<p>Predictive modeling in healthcare involves the development of data-driven and computational models which can predict what will happen, be it for a single individual or for an entire system. The adoption of predictive models can guide various stakeholders’ decision-making in the healthcare sector, and consequently improve individual outcomes and the cost-effectiveness of care. With the rapid development in healthcare of big data and the Internet of Things technologies, research in healthcare decision-making has grown in both importance and complexity. One of the complexities facing those who would build predictive models is heterogeneity of patient populations, clinical practices, and intervention outcomes, as well as from diverse health systems. There are many sub-domains in healthcare for which predictive modeling is useful such as disease risk modeling, clinical intelligence, pharmacovigilance, precision medicine, hospitalization process optimization, digital health, and preventive care. In my dissertation, I focus on predictive modeling for applications that fit into three broad and important domains of healthcare, namely clinical practice, public health, and healthcare system. In this dissertation, I present three papers that present a collection of predictive modeling studies to address the challenge of modeling heterogeneity in health care. The first paper presents a decision-tree model to address clinicians’ need to decide among various liver cirrhosis diagnosis strategies. The second paper presents a micro-simulation model to assess the impact on cardiovascular disease (CVD) to help decision makers at government agencies develop cost-effective food policies to prevent cardiovascular diseases, a public-health domain application. The third paper compares a set of data-driven prediction models, the best performing of which is paired together with interpretable machine learning to facilitate the coordination of optimization for hospital-discharged patients choosing skilled nursing facilities. This collection of studies addresses important modeling challenges in specific healthcare domains, and also broadly contribute to research in medical decision-making, public health policy and healthcare systems.</p>

[EN] Adaptation to the multiple facets of global change challenges the conventional means of sustainably planning and managing water resources at the river basin scale. Numerous demand or supply management options are available, from which adaptation measures need to be selected in a context of high uncertainty of future conditions. Given the interdependency of water users, agreements need to be found at the local level to implement the most effective adaptation measures. Therefore, this thesis develops an approach combining economics and water resources engineering to select a cost-effective programme of adaptation measures in the context of climate change uncertainty, and to define an equitable allocation of the cost of the adaptation plan between the stakeholders involved. A framework is developed to integrate inputs from the two main approaches commonly used to plan for adaptation. The first, referred to as "top-down", consists of a modelling chain going from global greenhouse gases emission scenarios to local hydrological models used to assess the impact of climate change on water resources. Conversely, the second approach, called "bottom-up", starts from assessing vulnerability at the local level to then identify adaptation measures used to face an uncertain future. Outcomes from these two approaches are integrated to select a cost-effective combination of adaptation measures through a least-cost optimization model developed at the river basin scale. The model is then used to investigate the trade-offs between different planning objectives defined in terms of environmental flow requirements, irrigated agriculture development, and the cost of the programme of measures. The performances of a programme of measures are finally assessed under different climate projections to identify robust and least-regret adaptation measures. The issue of allocating the cost of the adaptation plan is considered through two complementary perspectives. The outcome of a negotiation process between the stakeholders is modelled through the implementation of cooperative game theory to define cost allocation scenarios. These results are compared with cost allocation rules based on social justice principles to provide contrasted insights into a negotiation process. This innovative framework has been applied in a Mediterranean case study in the Orb River basin (France). Mid-term climate projections, downscaled from 9 General Climate Models, are used to assess the uncertainty associated with climate projections. Demand evolution scenarios have been developed to project agricultural and urban water demands on the 2030 time horizon. The least-cost river basin optimization model developed in GAMS allows the cost-effective selection of a programme of measures from a catalogue of 462 supply and demand management measures. Nine cost allocation scenarios based on different social justice principles have been discussed through face-to-face semi-structured interviews with 15 key informants and compared with solution concepts from cooperative game theory for a 3-player game defined at the river basin scale. The interdisciplinary framework developed in this thesis combines economics and water resources engineering methods, establishing a promising means of bridging the gap between bottom-up and top-down approaches and supporting the creation of cost-effective and equitable adaptation plans at the local level. / [ES] La adaptación a los múltiples aspectos del cambio global supone un reto para los enfoques convencionales de planificación y gestión sostenible de los recursos hídricos a escala de cuenca. Numerosas opciones de gestión de la demanda o de la oferta están disponibles, de entre las cuales es necesario seleccionar medidas de adaptación en un contexto de elevada incertidumbre sobre las condiciones futuras. Dadas las interdependencias existentes entre los usuarios