives: This project aims 1) to review the reporting practice of pharmacoepidemiologic studies that applied IPTW, 2) to compare the validity and precision of several approaches to constructing weight, 3) to use IPTW to estimate the effectiveness of glucosamine and chondroitin in treating osteoarthritis. Methods: We systematically retrieved pharmacoepidemiologic studies that were published in 2012 and applied IPTW to estimate the effect of a time-varying treatment. Under a variety of simulated scenarios, we assessed the performance of four analytic approaches what were commonly used in studies conducting IPTW analyses. Finally, using data from Osteoarthritis Initiative, we applied IPTW to estimate the long-term effectiveness of glucosamine and chondroitin on treating knee osteoarthritis. Results: The practice of reporting use of IPTW in pharmacoepidemiologic studies was suboptimal. The majority of reviewed studies did not report that the positivity assumption was assessed, and several studies used unstablized weights or did not report that the stabilized weights were used. With data simulation, we found that intention-to-treat analyses underestimated the actual treatment effect when there was non-null treatment effect and treatment non-adherence. This underestimation was linearly correlated with adherence levels. As-treated analyses that took into account the complex mechanism of treatment use generated approximately unbiased estimates without sacrificing the estimate precision when the treatment effect was non-null. Finally, after adjustment for potential confounders with marginal structural models, we found no clinically meaningful benefits of glucosamine/chondroitin in relieving knee pain, stiffness and physical function or slowing joint space narrowing. Conclusions: It may be prudent to develop best practices of reporting the use of IPTW. Studies performing intention-to-treat analyses should report the levels of adherence after treatment initiation, and studies performing as-treated analyses should take into the complex mechanism of treatment use in weight construction.

La réalisation d'un essai thérapeutique randomisé peut être difficile à mettre en place pour estimer sans biais l'effet causal d'une stratégie thérapeutique. Dans ce cas, l’étude observationnelle constitue une alternative pour évaluer l’effet causal d’un traitement. Quatre types de difficultés méthodologiques nous intéressent dans ce type d’étude : 1) le biais d’indication ; 2) La présence des facteurs de confusion temps-dépendantes (TD) ; 3) la relation variant dans le temps entre un traitement TD et un effet ; 4) dans la vie réelle, les patients prennent parfois plusieurs traitements, de façon séquentielle ou simultanée. Dans ces conditions, l’évaluation de l’effet propre à chaque traitement constitue un défi méthodologique. L’objectif de cette thèse est de proposer un cadre méthodologique qui permet d’estimer correctement les effets propres aux traitements dans un contexte de multithérapie dans une étude observationnelle en tenant compte de ces difficultés méthodologiques. Nous avons évalué la performance du modèle marginal structurel de Cox pour estimer les effets individuels et conjoints de deux traitements et démontré qu'il a des bonnes performances en présence des facteurs de confusion TD et d'une interaction entre les deux traitements. Nous avons également comparé la performance du modèle marginal structurel de Cox à exposition cumulée pondérée à celle du modèle de Cox à exposition cumulée pondérée standard pour estimer les effets variant dans le temps en présence de confusion temps dépendante et démontré qu'il a une meilleure performance et qu'il peut être appliqué aux données réelles quelque soit la force de confusion temps dépendante
Randomized controlled trials cannot be implemented in all situations for estimating effects of therapeutic strategies. Observational studies would then constitute an alternative for evaluating treatment effects. We have a specified interest in four types of methodological difficulties for such studies: 1) confounding by indication ; 2) presence of time-dependent confounding ; 3) The relationship between a given time-dependent treatment and its effect may vary over time ; 4) In real life, patients often receive multiple treatments, sequentially or simultaneously. In this context, the evaluation of individual effects of treatment is a methodological challenge. The overall objective of this thesis was to propose a methodological framework in which these methodological difficulties are accommodated, allowing the individual effects of treatments to be correctly estimated within the context of multi-treatments in an observational study. We evaluated the performance of the marginal structural Cox model when estimating the individual and joint effects of two treatments and showed that it performed well in the presence of three different scenarios of time-dependent confounding. We also showed the importance of estimating the interaction term when exploring the treatment effect from combination therapy. We compared the performance of weighted cumulative exposure marginal structural Cox model with that of a conventional TD WCE Cox model for estimating time-varying effects of treatments without bias in the presence of TD confounding. Our results showed that the WCE Cox MSM performed better and can be applied to real data whatever the strength of time dependent confounding

O trabalho discute a questão da precificação eficiente em sistemas de distribuição de energia, abordando desde a teoria econômica clássica aplicada aos modelos de produção e transporte da energia, passando por uma avaliação crítica da atual metodologia de estrutura tarifária vigente no Brasil, até o detalhamento de uma proposta consistente e simplificadora de estrutura de preços para a atividade da distribuição de energia. A teoria de monopólios naturais é o pano de fundo para uma discussão integrada dos modelos clássicos de estrutura de preços para o transporte da energia elétrica. Nesta avaliação do estado da arte, são abordadas as teorias da precificação linear, da precificação não linear e da precificação de ponta. A atual metodologia nacional de cálculo da estrutura tarifária de uso das redes de distribuição, aplicada pela Agência Nacional de Energia Elétrica ANEEL, é revisitada sob uma visão técnica crítica. Como resultado, são desconstruídos alguns conceitos e processos vigentes pela constatação de uma excessiva complexidade operacional aliada a uma carência de fundamentação econômica e matemática. Por fim, é proposta uma metodologia simplificadora para a estrutura de preços de uso das redes de distribuição de energia, objetivando maior eficiência econômica, maior simplicidade operacional na aplicação e sólida fundamentação teórica, reduzindo arbitrariedades e subjetividades existentes na atual metodologia.
The present work discusses the question of efficient pricing on electric power distribution systems. The subject is approached from the discussion of the classical economic theory applied to energy production and transport models, passing through a critical evaluation of the current rate structure used in Brazil, to the description of a consistent and simplified proposal for the electric power distribution rate design. The theory of natural monopolies is the background of an integrated discussion on classical rate design models concerning the electric energy transportation activity. By the classical problem analysis, some theories commonly approached are linear pricing, non linear pricing and peak load pricing. The current Brazilian methodology used for the rate design of the usage of distribution networks, applied by the National Regulatory Agency (ANEEL), is revisited under a critical technical vision. As a result, some concepts are reassessed due to the observed excessive operational complexity allied to the lack of economical and statistical foundation. Finally, a simplified methodology for the rate structure of the usage of electrical distribution networks is proposed. The methodology aims, at the same time, greater economic efficiency, simpler operational application and a solid theoretical foundation, thereby reducing arbitrariness and subjectivity found in the current methodology.

Background: Survival time is a common parameter of interest that can be estimated by using Cox Proportional Hazards models when measured continuously. An alternative way to estimate hazard ratios is to cut up time into equal-lengthed intervals and consider the by-interval outcome to be 0 if the person is alive during this interval and 1 otherwise. In this discrete-time approximation, instead of using a Cox model, one should perform pooled logistic regression to get unbiased estimate of survival time under the assumption of low death rate per interval. This fact is satisfied when shorter intervals is used in order to have fewer events in each time, however, by doing this, problems such as missing values can arise because the actual visits occur less frequently in a survival setting and one must therefore account for the missing values. Objective: We investigate the effect of two methods of filling in missing data, Last Observation Carried Forward (LOCF) and Multiple Imputation (MI), as well as Available Case Study. We compare these three different approaches to complete data analysis. Methods: Weighted pooled logistic regression is used to estimate the causal marginal treatment effect. Complete data were generated using Young's algorithm to obtain monthly information for all individuals, and from the complete data, observed data were selected by assuming follow-up visits occurred every six or three months. Thus, to analyze the observed data at a monthly level, we performed LOCF and MI to fill in the missing values and compared the results to those from a completely-observed data analysis. We also included an analysis of the observed-data without any imputation. We then applied these methods to the Canadian Co-infection Cohort to estimate the impact of alcohol consumption on liver fibrosis.Results: In most simulations, MI produced the least biased and least variant estimators, even outperforming analyses based on completely-observed data. In the presence of stronger confounding, MI-based estimators were more biased but nevertheless less variant than the estimators based on completely-observed data.Conclusion: Multiple Imputation is superior to last-observation carried forward and observed-data analysis when marginal structural models are used to adjust for time-varying exposure and variables in the context of survival analysis and data are missing or infrequently measured.
Contexte : Le temps de survie est un paramètre d'intérêt commun qui peut être évalué en faisant appel aux modèles à risques proportionnels de Cox lorsqu'il mesuré en continu. Un autre moyen d'estimer des risques relatifs est de diviser le temps en intervalles égaux et d'assigner une valeur de 0 ou de 1 à chaque intervalle selon que l'individu y est vivant ou non. Dans cette approximation à temps discret, on doit avoir recours à une régression logistique regroupée plutôt qu'à un modèle de Cox pour obtenir une estimation sans biais du temps de survie sous l'hypothèse que le taux de décès par intervalle est bas. Cette hypothèse est raisonnable lorsque les intervalles sont suffisamment courts pour éviter les événements multiples mais ce faisant, des problèmes de valeurs manquantes ou autres peuvent subvenir car les visites effectives ont lieu moins fréquemment dans un contexte de survie et la possibilité que des valeurs soient manquantes est bien réelle.Objectif : Nous examinons l'effet de deux méthodes d'imputation de valeurs manquantes, à savoir la reconduction de la dernière observation (RDO) et l'imputation multiple (IM), de même que la technique d'études des cas disponibles. Nous comparons ces trois approches en prenant comme point de référence l'analyse des cas complets.Méthodes : La régression logistique regroupée pondérée est utilisée afin d'estimer l'effet de traitement causal marginal. Des données complètes ont été générées au moyen de l'algorithme de Young afin d'obtenir des informations mensuelles au sujet de tous les individus ; des observations ont ensuite été sélectionnées à partir des données complètes en supposant que des visites de suivi aient lieu tous les trois ou six mois. Ainsi, en vue d'analyser les données observées sur une base mensuelle, on a effectué la reconduction de la dernière observation (RDO) et l'imputation multiple (IM) pour remplacer les données manquantes et comparer les résultats à ceux d'une analyse de données entièrement observables. On a également effectué une analyse des données observées avant imputation. On a ensuite appliqué ces techniques à la cohorte de co-infection canadienne afin d'évaluer l'impact de la consommation d'alcool sur la fibrose du foie. Résultats: Dans la plupart des simulations, les estimations fondées sur l'imputation multiple se sont avérées moins biaisées et moins variables que les autres, surpassant même celles fondées sur l'observation de données complètes. En présence d'effets confondants, les estimations fondées sur l'imputation multiple ont présenté un biais accru mais ont été moins variables que celles fondées sur les données entièrement observables.Conclusion : L'imputation multiple est supérieure à la reconduction de la dernière observation et à l'analyse des données brutes lorsque des modèles structuraux marginaux sont utilisés pour ajuster l'exposition temporelle et les variables dans un contexte d'analyses de survie où les données sont mesurées à basse fréquence ou incomplètes.

Background: It has been noted in epidemiology and biostatistics that when the odds ratio (OR) is used to measure the causal effect of a treatment or exposure, there is a discrepancy between the marginal OR and the conditional OR even in the absence of confounding. This is known as non-collapsibility of the OR. It is sometimes described (incorrectly) as a bias in the estimated treatment effect from a logistic regression model if an important covariate is omitted. Objectives: Distinguish confounding bias from non-collapsibility and measure the non-collapsibility effect on the OR in different scenarios. Methods: We used marginal structural models and standard logistic regression to measure the non-collapsibility effect and confounding bias. An analytic approach is proposed to assess the non-collapsibility effect in a point-exposure study. This approach can be used to verify the conditions for the absence of non-collapsibility and to examine the phenomenon of confounding without non-collapsibility. A graphical approach is employed to show the relationship between the non-collapsibility effect and the baseline risk or the marginal outcome probability, and it reveals the non-collapsibility behaviour with a range of different exposure effects and different covariate effects. In order to explore the non-collapsibility effect of the OR in the presence of time-varying confounding, an observational cohort study was simulated. Results and Conclusion: The total difference between the conditional and crude effects can be decomposed into a sum of the non-collapsibility effect and the confounding bias. We provide a general formula for expressing the non-collapsibility effect under different scenarios. Our analytic approach provided similar results to related formulae in the literature. Various interesting observations about non-collapsibility can be made from the different scenarios with or without confounding using the graphical approach. Somewhat surprisingly, the effect of the covariate plays a more important role in the non-collapsibility effect than does the effect of the exposure. In the presence of time-varying confounding, the non-collapsibility is comparable to the effect in the point-exposure study.
Contexte : Il a été observé en épidémiologie et en biostatistique que lorsque le "odds ratio" (OR) est utilisé pour mesurer l'effet causal d'un traitement ou d'une exposition, il y a une différence entre l'OR marginal et l'OR conditionnel et ce, même s'il y a absence de biais de confusion. Ceci est décrit comme le non-collapsibilité de l'OR. Il est parfois incorrectement décrit comme un biais dans l'effet estimé du traitement à partir d'un modèle de régression logistique, si une covariante importante est exclue.Objectifs : Distinguer le biais provenant du biais de confusion du non-collapsibilité et mesurer l'effet du non-collapsibilité sur l'OR dans plusieurs scénarios.Méthode : On a utilisé des modèles structuraux marginaux et la régression logistique ajustée pour mesurer l'effet du non-collapsibilité dans une étude d'exposition par points. Cette approche peut être utilisée pour vérifier les conditions de l'absence de non-collapsibilité et pour examiner le phénomène de biais de confusion sans non-collapsibilité. Une approche graphique est employée pour démontrer la relation entre le non-collapsibilité et le risque de base ou la probabilité du résultat marginal; ceci révèle le comportement de non-collapsibilité avec une étendue d'effets d'exposition et de covariance différents. De manière à explorer l'effet de non-collapsibilité de l'OR en présence de biais de confusion variant en fonction du temps, une étude d'observation de cohorte a été simulée.Résultats et Conclusion : La différence entre les effets conditionnels et bruts peut être décomposée dans la somme de l'effet de non-collapsibilité et du biais de confusion. Nous suggérons une formule générale pour exprimer l'effet du non-collapsibilité dans plusieurs scénarios différents. Notre approche analytique expose des résultats similaires à d'autres étant trouvés avec des formules présentes dans la littérature. Plusieurs observations intéressantes sur le non-collapsibilité peuvent être faites à partir de différents scénarios, avec ou sans biais de confusion, en utilisant notre approche graphique. De manière surprenante, l'effet d'une covariable joue un plus grand rôle dans le non-collapsibilité que l'effet de l'exposition. En présence de biais de confusion reliée au temps, l'effet du non-collapsibilité est comparable à l'effet de l'étude d'exposition par point.

This empirical register study intends to estimate average causal effects of relapse treatment on the risk for acute myocardial infarction (AMI) among patients with Diffuse B-Cell Lymphoma (DLBCL) within the potential outcome framework. The report includes a brief introduction to causal inference and survival anal- ysis and mentions specific causal parameters of interest that will be estimated. A cohort of 2887 Swedish DLBCL patients between 2007 and 2014 were included in the study where 560 patients suffered a relapse. The relapse treatment is hypothesised to be cardiotoxic and induces an increased risk of heart diseases. The identifiability assumptions need to hold to estimate average causal effects and are assessed in this report. The patient cohort is weighted using inverse probability of treatment and censoring weights and potential marginal survival curves are estimated from marginal structural Cox models. The resulting point estimate indicates a protective causal effect of relapse treatment on AMI but estimated bootstrap confidence intervals suggest no significant effect on the 5% significance level.