del agua a nivel local, hace falta buscar acuerdos a escala de cuenca para implementar las medidas de adaptación más eficaces. Por este motivo, esta tesis desarrolla una metodología que, combinando economía e ingeniería de los recursos hídricos, busca seleccionar un programa de medidas coste-eficaz frente a las incertidumbres del cambio climático, y asimismo definir un reparto justo del coste de la adaptación entre los actores implicados. El marco metodológico ha sido desarrollado para integrar contribuciones de los dos principales enfoques utilizados para la planificación de la adaptación. El primero, denominado descendente ("top-down"), consiste en una cadena de modelación que va desde los escenarios de emisiones de gases efecto invernadero a nivel global hasta los modelos hidrológicos utilizados a nivel local para evaluar así el impacto del cambio climático sobre los recursos hídricos. Por el contrario, el segundo enfoque denominado ascendente ("bottom-up") empieza por evaluar la vulnerabilidad del sistema a nivel local para después identificar medidas de adaptación frente a un futuro incierto. Los resultados de los métodos mencionados previamente se han integrado con el fin de seleccionar una combinación coste-eficaz de medidas de adaptación a través de un modelo de optimización a menor coste a escala de cuenca. El modelo se utiliza para investigar las soluciones de compromiso ("trade-offs") entre diversos objetivos de planificación como son los caudales ecológicos necesarios, el desarrollo del regadío y el coste del programa de medidas. Seguidamente, se han evaluado los programas de adaptación frente a varias condiciones climáticas para definir así un programa de medidas robusto y de arrepentimiento mínimo frente al cambio climático. En la última parte se aborda el problema del reparto justo de los costes del plan de adaptación, entendiendo que esto es una manera de favorecer su implementación. Para ello, se han modelado los resultados de un proceso de negociación entre los diferentes actores mediante escenarios de reparto basados en la teoría de juegos cooperativos. Posteriormente, se han comparado estos resultados con otras reglas de reparto de costes basadas en principios de justicia social, proporcionando así un punto de vista diferente al proceso de negociación. Este novedoso enfoque ha sido aplicado a una cuenca mediterránea, la cuenca del rio Orb (Francia). Para ello, se han empleado proyecciones climáticas a medio-plazo de datos reescalados de 9 Modelos de Circulación Global. Además, se han desarrollado escenarios de evolución de la demanda en los sectores urbano y agrícola para el horizonte de planificación de 2030. El modelo de optimización a menor coste a escala de cuenca desarrollado en GAMS permite seleccionar un programa de medidas, de entre las 462 medidas de gestión de la oferta o de la demanda. Nueve escenarios de reparto de costes basados en diferentes principios de justicia social han sido debatidos con informantes clave mediante entrevistas y comparados con conceptos de solución de la teoría de juegos cooperativos, considerando un juego de 3 jugadores a escala de cuenca. El marco interdisciplinario desarrollado durante esta tesis combina métodos de economía y de ingeniería de los recursos hídricos de manera prometedora y permite integrar los enfoques "top-down" y "bottom-up", contribuyendo a definir un plan de adaptación coste-eficaz y justo a nivel local. / [CA] L'adaptació als múltiples aspectes del canvi global implica un repte per als enfocaments convencionals de planificació i gestió sostenible dels recursos hídrics a escala de conca. Existeixen nombroses opcions de gestió de la demanda y de la oferta. De entre elles, cal seleccionar mesures d'adaptació en un context d'incertesa elevada sobre les condicions futures. Donades les interaccions entre els usuaris de l'aigua a nivell local, és necessari buscar acords a escala de conca per tal d'implementar les mesures d'adaptació més eficaces. Per aquest motiu, la tesi desenvolupa una metodologia que, mitjançant la combinació d'economia i enginyeria dels recursos hídrics, siga adient per seleccionar un programa de mesures cost-eficaç per a fer front a les incerteses del canvi climàtic i, a més a més, definir un repartiment just del cost d'adaptació entre els actors implicats. El marc metodològic ha estat desenvolupat amb el fi de permetre integrar contribucions del principals enfocaments que s'utilitzen per a la planificació de l'adaptació. El primer, que es denomina descendent ("top-down"), consisteix a una cadena de modelació que va des dels escenaris d'emissions de gas d'efecte hivernacle a nivell global fins als models hidrològics a nivell local per avaluar l'impacte del canvi climàtic sobre els recursos hídrics. Per contra, el segon enfocament, que es denomina ascendent ("bottom-up"), comença per avaluar la vulnerabilitat del sistema a nivell local per a tot seguit identificar mesures d'adaptació de cara a un futur incert. Els resultats del mètodes esmentats prèviament, s'han integrat per a seleccionar una combinació de mesures d'adaptació cost-eficaç mitjançant un model d'optimització a menor cost a escala de conca. El model s'utilitza per investigar les solucions de compromís ("trade-offs") entre els diversos objectius de planificació, com són els cabals ecològics necessaris, el desenvolupament del regadiu i el cost del programa de mesures. A continuació, s'avaluen els programes d'adaptació per a varies condicions climàtiques amb el fi de definir un programa de mesures robust i de penediment mínim per a fer front al canvi climàtic. En la darrera part, s'escomet el problema del repartiment just dels costs del pla d'adaptació, considerant que això és una manera de facilitar la implementació del pla. En conseqüència, els resultats d'un procés de negociació entre els diferents actors han estat modelats mitjançant escenaris de repartiment basats en la teoria de jocs cooperatius. Tot seguit, els resultats s'han comparat amb altres regles de repartiment de costos basades en principis de justícia social. Això ha proporcionat un punt de vista diferent al procés de