Standard marginal structural models (MSMs) are commonly applied to estimate causal effects in the presence of time-dependent confounding; these may be extended to history-adjusted MSMs to estimate effects conditional on time-updated covariates, and dynamic MSMs to estimate e¤ects of pre-speci…ed dynamic regimes (Cain et al., 2010). We address methods to assess the optimal time for treatment initiation with respect to CD4 count in HIV-infected persons, and apply these to CASCADE cohort data. We advocate the application of all three types of MSM to address such causal questions and investigate gaps in the literature concerning their application. Of importance is the construction of suitable inverse probability weights. We have structured this process as four key decisions, de…fining a range of strategies; all demonstrated a bene…ficial effect of ART in CASCADE. We found a trend towards greater treatment bene…fit at lower CD4 across a range of models. Via large simulated randomised trials based on CASCADE data, longer grace periods (permitted delay in treatment initiation) and in particular less-frequently observed CD4 indicated higher optimal regimes (earlier treatment initiation at higher CD4), although similar AIDS-free survival rates may be achieved at these higher optimal regimes. In realistically-sized observational simulations, the optimal regime estimates lacked precision, mainly due to broadly constant AIDS-free survival rates at higher CD4. Optimal regimes estimated from dynamic MSMs should be interpreted with regard to the shape of the outcome-by-regime curve and the precision. In our clinical setting, we found that allowing a 3-month grace period may increase precision with little bias under the interpretation of no grace period; under longer grace periods, the bias outweighed the efficiency gain. In our CASCADE population, immediate treatment was preferable to delay, although estimation was limited by relatively short follow-up. Comparison across the MSM approaches offers additional insights into the methodology and clinical results.

Les levures du genre Candida figurent parmi les pathogènes majeurs isolés chez les patients en soins intensifs et sont responsables d'infections systémiques : les candidoses invasives. Le retard et le manque de fiabilité du diagnostic sont susceptibles d'aggraver l'état du patient et d'augmenter le risque de décès à court terme. Pour respecter les objectifs de traitement, les experts recommandent de traiter le plus précocement possible les patients à haut risque de candidose invasive. Cette attitude permet de proposer un traitement précoce aux malades atteints, mais peut entraîner un traitement inutile et coûteux et favoriser l'émergence de souches de moindre sensibilité aux antifongiques utilisés.Ce travail applique des méthodes statistiques modernes à des données observationnelles longitudinales. Il étudie l'impact des traitements antifongiques systémiques sur la répartition des quatre principales espèces de Candida dans les différents prélèvements de patients en réanimation médicale, sur leur sensibilité à ces antifongiques, sur le diagnostic des candidémies ainsi que sur le pronostic des patients. Les analyses de séries de données temporelles à l'aide de modèles ARIMA (moyenne mobile autorégressive intégrée) ont confirmé l'impact négatif de l'utilisation des antifongiques sur la sensibilité des principales espèces de Candida ainsi que la modification de leur répartition sur une période de dix ans. L'utilisation de modèles hiérarchiques sur données répétées a montré que le traitement influence négativement la détection des levures et augmente le délai de positivité des hémocultures dans le diagnostic des candidémies. Enfin, l'utilisation des méthodes d'inférence causale a montré qu'un traitement antifongique préventif n'a pas d'impact sur le pronostic des patients non neutropéniques, non transplantés et qu'il est possible de commencer une désescalade précoce du traitement antifongique entre le premier et le cinquième jour après son initiation sans aggraver le pronostic
Candida species are among the main pathogens isolated from patients in intensive care units (ICUs) and are responsible for a serious systemic infection: invasive candidiasis. A late and unreliable diagnosis of invasive candidiasis aggravates the patient's status and increases the risk of short-term death. The current guidelines recommend an early treatment of patients with high risks of invasive candidiasis, even in absence of documented fungal infection. However, increased antifungal drug consumption is correlated with increased costs and the emergence of drug resistance whereas there is yet no consensus about the benefits of the probabilistic antifungal treatment.The present work used modern statistical methods on longitudinal observational data. It investigated the impact of systemic antifungal treatment (SAT) on the distribution of the four Candida species most frequently isolated from ICU patients', their susceptibilities to SATs, the diagnosis of candidemia, and the prognosis of ICU patients. The use of autoregressive integrated moving average (ARIMA) models for time series confirmed the negative impact of SAT use on the susceptibilities of the four Candida species and on their relative distribution over a ten-year period. Hierarchical models for repeated measures showed that SAT has a negative impact on the diagnosis of candidemia: it decreases the rate of positive blood cultures and increases the time to positivity of these cultures. Finally, the use of causal inference models showed that early SAT has no impact on non-neutropenic, non-transplanted patient prognosis and that SAT de-escalation within 5 days after its initiation in critically ill patients is safe and does not influence the prognosis

Generalized estimating equations (GEE) are popularly utilized for the marginal analysis of longitudinal data. In order to obtain consistent regression parameter estimates, these estimating equations must be unbiased. However, when certain types of time-dependent covariates are presented, these equations can be biased unless an independence working correlation structure is employed. Moreover, in this case regression parameter estimation can be very inefficient because not all valid moment conditions are incorporated within the corresponding estimating equations. Therefore, approaches using the generalized method of moments or quadratic inference functions have been proposed for utilizing all valid moment conditions. However, we have found that such methods will not always provide valid inference and can also be improved upon in terms of finite-sample regression parameter estimation. Therefore, we propose a modified GEE approach and a selection method that will both ensure the validity of inference and improve regression parameter estimation. In addition, these modified approaches assume the data analyst knows the type of time-dependent covariate, although this likely is not the case in practice. Whereas hypothesis testing has been used to determine covariate type, we propose a novel strategy to select a working covariate type in order to avoid potentially high type II error rates with these hypothesis testing procedures. Parameter estimates resulting from our proposed method are consistent and have overall improved mean squared error relative to hypothesis testing approaches. Finally, for some real-world examples the use of mean regression models may be sensitive to skewness and outliers in the data. Therefore, we extend our approaches from their use with marginal quantile regression to modeling the conditional quantiles of the response variable. Existing and proposed methods are compared in simulation studies and application examples.

The steep forearc slope along the northern sector of the obliquely convergent Hikurangi subduction zone is characteristic of non-accretionary and tectonically eroding continental margins, with reduced sediment supply in the trench relative to further south, and the presence of seamount relief on the Hikurangi Plateau. These seamounts influence the subduction process and the structurally-driven geomorphic development of the over-riding margin of the Australian Plate frontal wedge. The Poverty Indentation represents an unusual, especially challenging and therefore exciting location to investigate the tectonic and eustatic effects on this sedimentary system because of: (i) the geometry and obliquity of the subducting seamounts; (ii) the influence of multiple repeated seamount impacts; (iii) the effects of structurally-driven over-steeping and associated widespread occurrence of gravitational collapse and mass movements; and (iv) the development of a large canyon system down the axis of the indentation. High quality bathymetric and backscatter images of the Poverty Indentation submarine re-entrant across the northern part of the Hikurangi margin were obtained by scientists from the National Institute of Water and Atmospheric Research (NIWA) (Lewis, 2001) using a SIMRAD EM300 multibeam swath-mapping system, hull-mounted on NIWA’s research vessel Tangaroa. The entire accretionary slope of the re-entrant was mapped, at depths ranging from 100 to 3500 metres. The level of seafloor morphologic resolution is comparable with some of the most detailed Digital Elevation Maps (DEM) onshore. The detailed digital swath images are complemented by the availability of excellent high-quality processed multi-channel seismic reflection data, single channel high-resolution 3.5 kHz seismic reflection data, as well as core samples. Combined, these data support this study of the complex interactions of tectonic deformation with slope sedimentary processes and slope submarine geomorphic evolution at a convergent margin. The origin of the Poverty Indentation, on the inboard trench-slope at the transition from the northern to central sectors of the Hikurangi margin, is attributed to multiple seamount impacts over the last c. 2 Myr period. This has been accompanied by canyon incision, thrust fault propagation into the trench fill, and numerous large-scale gravitational collapse structures with multiple debris flow and avalanche deposits ranging in down-slope length from a few hundred metres to more than 40 km. The indentation is directly offshore of the Waipaoa River which is currently estimated to have a high sediment yield into the marine system. The indentation is recognised as the “Sink” for sediments derived from the Waipaoa River catchment, one of two target river systems chosen for the US National Science Foundation (NSF)-funded MARGINS “Source-to-Sink” initiative. The Poverty Canyon stretches 70 km from the continental shelf edge directly offshore from the Waipaoa to the trench floor, incising into the axis of the indentation. The sediment delivered to the margin from the Waipaoa catchment and elsewhere during sea-level high-stands, including the Holocene, has remained largely trapped in a large depocentre on the Poverty shelf, while during low-stand cycles, sediment bypassed the shelf to develop a prograding clinoform sequence out onto the upper slope. The formation of the indentation and the development of the upper branches of the Poverty Canyon system have led to the progressive removal of a substantial part of this prograding wedge by mass movements and gully incision. Sediment has also accumulated in the head of the Poverty Canyon and episodic mass flows contribute significantly to continued modification of the indentation by driving canyon incision and triggering instability in the adjacent slopes. Prograding clinoforms lying seaward of active faults beneath the shelf, and overlying a buried inactive thrust system beneath the upper slope, reveal a history of deformation accompanied by the creation of accommodation space. There is some more recent activity on shelf faults (i.e. Lachlan Fault) and at the transition into the lower margin, but reduced (~2 %) or no evidence of recent deformation for the majority of the upper to mid-slope. This is in contrast to current activity (approximately 24 to 47% shortening) across the lower slope and frontal wedge regions of the indentation. The middle to lower Poverty Canyon represents a structural transition zone within the indentation coincident with the indentation axis. The lower to mid-slope south of the canyon conforms more closely to a classic accretionary slope deformation style with a series of east-facing thrust-propagated asymmetric anticlines separated by early-stage slope basins. North of the canyon system, sediment starvation and seamount impact has resulted in frontal tectonic erosion associated with the development of an over-steepened lower to mid-slope margin, fault reactivation and structural inversion and over-printing. Evidence points to at least three main seamount subduction events within the Poverty Indentation, each with different margin responses: i) older substantial seamount impact that drove the first-order perturbation in the margin, since approximately ~1-2 Ma ii) subducted seamount(s) now beneath Pantin and Paritu Ridge complexes, initially impacting on the margin approximately ~0.5 Ma, and iii) incipient seamount subduction of the Puke Seamount at the current deformation front. The overall geometry and geomorphology of the wider indentation appears to conform to the geometry accompanying the structure observed in sandbox models after the seamount has passed completely through the deformation front. The main morphological features correlating with sandbox models include: i) the axial re-entrant down which the Poverty Canyon now incises; ii) the re-establishment of an accretionary wedge to the south of the indentation axis, accompanied by out-stepping, deformation front propagation into the trench fill sequence, particularly towards the mouth of the canyon; iii) the linear north margin of the indentation with respect to the more arcuate shape of the southern accretionary wedge; and, iv) the set of faults cutting obliquely across the deformation front near the mouth of the canyon. Many of the observed structural and geomorphic features of the Poverty Indentation also correlate well both with other sediment-rich convergent margins where seamount subduction is prevalent particularly the Nankai and Sumatra margins, and the sediment-starved Costa Rican margin. While submarine canyon systems are certainly present on other convergent margins undergoing seamount subduction there appears to be no other documented shelf to trench extending canyon system developing in the axis of such a re-entrant, as is dominating the Poverty Indentation. Ongoing modification of the Indentation appears to be driven by: i) continued smaller seamount impacts at the deformation front, and currently subducting beneath the mid-lower slope, ii) low and high sea-level stands accompanied by variations on sediment flux from the continental shelf, iii) over-steepening of the deformation front and mass movement, particularly from the shelf edge and upper slope.

Background: Electronic healthcare records (EHRs) provide opportunities to estimate the effects of type two diabetes (T2DM) treatments on outcomes such as cancer and cardiovascular disease. Marginal structural models (MSMs) with inverse probability of treatment weights (IPTW) can correctly estimate the causal effect of time-varying treatment in the presence of time-dependent confounders such as HbA1c. Dynamic MSMs can be used to compare dynamic treatment strategies. This thesis applies weighted MSMs and dynamic MSMs to explore risks and benefits of early-stage T2DM treatments, and considers the practicalities/impact of using these models in a complex clinical setting with a challenging data source. Methods and Findings: A cohort of patients with newly diagnosed T2DM was identified from the Clinical Practice Research Datalink. MSMs with IPTW were used to estimate the causal effect of metformin monotherapy on cancer risk, and the effects of metformin and sulfonylurea monotherapies on risks of MI, stroke, all-cause mortality, and HbA1c trajectory. Dynamic MSMs were implemented to compare HbA1c thresholds for treatment initiation on risks of MI, stroke, all-cause mortality (ACM) and glucose control. No association was found between metformin use and cancer risk. Metformin and sulfonylureas led to better HbA1c control than diet only, as expected, and there was some evidence of reduced MI risk with long-term metformin use. Changes in estimates between standard models and weighted models were generally in the expected direction given hypothesised time-dependent confounding. For stroke and ACM, results were less conclusive, with some suggestions of residual confounding. Higher HbA1c thresholds for treatment initiation reduced the likelihood of reaching target HbA1c, and there was a suggestion that higher initiation thresholds increased MI risk. Conclusions: Fitting weighted MSMs and dynamic MSMs was feasible using routine primary care data. The models appeared to work well in controlling for strong time-dependent confounding with short-term outcomes; results for longer-term outcomes were less conclusive.