negociació. Aquest enfocament innovador s'ha aplicat a una conca mediterrània, la conca del riu Orb (França). Amb aquesta finalitat s'han utilitzat projeccions climàtiques a mig termini de dades reescalades de 9 Models de Circulació Global (MCG). A més a més, s'han desenvolupat escenaris d'evolució de la demanada en els sectors agrícola i urbà per a l'horitzó de planificació de 2030. El model d'optimització a menor cost a escala de conca desenvolupat en GAMS permet seleccionar un programa de mesures, de entre les 462 mesures de gestió de la oferta o de la demanda. Els nou escenaris de repartiment de costs han estat debatuts amb informants clau, mitjançant entrevistes, i comparats amb conceptes de solució de la teoria de jocs cooperatius, considerant un joc de 3 jugadors a escala de conca. El marc interdisciplinari desenvolupat al llarg de la tesi combina mètodes d'economia i d'enginyeria dels recursos hídrics de manera prometedora i permet la integració d'enfocaments "top-down" i "bottom-up", fet que contribueix a definir un pla d'adaptació cost-eficaç i just a escala local. / Girard, CDP. (2015). Integrating top-down and bottom-up approaches to design a cost-effective and equitable programme of measures for adaptation of a river basin to global change [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/59461 / Premios Extraordinarios de tesis doctorales

Introduction: Quality improvement (QI) encompasses a wide range of healthcare studies and activities with the common goal of improving patient outcomes, healthcare system performance, and professional development. QI is characterized by a diversity of definitions, stakeholders, clinical fields and study designs, which creates challenges for rigorous reporting and evaluation of these studies. Understanding and addressing the methodological issues that arise from conducting QI studies from multiple clinical disciplines is critical for generating good evidence for healthcare improvement to tackle health system challenges. Objectives: This thesis addressed three independent objectives: (i) Determine the quality of reporting of QI studies in neonatology. (ii) Compare different statistical methods that can be used to analyze data from a cluster randomized controlled trial with repeated measures data and examine how the estimate of intervention effects varies between these approaches. (iii) Determine the cost-effectiveness of providing timely surgery or timely rehabilitation for patients with hip fracture. Methods: Objective 1: We conducted a systematic survey of quality improvement studies in neonatology to examine the extent to which these publications adhered to SQUIRE 2.0, the guidelines for reporting studies that sought to improve the quality, safety, and value of healthcare. Using the same set of articles, we examined how various methodological attributes, such as stakeholder engagement, outcome measures, and statistical process controls, are reported in these studies. Objective 2: To compare the differences in the statistical estimates of intervention effects between linear mixed models and Generalized Estimating Equations, for the CP@Clinic Program cluster randomized RCT, which contains routinely collected monthly outcome data aggregated at the cluster level. Objective 3: We constructed a Markov cohort model to estimate the cost-effectiveness of receiving timely surgery within 24 hours of admission to the emergency department, receiving immediate admission to inpatient rehabilitation following acute care discharge, receiving both, or none. Results: Objective 1: In our assessment of reporting quality, we found that adherence to SQUIRE 2.0 guidelines was inadequate and that journals should endorse the SQUIRE 2.0 guideline for improvement publications to alleviate this issue. We found that process measures was the most frequently reported methodological attribute (89%), while stakeholder engagement with leadership (32%) or caregivers (10%) were infrequently reported or conducted. Objective 2: In comparing statistical methods for analyzing a cluster randomized controlled trial with correlated data, we found that it was critical to apply a correction to the variance estimator of generalized estimating equations to produce robust estimates of the intervention effects. Objective 3: In our economic evaluation, both timely surgery alone and the combination of timely surgery and timely rehabilitation yielded cost-effective improvements in the quality-adjusted life-years of patients with hip fracture. However, the combination of receiving timely surgery and timely rehabilitation requires a high willingness-to-pay threshold, above $128,000 per quality-adjusted life-years, to be considered cost-effective. Conclusions: Overall, understanding the state of reporting and the broad spectrum of methods and methodologic issues for evaluating quality improvement initiatives will advance its rigorous research, evaluation, reporting, and contribution towards informed decision-making for tackling pressing healthcare issues. / Thesis / Doctor of Philosophy (PhD) / Quality improvement (QI) is a field of healthcare research that can be defined in many ways, and research in this field is conducted by researchers from various medical disciplines. Consequently, challenges may arise in reporting and evaluating QI interventions. Thus, it is important to examine how QI interventions are reported in academic literature and the methods used to evaluate their effectiveness in improving health. The current thesis aims to address these issues through three independent objectives: (1) examine the details reported in QI studies in neonatology, (2) compare different statistical methods that can be used to analyze data from a community paramedicine cluster randomized controlled trial, and (3) investigate whether providing timely surgery and timely hospital-based rehabilitation is a cost-effective way to improve the quality of life of patients who have experienced hip fracture. The findings of these studies will provide insights into the challenges of reporting and evaluating QI interventions, and suggest ways to improve them.