Este trabalho tem como objetivo a identificação de feições que permitam (1) a construção do arcabouço crustal profundo e da porção superior do manto em parte da Costa de Angola, (2) a comparação deste arcabouço com o embasamento aflorante e (3) a tentativa de adequar estes resultados aos modelos de ruptura continental já publicados. Para alcançar estes objetivos foi feita a interpretação de cinco linhas sísmicas de reflexão profundas (25 Km de profundidade) na costa de Angola, nas Bacias de Kwanza e Baixo Congo, adquiridas pela ION-GXT. As feições identificadas na sísmica de reflexão auxiliaram na determinação dos limites da crosta continental superior e inferior, no reconhecimento das camadas que compõem a crosta oceânica e na identificação da Descontinuidade de Mohorovicic (que marca o limite entre crosta e manto). A interpretação sísmica associada a dados da literatura (que proporcionaram valores de densidade para os pacotes identificados na interpretação sísmica) permitiram a realização de uma modelagem gravimétrica que foi comparada ao dado gravimétrico adquirido durante a aquisição sísmica. A modelagem gravimétrica serviu para validar a interpretação sísmica, atuando como um controle de qualidade para a interpretação. Caso a anomalia gravimétrica gerada pela modelagem não estivesse de acordo com a anomalia medida, a interpretação sísmica era revista na tentativa de um melhor ajuste entre o resultado modelado e o medido. Este ajuste, no entanto, sempre foi feito honrando os refletores que estavam bem marcados na sísmica. Somado a isto, ainda foi utilizado o dado magnético adquirido no campo, no auxilio da interpretação. O arcabouço crustal obtido com a utilização deste método permitiu a comparação dos resultados da interpretação com os modelos de evolução de margens passivas existentes na literatura, mostrando muitos pontos em comum aos modelos que defendem a possibilidade de ocorrência de manto exumado em margens passivas pobres em magmatismo. A interpretação final destes dados mostrou um domínio proximal marcado por uma crosta continental espessa porém pouco afinada em contato com um domínio distal marcado por uma crosta continental muito afinada (crosta hiper-estirada) e, em direção ao centro do oceano, uma região em que ocorre a exumação do manto. A passagem do domínio proximal para o distal ocorre de forma rápida em uma região denominada Zona de Estrangulamento. À oeste do manto exumado é possível identificar a crosta oceânica. O cruzamento dos resultados obtidos neste trabalho com dados do embasamento aflorante no continente africano sugerem um controle do deste nos valores finais de afinamento da crosta continental sob a bacia e nas regiões de manto exumado. Trabalhos recentes realizados na costa de Angola e do Brasil mostram feições semelhantes às identificadas nesta dissertação.
The main objectives of this study are to identify features on seismic data that allow (1) the building of a deep crustal framework and of the upper portion of the mantle, in part of the Angolan margin; (2) to compare this framework with the adjacent outcropping basement of the African continent and; (3) to try to fit these results to the published continental breakup models. In order to achieve these objectives, five deep reflection seismic lines (25 km of depth) situated in the in Kwanza and Lower Congo Basins on the passive margin of Angola were interpreted. The features identified on seismic were useful to recognize the tripartite division that caracterize the oceanic crust and in defining the Mohorovicic Discontinuity (that represents the limit between crust and mantle). The seismic interpretation associated with the data obtained from the scientific literature (that provided density values for the packages identified on seismic interpretation) allowed the establishment of a gravity modeling that was compared to the gravity data acquired during the seismic acquisition. The gravity model was useful to validate the seismic interpretation, acting as a quality control of the latter. In case of the gravity anomaly generated by the modeling not being in accordance with the measured anomaly, the seismic interpretation was revised in order to obtain a better adjustment between the modeled and the measured result. This adjustment, however, was always done honoring the reflectors that were clearly positioned on seismic. In addition, the magnetic data acquired on the field was used to help on interpretation. The crustal framework obtained by the methodology described above was compared with the passive margin evolution models found on scientific literature, showing some points in common with the models that postulate the occurrence of exhumed mantle in magma-poor passive margins. The final interpretation of these data showed the existence of a proximal domain characterized by a thick continental crust slightly thinned in contact with a distal domain marked by a hyper-extended continental crust. Oceanwards there is a region where the exhumation of the mantle took place. The passage of the proximal to the distal domain is abrupt, here termed as a Necking Zone. Oceanic crust is identified to the west of exhumed mantle. The comparison of the results obtained in this study with data from the outcropping basement on the African continent suggests a basement control on the vales of continental crust thinning attained under the basins and on the regions of exhumed mantle. Recent works done on the Angolan and Brazilian margins show features similar to the ones identified on this dissertation.

Background: Oral cancer is a malignant disease contributing to one third of the total cancer burden in India. There is a worldwide social disparity in oral cancer incidence and survival. Life course epidemiology has shown that early-life socioeconomic conditions (SEC) could influence adult health through various pathways. Thus, the socioeconomic disparities in the occurrence of oral cancer underscore the importance of understanding the ‘life course processes’ operating between SEC at different stages in life and oral cancer. In addition to understanding socioeconomic disparities, practical solutions are required to reduce the burden of the disease. Early diagnosis and prompt treatment could reduce morbidity and mortality. Though visual screening helps in early diagnosis, it requires training and calibration of the screeners. Developing a simple screening model that can be utilized by untrained health care workers will be helpful in triaging asymptomatic adults with oral cancer. Therefore a study was designed with the following hypotheses. Research hypotheses 1. Accumulation of socioeconomic disadvantage over the life course is associated with oral cancer in the Indian population. 2. Early-life socioeconomic disadvantage has a lasting effect on the oral cancer outcome in adulthood in the Indian population. 3. An oral cancer screening model developed for the Indian population, to screen high-risk people from rural/remote areas, has good predictive ability. Methods: A multicentre hospital based case-control study was conducted between July 2011 and August 2012 in Karnataka, India. Cases were newly diagnosed oral and oropharyngeal cancer patients and controls were patient-visitors or patients seeking care for other reasons. Data were collected through direct interviews, oral examination and record abstraction. Cases were ascertained from hospital records. A semi-structured questionnaire was designed to collect life course information on SEC, family structure, housing conditions, parental habits of tobacco, quid and alcohol use, parental education, family history of malignancy, participants’ own diet, tobacco, quid, alcohol use and oral hygiene behaviour. A life-grid was used to improve recall accuracy. All consenting participants underwent an oral examination following an interview by a trained examiner. Oral soft and hard tissues were examined for the presence of any oral mucosal lesions, teeth present and oral hygiene status. Data were analysed using SAS v 9.2. Conventional logistic regression models were used to determine the associations between life course SEC and oral cancer. Marginal structural model (MSM) was built to estimate the controlled direct effect of childhood SEC on oral cancer in adulthood. The validity of effect measures was checked with sensitivity analysis. A multivariable logistic regression model was used to develop a screening model for identifying individuals at high-risk for developing oral cancer. The development of the model involved deriving risk scores for the predictors of oral cancer. The predictive ability of the screening model was examined with c statistics, sensitivity, specificity and predictive values. Results: A total of 180 incident cases and 272 controls participated in the study. Of them, 163 cases and 264 controls had complete information on SEC at all three stages. Nearly two-thirds (65%) of participants were stable in low SEC across all stages. Low SEC at all the three stages (childhood, early adulthood and later adulthood) was associated with oral cancer after adjusting for age and sex. The association was strongest for those who remained in the low SEC at all the three stages. Odds ratios (OR) for oral cancer in socially mobile groups were intermediate to that of the stable groups. The largest differences in OR for oral cancer were observed between the stable groups. The total effect model showed that the risk was 63% [Risk ratio (RR) = 1.63 (95% CI = 1.38– 1.92)] higher for those who lived in low SEC in childhood than for those in high SEC. From the MSM, the estimated risk for developing oral cancer for those in low SEC during early-life was 48% [RR = 1.48 (95% CI = 1.43–1.53)], 24% [RR = 1.24 (95% CI = 0.88–1.74)] and 94% [RR = 1.94 (95% CI = 1.66–2.27)] greater than those in the high SEC after controlling for smoking, chewing and alcohol respectively. However, the adjusted effect of low SEC on oral cancer was null when analysed using conventional regression. A screening model was developed using statistical methods that involved smoking, chewing quid and/or tobacco, alcohol, family history of upper aero-digestive tract (UADT) cancer, diet and oral hygiene behaviour as predictors. Total risk score that was derived from odds ratio ranged from 0 to 28. Area under the curve of the Receiver Operating Characteristic (ROC) curve for risk scores was 0.866. The sensitivity (0.928) and negative predictive value (0.927) were higher while specificity (0.603) and positive predictive value (0.607) were lower for risk scores cut-off of 6. Conclusions: Low SEC in childhood and early adulthood are important in determining oral cancer in later adulthood. Early-life socioeconomic disadvantage increases the risk for oral cancer that is not mediated by later life risk factors when MSM was used. The developed screening model using risk scores had satisfactory predictive ability in the study population. However, validation of the model in other settings is necessary before it can be recommended to identify subgroups of the people to be referred for further clinical evaluation.
Thesis (Ph.D.) -- University of Adelaide, School of Dentistry, 2014

Chapter 1: I analyze economies of scale for fire and police services by considering how per-household costs are affected by a municipality’s size. Using 2005-2008 municipal data for the Province of Ontario, I employ a partial-linear model to non-parametrically estimate per-household cost curves for each service. The results show that cost per household is a U-shaped function of municipal size for each service. For fire services, these costs are minimized at a population of about 20,000 residents, while for police services they are minimized at about 50,000 residents. Based on these results, implications are drawn for municipal amalgamation policy. Chapter 2: I review how the literature has continued to exclude the business property tax (BPT) from the marginal effective tax rate (METR) on capital investment for over 25 years. I recast the METR theory as it relates to the BPT and compute 2013 estimates of the METR for all 10 provinces in Canada with provincial BPTs included. Building on these estimates, I compute the METR inclusive of municipal BPTs for the largest municipality in each province. I find the BPT to be substantially damaging to municipal, provincial and international competitiveness. With the business property tax representing over 60% of the Canadian METR, among the various capital taxes it is by far the largest contributor to Canada’s investment barrier. Chapter 3: I estimate the responsiveness of structure investment and the tax base to commercial property taxes, taking a new step toward resolving the “benefit view” vs. “capital tax view” debate within the literature. Using a first-difference structural model to analyze 2006-2013 municipal data for the Province of Ontario, I improve upon past studies and build onto the literature in a number of ways. I find that commercial structure investment and tax base are highly sensitive to the property tax with Ontario’s assessment-weighted average tax elasticity (and tax-base elasticity) ranging from -0.80 to -0.90 at 2011 taxation levels. The results support the capital tax view of the business property tax, building onto the growing consensus that business property taxes substantially impact investment in structures and the value of the tax base.

Depression increases the risk of suicide death and non-fatal suicide attempt. Between 2 - 6% of persons with depression will die by suicide1 and 25 - 31% of persons with depression will make a non-fatal suicide attempt during their lifetime.2,3 Despite the strong association between depression and suicidal behavior, the vast majority of persons with depression will not engage in suicidal behavior, making it difficult to accurately predict who is at risk for suicide and non-fatal suicide attempt. Identifying high risk persons who should be connected to suicide prevention interventions is an important public health goal. Furthermore, depression often co-occurs with other mental disorders, which may exert an interactive influence on the risk of suicide and suicide attempt. Understanding the joint influence of depression and other mental disorders on suicide outcomes may inform prevention strategies. The goals of this dissertation were to predict suicide and non-fatal suicide attempt among persons with depression and to quantify the causal joint effect of depression and comorbid psychiatric disorders on suicide and suicide attempt. For all three studies, we used data from Danish registries, which routinely collect high-quality data in a setting of universal health care with long-term follow-up and registration of most health and life events.4 In Study 1, we predicted suicide deaths among men and women diagnosed with depression using a case-cohort design (n = 14,737). Approximately 800 predictors were included in the machine learning models (classification trees and random forests), spanning demographic characteristics, income, employment, immigrant status, citizenship, family suicidal history (parent or spouse), previous suicide attempts, mental disorders, physical health disorders, surgeries, prescription drugs, and psychotherapy. In depressed men, we found interactions between hypnotics and sedatives, analgesics and antipyretics, and previous poisonings that were associated with a high risk of suicide. In depressed women, there were interactions between poisoning and anxiolytics and between anxiolytics and hypnotics and sedatives that were associated with suicide risk. The variables in the random forests that contributed the most to prediction accuracy in depressed men were previous poisoning diagnoses and prescriptions of hypnotics and sedatives and anxiolytics. In depressed women, the most important predictors of suicide were receipt of state pension, prescriptions for psychiatric medications (anxiolytics and antipsychotics) and diagnoses of poisoning, alcohol related disorders, and reaction to severe stress and adjustment disorders. Prescriptions of analgesics and antipyretics (e.g., acetaminophen) and antithrombotic agents (e.g., aspirin) emerged as important predictors for both depressed men and women. Study 2 predicted non-fatal suicide attempts among men and women diagnosed with depression using a case-cohort design (n = 17,995). Among depressed men, there was a high risk of suicide attempt among those who received a state pension and were diagnosed with toxic effects of substances. There was also an interaction between reaction to severe stress and adjustment disorder and not receiving psychological help that was associated with suicide attempt risk among depressed men. In depressed women, suicide attempt risk was high in those who were prescribed antipsychotics, diagnosed with specific personality disorders, did not have a poisoning diagnosis, and were not receiving a state pension. For both men and women, the random forest results showed that the strongest contributors to prediction accuracy of suicide attempts were poisonings, alcohol related disorders, reaction to severe stress and adjustment disorders, drugs used to treat psychiatric disorders (e.g., drugs used in addictive disorders, anxiolytics, hypnotics and sedatives), anti-inflammatory medications, receipt of state pension, and remaining single. Study 3 examined the joint effect of depression and other mental disorders on suicide and non-fatal suicide attempts using a case-cohort design (suicide death analysis n = 279,286; suicide attempt analysis n = 288,157). We examined pairwise combinations of depression with: 1) organic disorders, 2) substance use disorders, 3) schizophrenia, 4) bipolar disorder, 5) neurotic disorders, 6) eating disorders, 7) personality disorders, 8) intellectual disabilities, 9) developmental disorders, and 10) behavioral disorders. We fit sex-stratified joint marginal structural Cox models to account for time-varying confounding. We observed large hazard ratios for the joint effect of depression and comorbid mental disorders on suicide and suicide attempts, the effect of depression in the absence of comorbid mental disorders, and for the effect of comorbid mental disorders in the absence of depression. We observed positive and negative interdependence between different combinations of depression and comorbid mental disorders on the rate of suicide and suicide attempt, with variation by sex. Overall, depression and comorbid mental disorders are harmful exposures, both independently and jointly. All of the studies in this dissertation highlight the important role of interactions between risk factors in suicidal behavior among persons with depression. Depression is one of the most commonly assessed risk factors for suicide,5,6 and our findings underscore the value of considering additional risk factors such as other psychiatric disorders, psychiatric medications, and social factors in combination with depression. The results of this dissertation may help inform potential risk identification strategies which may facilitate the targeting of suicide prevention interventions to those most vulnerable.

Objective: The project aimed to compare marginal structural models, and propensity score adjusted models with Cox Proportional Hazards models to address confounding by indication due to time-dependent confounders. These methods were applied to data from approximately 120,000 women in the Women’s Health Initiative to evaluate the causal effect of antidepressant medication with respect to diabetes risk. Methods: Four approaches were compared. Three Cox Models were used. The first used baseline covariates. The second used time-varying antidepressant medication use, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates. The third used time-varying antidepressant medication use, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates and propensity to taking antidepressants at baseline. Our fourth method used a Marginal Structural Cox Model with Inverse Probability of Treatment Weighting that included time-varying antidepressant medication, BMI and presence of elevated depressive symptoms and adjusted for other baseline covariates. Results: All approaches showed an increase in diabetes risk for those taking antidepressants. Diabetes risk increased with adjustment for time-dependent confounding and results for these three approaches were similar. All models were statistically significant. Ninety-five percent confidence intervals overlapped for all approaches showing they were not different from one another. Conclusions: Our analyses did not find a difference between Cox Proportional Hazards Models and Marginal Structural Cox Models in the WHI cohorts. Estimates of the Inverse Probability of Treatment Weights were very close to 1 which explains why we observed similar results.