De nos jours, il est de plus en plus fréquent de recourir à des mesures intermédiaires d’efficacité telles que la survie sans progression (SSP) et le temps avant la progression de la tumeur (TPT) afin d’estimer l’efficacité d’un nouvel agent anticancéreux. Cependant, l’absence de mesures finales comme la survie globale (SG) complexifie la prise de décision par rapport au remboursement des nouveaux traitements anticancéreux. Ainsi, cette thèse se concentre sur différents aspects de l’intégration des mesures intermédiaires d’efficacité dans les évaluations économiques en oncologie, spécifiquement en cancer du sein métastatique. Une première étude a évalué la relation entre la SSP/TPT et la SG dans le contexte du cancer du sein métastatique. Une revue systématique de la littérature a identifié les études cliniques randomisées portant sur l’efficacité d’un traitement anticancéreux chez les femmes atteintes d’un cancer du sein métastatique et rapportant des données de SSP/TPT et de SG. Les résultats de cette étude ont démontré qu’il existe une relation statistiquement significative, d’une part, entre la SSP/TPT médiane et la SG médiane (r = 0.428; p ≤ 0,01), et d’autre part, entre l’effet de traitement sur la SSP/TPT et l’effet de traitement sur la SG (r = 0.427; p ≤ 0,01). Selon les résultats obtenus, la SSP/TPT pourrait être considérée comme un substitut valide de la SG, justifiant ainsi son utilisation dans les évaluations économiques en cancer du sein métastatique. Une deuxième étude a évalué l’utilisation des mesures intermédiaires de survie dans les évaluations économiques en cancer avancé et identifié les méthodes utilisées pour intégrer ces mesures en l’absence de données de SG. Une revue systématique de la littérature a été réalisée pour recenser les évaluations économiques de type coût-efficacité et coût-utilité ayant intégré des mesures intermédiaires de survie. Cette étude a démontré l’ampleur de l’utilisation des mesures intermédiaires de survie dans les évaluations économiques en cancer avancé. Par ailleurs, plusieurs approches ont été identifiées pour pallier l’absence de données de SG, notamment l’utilisation d’un risque de décès post-progression équivalent pour les groupes à l’étude, le recours à des comparaisons indirectes basées sur de nombreuses hypothèses, l’utilisation d’une mesure intermédiaire comme proxy de la SG, le recours à l’opinion d’experts et l’utilisation de données associées à un traitement différent ou une ligne de traitement différente. Enfin, une troisième étude s’est penchée sur le développement d’un modèle pharmacoéconomique générique canadien intégrant les mesures intermédiaires de survie en cancer du sein métastatique. Ce modèle de Markov inclut des paramètres spécifiques aux traitements sous évaluations (coût de traitement, données de survie et incidence des effets indésirables) de même que des paramètres globaux qui ne dépendent pas des traitements évalués (caractéristiques des patientes, valeurs d’utilité associées aux états de santé du modèle, pertes d’utilité et coûts des effets indésirables, coûts d’administration des traitements, coûts de suivi médical et coûts des soins prodigués en fin de vie). Le modèle a été validé en évaluant sa capacité à répliquer des résultats d’études existantes. Ce modèle permet d’uniformiser l’évaluation économique des nouveaux traitements en cancer du sein métastatique et pourrait par conséquent, devenir un outil d’aide à la décision de référence pour les organismes responsables du remboursement des médicaments au Canada. Bref, les résultats de ces trois études répondent à une problématique importante dans l’évaluation économique des traitements en oncologie et pourront contribuer à faciliter la prise de décision en santé. / Nowadays, intermediate endpoints such as progression-free survival (PFS) and time to progression (TTP) are frequently used in clinical trials of advanced cancer. However, use of such endpoints instead of overall survival (OS) poses a significant challenge in the economic evaluation of anticancer drugs. This thesis focuses on different aspects of the integration of intermediate endpoints in the economic evaluation of anticancer drugs, especially in the context of metastatic breast cancer. A first study assessed the relationship between PFS/TPT and OS in metastatic breast cancer using a trial-based approach. A systematic review of the literature was performed to identify randomized clinical trials of metastatic breast cancer therapy reporting both PFS/TTP and OS data. Results of this study indicated a statistically significant relationship between the median PFS/TTP and the median OS (r = 0.428; p < 0.01), and between the treatment effect on PFS/TTP and the treatment effect on OS (r = 0.427; p < 0.01). Findings of this study suggest that PFS/TTP may be considered as a potential surrogate for OS, thus justifying its use in cost-effectiveness or cost-utility analyses of metastatic breast cancer therapy. A second study evaluated the use of intermediate endpoints in the economic evaluation of new treatments for advanced cancer and the methodological approaches adopted when OS data are unavailable or of limited use. A systematic review of the literature was conducted to identify cost-effectiveness and cost-utility analyses using an intermediate endpoint as an outcome measure. This study showed that intermediate endpoints are widely used in the economic evaluation of new treatments for advanced cancer. Several approaches are used in the absence of OS data such as assuming an equal risk of death for all treatment groups, using indirect comparison based on numerous assumptions, using of a proxy for OS, using unpublished external information (consultation with clinical experts), and using published external information from different treatment settings. Finally, a third study aimed to develop a global economic model to assess the cost-effectiveness of new treatments for metastatic breast cancer in Canada. This Markov model, which integrates intermediate endpoints, includes parameters specific to the treatments under evaluation (drug treatment, survival outcomes, and incidence of treatment-related adverse events (AEs)), as well as global parameters that are consistent regardless of the treatment under evaluation (patient characteristics, health states utilities, disutilities and costs associated with treatment-related AEs, as well as costs associated with drug administration, medical follow-up, and end-of-life care). The model was validated by assessing its ability to replicate results of existing studies. This model standardizes the economic evaluation of new therapies for metastatic breast cancer, and could thus be used as a benchmark by drug reimbursement authorities in Canada. In summary, the results of these three studies address an important challenge encountered in the economic evaluation of anticancer drugs, and therefore, can be very valuable for decision-making purposes.

Introdução - Os custos para o tratamento da doença arterial coronariana (DAC) são altos em todo o mundo. Foi realizada uma análise post hoc de custo-efetividade de três estratégias terapêuticas para DAC multiarterial. Métodos - De maio de 1995 a maio de 2000, um total de 611 pacientes foram aleatoriamente designados para CRM (n = 203), ICP (n = 205) ou TM (n = 203). Este estudo de análise de custos baseou-se na perspectiva do Sistema Público de Saúde. Os custos iniciais de procedimentos e acompanhamento de medicamentos, exames cardiológicos e hospitalizações por complicações foram calculados após a randomização. Anos de vida e anos de vida ajustados pela qualidade (QALY) foram usados como medidas de eficácia. As razões de custo-efetividade incremental (RCEI) foram obtidas usando métodos de bootstrap não paramétricos com 5.000 replicações. Resultados - Os custos iniciais do procedimento foram menores para o TM. No entanto, os custos acumulados de 5 anos foram menores para a CRM. Em comparação com a linha de base, as 3 opções de tratamento produziram melhorias significativas no QALY. Após 5 anos, a ICP e a CRM tiveram melhores resultados de QALY em comparação com o TM. Os resultados da RCEI favoreceram a CRM e a ICP quando comparadas ao TM, já a ICP em relação à CRM foi mais custo-efetiva em 61% para limiares até 3 PIB per capita por QALY. Por outro lado, a análise de sensibilidade mostrou o TM como a terapia preferida em comparação com a CRM e ICP, na análise considerando custos mais elevados. Conclusão - No seguimento de 5 anos, a ICP e CRM mostraram ser os tratamentos com QALYs cumulativos mais altos entre pacientes com DAC multiarterial quando comparados com TM. Além disso, apesar dos custos iniciais serem mais elevados, a comparação de custo-efetividade após 5 anos de acompanhamento entre os 3 tratamentos mostrou que ambas as intervenções (CRM e ICP) são estratégias custo-efetivas em comparação com a TM / Background. The costs for treating coronary artery disease (CAD) are high worldwide. We performed a post hoc analysis of cost-effectiveness of 3 therapeutic strategies for multivessel CAD. Methods. From May 1995 to May 2000, a total of 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALY) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results. Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the 3 treatment options produced significant improvements in QALY. After 5 years, PCI and CABG had better QALY results compared with MT. The ICER results favored CRM and PCI when compared to the TM, since the PCI in relation to the CRM was more costeffective in 61% for the thresholds up to 3 GDP per capita per QALY. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusion. At 5-year follow-up, the 3 treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of costeffectiveness after 5 years of follow-up among the 3 treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT

Introdução - Os custos para o tratamento da doença arterial coronariana (DAC) são altos em todo o mundo. Foi realizada uma análise post hoc de custo-efetividade de três estratégias terapêuticas para DAC multiarterial. Métodos - De maio de 1995 a maio de 2000, um total de 611 pacientes foram aleatoriamente designados para CRM (n = 203), ICP (n = 205) ou TM (n = 203). Este estudo de análise de custos baseou-se na perspectiva do Sistema Público de Saúde. Os custos iniciais de procedimentos e acompanhamento de medicamentos, exames cardiológicos e hospitalizações por complicações foram calculados após a randomização. Anos de vida e anos de vida ajustados pela qualidade (QALY) foram usados como medidas de eficácia. As razões de custo-efetividade incremental (RCEI) foram obtidas usando métodos de bootstrap não paramétricos com 5.000 replicações. Resultados - Os custos iniciais do procedimento foram menores para o TM. No entanto, os custos acumulados de 5 anos foram menores para a CRM. Em comparação com a linha de base, as 3 opções de tratamento produziram melhorias significativas no QALY. Após 5 anos, a ICP e a CRM tiveram melhores resultados de QALY em comparação com o TM. Os resultados da RCEI favoreceram a CRM e a ICP quando comparadas ao TM, já a ICP em relação à CRM foi mais custo-efetiva em 61% para limiares até 3 PIB per capita por QALY. Por outro lado, a análise de sensibilidade mostrou o TM como a terapia preferida em comparação com a CRM e ICP, na análise considerando custos mais elevados. Conclusão - No seguimento de 5 anos, a ICP e CRM mostraram ser os tratamentos com QALYs cumulativos mais altos entre pacientes com DAC multiarterial quando comparados com TM. Além disso, apesar dos custos iniciais serem mais elevados, a comparação de custo-efetividade após 5 anos de acompanhamento entre os 3 tratamentos mostrou que ambas as intervenções (CRM e ICP) são estratégias custo-efetivas em comparação com a TM / Background. The costs for treating coronary artery disease (CAD) are high worldwide. We performed a post hoc analysis of cost-effectiveness of 3 therapeutic strategies for multivessel CAD. Methods. From May 1995 to May 2000, a total of 611 patients were randomly assigned to CABG (n=203), PCI (n=205), or MT (n=203). This cost analysis study was based on the perspective of the Public Health Care System. Initial procedural and follow-up costs for medications, cardiology examinations, and hospitalizations for complications were calculated after