Tese de mestrado, Geologia (Estratigrafia, Sedimentalogia e Paleontologia) Universidade de Lisboa, Faculdade de Ciências, 2017
The Sines Contourite Drift, located in the Southwest Portuguese margin, is a distal drift of the Contourite Depositional System of the Gulf of Cadiz, built by the influence of the Mediterranean Outflow Water (MOW). This drift is located between 1000 and 2000 m water depth on the Alentejo margin continental slope. The Sines Drift is bounded by four major morphologic features: the 1.4 km high Pereira de Sousa Fault escarpment to the west, the upper continental slope to the east and the Setúbal and São Vicente canyons to the north and south, respectively. This work presents a seismic stratigraphic analysis and proposes an evolutionary model for the Sines Drift, as well as the identification of its main driving mechanisms and constraints. In pursuing such objectives, the following dataset was used: i) new and unpublished seismic reflection profiles acquired during the MOWER/CONDRIBER cruise in September-October 2014; ii) pre-existent multichannel seismic profiles BIGSETS, STEAM and GSI; iii) SWIM multibeam bathymetry; iv) lithostratigraphic and chronological data from Site U1391 of IODP (Integrated Ocean Drilling Program) Expedition 339 carried out in 2011-2012. Three evolutionary phases are identified for the Sines Drift development: 1) a sheeted-contourite-drift phase (<5.3-3.2 Ma) built since the Late Miocene by an initially weak flowing MOW; 2) a mounded-contourite-drift phase (3.2-0.7 Ma) from Late Pliocene to Early Quaternary times characterized by a mounded drift in the south and sheeted in the north, with a succession of sinuous N-S paleomoats in the east built as a result of a MOW enhancement; and 3) a plastered-contourite-drift phase from Mid-Pleistocene (0.7 Ma) till the present-day, characterized by the present depositional (sandy-muddy drifts) and erosional (moats) contourite features associated with two major events of MOW intensification. The growth of the Sines Drift was constrained by seafloor paleomorphologies that resulted from the rifting processes of the Southwest Portuguese margin, inherited from the Mesozoic rifting phases. The paleomorphologies provided accommodation space for drift growth and conditioned its overall architecture. The N-S horsts and grabens built during the Mesozoic rifting confined drift deposition and did not allow its lateral migration. The formation of the Sines Drift has also been influenced by climatic fluctuations and sea-level changes especially during the Quaternary. The succession of sinuous paleomoats beneath the present-day moat suggests a persistent and northward flowing MOW with several phases of enhancement. It was also perceived that the São Vicente and Setúbal canyons took most of the downslope sediment supply, as well as the occurrence of mass-movement processes in the west associated with the steep gradient of the Pereira de Sousa escarpment. All these results suggest the Sines Drift had a complex evolution controlled by several factors at different scales.
Contornitos são corpos sedimentares depositados ou retrabalhados por correntes de fundo que circulam paralelamente aos contornos batimétricos da margem. A formação dos contornitos é afetada, a longo e curto prazo, por fatores externos e/ou internos que podem modificar o padrão de circulação das correntes. Os depósitos contorníticos podem atingir dimensões consideráveis com vários quilómetros de largura e comprimento, os quais conservam informação paleoclimática e paleoceanográfica. Os contornitos também desempenham um papel importante no estudo dos riscos naturais submarinos, associados à ocorrência de deslizamentos, e na indústria de exploração petrolífera, como potenciais reservatórios e selantes. Um extenso Sistema Deposicional Contornítico (CDS, Contourite Depositional System) formou-se no Golfo de Cádis, desde o fim do Miocénico Superior (5.33 Ma), pela ação da Água de Saída Mediterrânica (MOW, Mediterranean Outflow Water). Este CDS abrange vários depósitos contorníticos e outras formas sedimentares, deposicionais e erosivas, ao longo da margem continental Sul e Sudoeste Ibérica. O Contornito de Sines, localizado na margem Sudoeste Portuguesa, é um contornito distal do CDS do Golfo de Cádis. Este corpo situa-se entre 1000 e 2000 m de profundidade na Bacia do Alentejo, com aproximadamente 70 km de comprimento, 40 km de largura, 1 km de espessura, morfologia assimétrica e configuração agradante com inclinação para oeste. O Contornito de Sines está limitado por quatro morfoestruturas: a escarpa da Falha Pereira de Sousa com 1.4 km de altura a oeste, a plataforma continental a este e os canhões de Setúbal e São Vicente a norte e sul, respetivamente. Este trabalho apresenta uma análise sismostratigráfica e propõe um modelo evolutivo para o Contornito de Sines, além da identificação dos principais mecanismos e constrangimentos que controlaram a sua evolução. Para atingir estes objetivos, recorreu-se ao seguinte conjunto de dados: i) linhas de reflexão sísmica multicanal não publicadas, adquiridas durante a campanha MOWER/CONDRIBER em setembro-outubro de 2014; ii) linhas de reflexão sísmica multicanal, pré-existentes, dos projetos BIGSETS, STEAM e GSI; iii) batimetria multifeixe SWIM e iv) dados litostratigráficos e cronológicos da sondagem U1391 da Expedição 339 do IODP (Integrated Ocean Drilling Program), realizada em 2011-2012. A metodologia utilizada durante este trabalho consistiu em interpretação de estratigrafia sísmica, análise batimétrica, calibração e correlação cronostratigráfica dos horizontes e unidades sísmicas com a sondagem U1391 e representação gráfica das propriedades litológicas e físicas da sondagem referida. A interpretação sismostratigráfica dos dados apresentados permitiu identificar seis unidades sísmicas (U1 a U6), com idades compreendidas entre o Miocénico Superior e o Presente. Estas unidades foram depositadas sobre uma superfície basal erosiva (B) e estão separadas por cinco horizontes sísmicos (H2 a H6), que marcam descontinuidades na sucessão sísmica. As unidades sísmicas apresentam fácies transparente a maior profundidade, com configuração em cunha, que transita para uma fácies estratificada de elevada amplitude e configuração lobular a menor profundidade. A análise litostratigráfica da sondagem U1391 permitiu a calibração cronostratigráfica das unidades sísmicas interpretadas, bem como a caracterização da sua litologia. As unidades U2 (onde a sondagem U1391 atingiu a sua máxima profundidade) e U3, situadas entre os 671.5 e 566.1 m de profundidade, têm idades compreendidas entre o Pliocénico Superior e o Quaternário Inferior (3.2-2.5 Ma). Estas unidades são constituídas por vasa carbonatada, de composição dolomítica (~0.87 m) aos 632 m de profundidade e um debrito (~0.35 m) aos 604 m de profundidade. Às unidades U4 e U5, recuperadas entre 566.1 e 196.1 m de profundidade, foram atribuídas idades entre o Pleistocénico Inferior a Médio (2.5-0.7 Ma) e são constituídas por contornitos finos intercalados por sucessões de vasa carbonatada. A unidade sedimentar mais recente, U6, depositou-se desde o Pleistocénico Médio (0.7 Ma) até ao Presente. A unidade U6 é composta por alternância de depósitos contorníticos finos e grosseiros recuperados entre 196.1 m de profundidade e o fundo oceânico. Estes depósitos apresentam sucessões com bigradação, gradação normal e inversa (separadas por contactos gradacionais, bioturbados e, mais raramente, descontinuidades). Esta unidade contém seis intervalos contorníticos arenosos, areias finas a grosseiras, a 2, 50, 83, 96, 115 e 150 m de profundidade. Foram identificadas três fases na evolução deposicional do Contornito de Sines: 1) uma primeira fase de contornito com configuração em camada (sheeted drift) (<5.3-3.2 Ma), construída desde o final do Miocénico Superior, por uma corrente MOW de fraca intensidade; 2) uma fase de contornito monticular (mounded drift) (3.2-0.7 Ma), desde o Pliocénico Superior ao Quaternário Inferior, caracterizada por uma morfologia monticular a sul e agradante a norte, com uma sucessão de paleo-fossas sinuosas ao longo da margem continental a este, que atestam a ocorrência de uma intensificação moderada a elevada da MOW e 3) uma fase final de contornito agradante (plastered drift), desde o Pleistocénico Médio (0.7 Ma) até ao Presente, caracterizada pelas atuais formas deposicionais (contornitos argilosos a arenosos) e erosivas (fossas), associadas a dois eventos de intensificação da MOW. A formação do Contornito de Sines terá tido início no Miocénico Superior, possivelmente após o final da Crise de Salinidade do Messiniano, que afetou a região Mediterrânica entre 5.33 e 5.96 Ma, a qual teve repercussões drásticas para a circulação oceânica entre o Mediterrâneo e o Atlântico. Após a Crise de Salinidade do Messiniano e o restabelecimento da circulação através do Estreito de Gibraltar, a MOW possuía fraca intensidade. A sucessão de paleo-fossas subjacentes à fossa atual sugere uma corrente semipermanente e persistente ao longo da margem Sudoeste Portuguesa, em direção a norte, com vários eventos de intensificação. A edificação do Contornito de Sines foi constrangida pelas paleo-morfologias do fundo do mar que resultaram dos processos de rifting, herdados das fases de rifting Mesozóicas na margem Sudoeste Portuguesa. Estas paleo-morfologias forneceram espaço de acomodação para o crescimento do contornito e condicionaram a sua arquitetura deposicional. Os horsts e grabens, com orientação aproximada N-S, resultantes do rifting Mesozóico, confinaram a formação do contornito impedindo a sua migração lateral. A edificação do Contornito de Sines foi também influenciada por variações climáticas e eustáticas, especialmente durante a sua última fase de desenvolvimento. Durante o Quaternário, os eventos de intensificação da MOW correlacionam-se com dois eventos climáticos do Pleistocénico, registados na região Mediterrânica e nos depósitos contorníticos do Golfo de Cádis: o Middle Pleistocene Revolution (0.7-0.78 Ma) e o Late Quaternary Discontinuity (0.4 Ma). Os sedimentos que constituem o Contornito de Sines são maioritariamente sucessões contorníticas de composição carbonatada, com uma maior componente biogénica na primeira fase de desenvolvimento (sheeted drift), e uma maior componente siliciclástica (contornitos arenosos), na última fase de desenvolvimento (plastered drift). A componente biogénica na primeira fase provavelmente indica a ocorrência de fenómenos de afloramento costeiro e deposição hemipelágica ao longo da margem Oeste Portuguesa, enquanto que a maior contribuição siliciclástica na última fase está associada a eventos de intensificação da MOW. O Contornito de Sines evoluiu de um sistema deposicional inicialmente carbonatado para siliciclástico na última fase de desenvolvimento, testemunhando variações de intensidade da MOW. Os sedimentos carreados para a margem do Alentejo são maioritariamente fornecidos por deposição hemipelágica, fenómenos de afloramento costeiro e resultante de erosão da margem continental pela circulação da MOW. O Contornito de Sines não é significativamente afetado por processos gravíticos, sendo registado apenas uma ocorrência no Pliocénico (debrito de ~0.35 m). A baixa incidência de processos gravíticos resulta, provavelmente, da morfologia da margem e da existência dos canhões de Setúbal e São Vicente, que canalizam grande parte do material deslocado. No entanto, existem depósitos de movimento de massa que afetam o sector ocidental do Contornito de Sines, que estão associados ao elevado declive da escarpa da Falha Pereira de Sousa. A formação destes depósitos poderá estar associada a vários fatores intrínsecos e extrínsecos à área em estudo. No que se refere aos fatores intrínsecos, destaca-se a potencial geração de planos de descolamento nas interfaces entre sedimentos contorníticos arenosos e vasosos caso se encontrem sobre pressão, com excesso de fluídos e/ou intercalados por sedimentos menos porosos. No que respeita aos fatores extrínsecos, a atividade sísmica registada na margem Sudoeste Ibérica poderá espoletar a ocorrência de deslizamentos submarinos no Contornito de Sines. Os resultados obtidos sugerem que o Contornito de Sines teve uma evolução complexa, controlada por vários fatores, a diferentes escalas.