randomization. Life-years and quality-adjusted life years (QALY) were used as effectiveness measures. Incremental cost-effectiveness ratios (ICER) were obtained by using nonparametric bootstrapping methods with 5000 resamples. Results. Initial procedural costs were lower for MT. However, the subsequent 5-year cumulative costs were lower for CABG. Compared with baseline, the 3 treatment options produced significant improvements in QALY. After 5 years, PCI and CABG had better QALY results compared with MT. The ICER results favored CRM and PCI when compared to the TM, since the PCI in relation to the CRM was more costeffective in 61% for the thresholds up to 3 GDP per capita per QALY. On the other hand, sensitivity analysis showed MT as the preferred therapy compared with CABG and PCI, in the analysis considering higher costs. Conclusion. At 5-year follow-up, the 3 treatment options yielded improvements in quality of life, with comparable and acceptable costs. However, despite higher initial costs, the comparison of costeffectiveness after 5 years of follow-up among the 3 treatments showed both interventions (CABG and PCI) to be cost-effective strategies compared with MT

Made available in DSpace on 2011-05-04T12:36:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2010 / Nas últimas décadas, os gastos crescentes no setor saúde vêm preocupando diversos países, em especial aqueles cuja atenção à saúde é garantida pelo setor público. A grande pressão pela incorporação de tecnologias cada vez mais caras, além de impactar no orçamento dos países, produz restrição ao acesso dos serviços de saúde, visto que não é possível garantir todas as intervenções a todos. Diante desta situação, técnicas para a racionalização dos gastos, tais como as análises econômicas em saúde, são utilizadas na tentativa de maximizar a saúde, mas resguardando a viabilidade financeira dos sistemas públicos de saúde. Países desenvolvidos com forte financiamento público, assim como Austrália, Canadá e Reino Unido têm empregado cada vez mais estas ferramentas para a tomada de decisão acerca da incorporação de novas tecnologias. O Brasil, na última década, também tem empreendido esforços para a adoção de critérios de custo-efetividade, tanto na entrada de medicamentos no mercado privado, com a alteração da lei de registro e com a criação da Câmara de Regulação do Mercado de Medicamentos (CMED), quanto com o estabelecimento de uma Comissão de Incorporação de Tecnologias do Ministério da Saúde (CITEC). As decisões da CITEC são subsidiadas por estudos desenvolvidos pela área de Avaliação de Tecnologias em Saúde (ATS) do Departamento de Ciência e Tecnologia (DECIT) do Ministério da Saúde. Neste aspecto, as Agências Nacionais de Vigilância Sanitária e de Saúde Suplementar também instituíram áreas de ATS para responder as suas demandas. E, apesar do avanço na institucionalização de áreas que utilizam análises econômicas na incorporação de tecnologias, ainda há uma fragilidade institucional nas etapas seguintes do ciclo de vida destas. O País também carece de profissionais capacitados e padece de uma desorganização neste campo causa da principalmente pela sobreposição de atividades e atribuições das áreas que realizam a ATS no governo federal. Ademais, para que as análises econômicas em saúde sejam realmente úteis na tomada de decisão é imprescindível a definição de um limite custo-efetividade para o Brasil. / In recent decades, increasing spending in the health sector is worrying many countries, particularly those whose health care is guaranteed by the public sector. The big push for the incorporation of technologies increasingly expensive is impacting the budgets of countries and producing a restriction on access to health services, since we cannot guarantee all interventions for everybody. Facing this situation, techniques for the rationalization of expenditures, such as health economic analysis, are used in an attempt to maximize health, but protecting the financial viability of public health systems. Developed countries with strong public support, such as Australia, Canada and the UK have progressively more used this tool for decision making regarding the incorporation of new technologies. Brazil, more recently, has also made efforts to adopt criteria of cost-effectiveness, both at the entrance of drugs in the private market, with the adjustment of the law of register and the establishment of the Board of Market Regulation of Medicines (CMED) and the Commission of Technology Incorporation of the Ministry of Health (CITEC). The decisions of CITEC are subsidized by studies undertaken by the area of Health Technology Assessment (HTA) at Department of Science and Technology (DECIT) of the Ministry of Health. The Brazilian Health Surveillance Agency and Brazilian National Private Health Insurance Agency also established areas of HTA to answer to their demands. Despite advances in the institutionalization of areas that use economic analysis in the incorporation of technologies, there is fragility in the following stages of the life cycle of these. The country also lacks qualified professionals and suffers from a disruption in this field mainly caused by overlapping of activities and tasks of the areas that hold the HTA in the Federal Government. Moreover, for the health economic analyses are really useful in decision making is essential to define threshold costeffectiveness for Brazil.

Dans la première partie de cette thèse, nous considérons plusieurs problèmes d'estimation de paramètre de dimension finie pour les séquences de Markov dans l'asymptotique des grands échantillons. Le comportement asymptotique des estimateurs bayésiens et les estimateurs obtenus par la méthode des moments sont décrits. Nous montrons que sous les conditions de régularité ces estimateurs sont consistants et asymptotiquement normaux et que l'estimateur bayésien est asymptotiquement efficace. Les estimateur-processus du maximum de vraisemblance un-pas et deux-pas sont étudiés. Ces estimateurs nous permettent de construire des estimateurs asymptotiquement efficaces sur la base de certainsestimateurs préliminaires, par exemple, les estimateurs obtenus par la méthode des moments ou l'estimateur deBayes et la structure de l'estimateur du maximum de vraisemblance un-pas. Nous proposons notamment des processus autorégressifs non linéaires comme exemple et nous illustrons les propriétés de ces estimateurs à l'aide de simulations numériques. Dans la deuxième partie, nous donnons les applications de processus de Markov en économie de la santé. Nous comparons les modèles de Markov homogènes et non-homogènes pour l'analyse coût-efficacité de l'utilisation depansements transparents contenant un gel de gluconate de chlorhexidine par rapport aux pansements transparents standard. Le pansement antimicrobien protège les accès vasculaire centrale et réduit le risque de bactériémies liées aux cathéters. L'impact de l'approche de modélisation sur la décision d'adopter des pansements antimicrobiens pour les patients gravement malades est discuté. / In the first part of this dissertation we consider several problems of finite-dimensional parameter estimation for Markov sequences in the asymptotics of large samples. The asymptotic behavior of the Bayesian estimators and the estimators of the method of moments are described. It is shown that under regularity conditions these estimators are consistent and asymptotically normal. We show that the Bayesian estimator is asymptotically efficient. The one-step and two-step maximum likelihood estimator-processes are studied. These estimators allow us to construct the asymptotically efficient estimators based on some preliminary estimators, say, the estimators of the method of moments or Bayes estimator and the one-step maximum likelihood estimator structure. We propose particular non-linear autoregressive processes as examples and we illustrate the properties of these estimators with the help of numerical simulations. In the second part we give theapplications of Markov processes in health economics. We compare homogeneous and non-homogeneous Markov models for cost-effectiveness analysis of routine use of transparent dressings containing a chlorhexidine gluconate gel pad versus standard transparent dressings. The antimicrobial dressing protects central vascular accesses reducing the risk of catheter-related bloodstream infections. The impact of the modeling approach on the decision of adopting antimicrobialdressings for critically-ill patients is discussed.

The growing demand for clean water has led to the adoption of the EU Water Framework Directive (Directive 2000/60 EC). New legislation has a major impact on the water management and the national economy and provides numerous requirements, including "good status" of all water bodies. The Framework Directive also implies the need for an economic analysis of the optimal process to achieve good status by using the cost-effectiveness analysis (CEA). The application of this method in water management is struggling with a number of methodological complications. One of the affected areas in the Czech Republic is the catchment of the Orlik Reservoir that faces excessive eutrophication. Eutrophication is caused by excessive introduction of phosphorus. The main sources of phosphorus are municipal wastewater, aquaculture and agriculture. As illustrated by professional research mentioned in this work and the actual processing of CEA of the catchment of the Orlik Reservoir, a wide range of methodological problems can be avoided by using appropriate tools. This thesis also presents that achieving of good status of the catchment would require annual cost of CZK 602 million. The most significant cost bearers are according to the CEA fisheries and municipalities.