The Gulf of Mexico Basin Opening project (GUMBO) is a study of the lithological composition and structural evolution of the Gulf of Mexico (GoM) that uses Ocean Bottom Seismometer (OBS) data from four transects in the Northern GoM. I examine 39 OBS shot records in the easternmost transect for shear wave arrivals and pick shear wave travel times from the 11 usable records. I then carry out a tomographic inversion of seismic refraction travel times. I use the resulting shear-wave velocity model in conjunction with a previously constructed P-wave model to examine the relationship between Vp and Vs. I compare velocities in the sediment and basement with empirical velocities from previous studies for the purpose of constraining lithological composition below the transect and make an interpretation of the structural evolution of the eastern GoM. The seismic velocities for crust landward of the Florida Escarpment are consistent with normal continental crust. Seaward of the Escarpment, velocities in the upper oceanic crust are anomalously high (Vp = 6.5 – 7 km/sec; Vs = 4.0 – 4.6 km/sec). A possible explanation for this observation is that GoM basalt formation consisted of basaltic sheet flows, forming oceanic crust that does not contain the vesicularity and lower seismic velocities found in typical pillow basalts. Increased magnesium and iron content could also account for these high velocities. Seismic refraction and reflection data provide a means of investigating the nature of the Moho in the northeastern GoM. I use a finite difference method to generate synthetic record sections for data from eight instruments that are part of the two easternmost GUMBO seismic lines (lines 3 & 4). I then vary the thickness of the Moho in these synthetic models and compare the results with the original receiver gather to examine the effects this variability has on amplitudes. The data from the instruments chosen for these two lines are representative of continental and transitional crust. The finite difference models indicate that the Moho beneath GUMBO 3 is ~1500 m thick based on the onset and amplitudes of PmP arrivals. All five instruments display consistent results. The instruments along GUMBO 4 suggest a Moho almost twice as thick as GUMBO 3 on the landward end of the transect that grades into a Moho of similar thickness (1750 m) in the deep water GoM. The three instruments used to model the Moho in this area show that the Moho ranges from ~1750 to 3500 m in thickness. The sharper boundary beneath continental crust in GUMBO Line 3 supports other evidence that suggests magmatic underplating and volcanism in the northern GoM during the mid-Jurassic. The thicker Moho seen on the landward end of GUMBO Line 4 that is overlain by continental crust was likely unaffected by GoM rifting. Therefore, the Moho beneath the Florida Platform might be as old as the Suwannee Terrane, and complex Moho structure is not uncommon for ancient continental crust.
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Spatial and social dependence shape human activity-travel pattern decisions and their antecedent choices. Although the transportation literature has long recognized the importance of considering spatial and social dependencies in modeling individuals’ choice behavior, there has been less research on techniques to accommodate these dependencies in discrete choice models, mainly because of the modeling complexities introduced by such interdependencies. The main goal of this dissertation, therefore, is to propose new modeling approaches for accommodating flexible spatial and social dependency structures in discrete choice models within the broader context of activity-based travel demand modeling. The primary objectives of this dissertation research are three-fold. The first objective is to develop a discrete choice modeling methodology that explicitly incorporates spatial dependency (or correlation) across location choice alternatives (whether the choice alternatives are contiguous or non-contiguous). This is achieved by incorporating flexible spatial correlations and patterns using a closed-form Generalized Extreme Value (GEV) structure. The second objective is to propose new approaches to accommodate spatial dependency (or correlation) across observational units for different aspatial discrete choice models, including binary choice and ordered-response choice models. This is achieved by adopting different copula-based methodologies, which offer flexible dependency structures to test for different forms of dependencies. Further, simple and practical approaches are proposed, obviating the need for any kind of simulation machinery and methods for estimation. Finally, the third objective is to formulate an enhanced methodology to capture the social dependency (or correlation) across observational units. In particular, a clustered copula-based approach is formulated to recognize the potential dependence due to cluster effects (such as family-related effects) in an ordered-response context. The proposed approaches are empirically applied in the context of both spatial and aspatial choice situations, including residential location and activity participation choices. In particular, the results show that ignoring spatial and social dependencies, when present, can lead to inconsistent and inefficient parameter estimates that, in turn, can result in misinformed policy actions and recommendations. The approaches proposed in this research are simple, flexible and easy-to-implement, applicable to data sets of any size, do not require any simulation machinery, and do not impose any restrictive assumptions on the dependency structure.
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