Au Canada, il y a environ 21 000 décès et 84 069 hospitalisations liés à un infarctus du myocarde (IM) par année, ce qui représente environ 1,27 milliard de dollars canadiens ($ CA) en coûts directs reliés aux traitements aigus et chroniques. Parmi ces traitements, la double thérapie antiplaquettaire (DAPT) a été démontrée efficace pour diminuer le risque de complications reliées à l’IM. Cependant, malgré ces avantages cliniques, la persistance au traitement observée dans la vie réelle au Québec avec le DAPT à base de ticagrélor est inférieure à celle des autres inhibiteurs du récepteur P2Y12. L’objectif de ce projet était d’élaborer un modèle décisionnel permettant d’évaluer le rapport coût-utilité du ticagrélor-DAPT dans des conditions de persistance imparfaite chez les patients québécois souffrant d’IM et ainsi, déterminer si une intervention à l’échelle de la province visant à accroître la persistance serait justifiable. Un arbre de décision, modélisant l’évolution des patients atteints d’un IM sur une période d’un an, a été développé pour comparer quatre durées de persistance avec une observance parfaite avec le ticagrélor-DAPT (3, 6, 9 et 12 mois) à une stratégie d’observance parfaite avec 12 mois de clopidogrel-DAPT (traitement de référence). Trois événements cliniques ont été modélisés : l’IM récurent, le décès cardiovasculaire et le saignement majeur. Les probabilités de ces événements ont été extraites d’essais cliniques randomisés pertinents en utilisant les courbes de survie de Kaplan-Meier publiées. Les utilités nécessaires pour calculer les QALYs ont été dérivées de la littérature. Les coûts ont été estimés à partir de la littérature canadienne et de la liste des médicaments de la Régie de l'assurance maladie du Québec et ont été exprimés en $ CA de 2018. L’analyse principale consistait en une simulation probabiliste de Monte-Carlo. À un coût moyen par année de vie gagnée ajustée pour la qualité de vie (QALY) de 43 398 $ CA, les résultats de l’analyse principale ont démontré que 3 mois de ticagrélor-DAPT avait 59,31 % des chances d’être rentable à un seuil décisionnel (« willingness-to-pay ») de 50 000 $ CA par QALY. De plus, les analyses de sensibilité démontrent que le rapport coût-efficacité du ticagrélor-DAPT était sensible au coût du décès cardiovasculaire et au coût du ticagrélor. En présumant un coût de ticagrélor compatible avec un médicament générique, 3 mois, 6 mois et 9 mois de ticagrélor-DAPT étaient dominants et 12 mois de ticagrélor-DAPT avaient une forte probabilité d'être rentable (98,8 %). Cette analyse en arrive aussi à la conclusion que 3 mois de ticagrélor-DAPT sont probablement rentables par rapport à 12 mois de clopidogrel-DAPT. Avec un niveau de preuve de modéré à fort, nous concluons donc qu'aucune intervention particulière n'est justifiée en ce qui concerne la politique provinciale pour améliorer le taux de persistance au ticagrélor après un IM. / In Canada, there are approximately 21,000 deaths and 84,069 hospitalizations related to myocardial infarction (MI) per year, representing approximately Can$1.27 billion in direct costs related to acute and chronic care. Despite the demonstrated health benefits of dual antiplatelet therapy (DAPT) after an MI, observed real-world persistence to treatment with ticagrelor-based DAPT in Québec is lower than that observed with other P2Y12 receptor inhibitors. The objective of this project was to develop a decision-making model to evaluate the cost-utility ratio of ticagrelor-DAPT under conditions of imperfect persistence in Quebec patients suffering from MI, and thus to determine whether a province-wide intervention to increase persistence would be justifiable. A decision tree describing the patient course in the first year following an MI was developed in order to compare four different durations of persistence with perfect adherence with ticagrelor-DAPT (3, 6, 9 and 12 months) to perfect adherence with a 12-month regimen clopidogrel-DAPT (reference treatment). Three clinical events were modeled: recurrent MI, cardiovascular death and major bleeding. The probabilities of these events were extracted from relevant randomized clinical trials using published Kaplan-Meier survival curves. The utilities needed to calculate the QALYs were derived from the literature. The costs were estimated from the Canadian literature and the list of medications from the Régie de l'assurance maladie du Québec and were expressed in Can$ 2018. The reference case analysis consisted of a probabilistic Monte Carlo simulation. At a mean cost per quality adjusted life year (QALY) gained of Can$43,398, the results of the base case analysis showed that 3 months of ticagrelor-DAPT had a 59.31% likelihood of being considered cost-effective using a willingness-to-pay threshold of Can$50,000/QALY. Moreover, the sensitivity analyses showed that the cost-effectiveness of ticagrelor-DAPT was sensitive to the cost of cardiovascular death and the cost of ticagrelor. Assuming a cost of ticagrelor compatible with a generic drug, the 4 durations of persistence with ticagrelor-DAPT are almost guaranteed to be profitable. When a generic cost of ticagrelor was assumed, 3 months, 6 months and 9 months of ticagrelor-DAPT were dominant and 12 months of ticagrelor-DAPT were highly likely to be cost-effective (98.8%). This analysis also conclude that as little as 3 months of ticagrelor-DAPT is likely to be cost-effective compared to 12 months of clopidogrel-DAPT. With a moderate to strong level of evidence, we therefore conclude that no specific intervention is warranted at the provincial policy level to improve persistence rate with ticagrelor treatment after MI.