Estudo comparativo entre os custos dos tratamentos clínico, cirúrgico ou percutâneo em portadores de doença multiarterial coronária estável - 5 anos de seguimento [tese]. São Paulo: Faculdade de Medicina, Universidade de São Paulo, 2013. INTRODUÇÃO: As principais opções terapêuticas para a doença multiarterial coronária incluem cirurgia de revascularização miocárdica (CRM), intervenção coronária percutânea (ICP) e tratamento clínico (TC). Essas três estratégias terapêuticas apresentam eficácia similar em determinados subgrupos de pacientes. No presente momento, estudos direcionados à análise econômica são escassos, e contemplam, principalmente, os custos comparativos entre as intervenções cirúrgica e percutânea. OBJETIVOS: Analisar, prospectivamente, o custo comparativo das três formas terapêuticas da doença multiarterial coronária estável, durante cinco anos de seguimento. MÉTODOS: Foi computado o custo terapêutico global de 611 pacientes do ensaio clínico The Second Medicine, Angioplasty, or Surgery Study (MASS II), baseado na remuneração provida pelo sistema de saúde suplementar do Instituto do Coração do HC/FMUSP, tomando-se os valores em moeda nacional corrente. Realizou-se, posteriormente, análise de custo-efetividade para o tempo livre de eventos clínicos e o tempo livre de eventos acrescido de tempo livre de angina. RESULTADOS: O TC apresentou 3.79 e 2.07 QALY (quality-adjusted lifeyears); o ICP apresentou 3.59 e 2.77 QALY; e o CRM apresentou 4.4 e 2.81 QALY, respectivamente, para sobrevida livre de eventos e sobrevida livre de eventos e angina. Os custos para sobrevida livre de eventos foram R$ 16.327,80 para TC, R$ 35.940,60 para ICP e R$ 32.873,40 para CRM. A análise pareada dos custos para sobrevida livre de eventos mostrou que houve diferença significante favorecendo TC contra ICP (P < 0,01), e em comparação com CRM (P < 0,01); e CRM versus ICP (P = 0,01). Os custos para sobrevida livre de eventos e angina foram R$ 29.795,40, R$ 46.495,80 e R$ 44.305,20, respectivamente. A comparação pareada dos custos livres de eventos mais livres de angina demonstrou que houve diferença significante favorecendo TC contra ICP (P = 0,04), e em comparação com CRM (P < 0,001). Não houve diferença entre CRM e ICP (P > 0,05). CONCLUSÃO: A análise comparativa entre as diferentes opções terapêuticas desta amostra revelou que TC foi mais custo-efetivo que CRM, e esta, por sua vez, mais custo-efetivo que ICP / BACKGROUND: The therapeutic options for multivessel coronary artery disease are coronary artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI), or medical treatment alone (MT). These three therapeutic strategies present similar efficacy for specific subgroups. At the present moment, economic outcome trials are scant, and contemplate comparative cost between surgical or percutaneous intervention. OBJECTIVE: To analyze, prospectively, the comparative cost from three therapeutic strategies in multivessel coronary artery disease, at 5-year of follow-up. METHODS: We analyzed cumulative costs of 611 patients from clinical trial The Second Medicine, Angioplasty, or Surgery Study (MASS II). The economic analysis is based on remuneration provided by the supplementary health system of the Heart Institute of the Clinical Hospital of FMUSP, expressing these values in Brazilian currency. It was compared to the cumulative costs of each therapeutic strategy in the 5-year follow-up period. A cost-effectiveness analysis was then conducted for event-free survival and event plus angina-free survival. Cost-effectiveness analysis was performed by quality-adjusted life- year (QALY) analysis. RESULTS: Respectively, for event-free survival and event plus angina-free survival, MT presented 3.79 quality-adjusted life-years (QALY) and 2.07 QALY; PCI presented 3.59 and 2.77 QALY; and CABG demonstrated 4.4 and 2.81 QALY. The event-free costs were R$ 16327.80 for MT; R$ 35940.60 for PCI; and R$ 32873.40 for CABG. The paired comparison of the event-free costs showed that there was a significant difference favoring MT versus PCI (P < 0.01) and versus CABG (P < 0.01) and CABG versus PCI (P =0.01). The event-free plus angina-free costs were R$ 29795.40, R$ 46495.80 e R$ 44305.20, respectively. The paired comparison of the event-free plus angina-free costs showed that there was a significant difference favoring MT versus PCI (P =0.04), and versus CABG (P < 0.001); there was no difference between CABG and PCI (P > 0.05). CONCLUSION: The comparative analysis among the different therapeutic strategies demonstrated that MT was more cost-effective than CABG, and this than PCI

Le bénéfice de survie restreint à un horizon temporel donné a été proposé comme mesure alternative aux mesures relatives de l’effet d’un traitement notamment dans le cas de non proportionnalité des risques de décès. Le bénéfice de survie restreint correspond à la différence des survies moyennes entre deux bras de traitement et s’exprime en nombre d’années de vie gagnées. Dans la littérature, cette mesure est présentée comme plus intuitive que le hazard ratio et plusieurs auteurs ont proposé son utilisation pour le design et l’analyse d’un essai clinique. Toutefois, ce n’est pas actuellement la mesure qui est utilisée de manière courante dans les essais randomisés. Cette mesure s’applique quelle que soit la distribution des temps de survie et est adaptée si l’hypothèse des risques proportionnels n’est pas respectée. De plus, le bénéfice de survie restreint peut être utilisé en évaluation médico-économique où la mesure d’un effet absolu est nécessaire (nombre d’années de vie gagnées pondérées ou non par la qualité de vie). Si l’on souhaite estimer le bénéfice de survie restreint à partir d’une méta-analyse sur données individuelles, se pose alors la question de prendre en compte l’effet essai dû à la structure hiérarchique des données. L’objectif de cette thèse était de comparer des méthodes statistiques d’estimation du bénéfice de survie restreint à partir de données individuelles d’une méta-analyse d’essais cliniques randomisés. Le point de départ a été une étude de cas (étude coût-efficacité) réalisée à partir des données de la Meta-Analysis of Radiotherapy in Lung Cancer. Cette étude a montré que les cinq méthodes d’estimation étudiées conduisaient à des estimations différentes du bénéfice de survie et de son intervalle de confiance. Le choix de la méthode d’estimation avait également un impact sur les résultats de l’analyse coût-efficacité. Un second travail a consisté à mener une étude de simulation pour mieux comprendre les propriétés des méthodes d’estimation considérées en termes de biais moyen et d’erreur-type. Enfin, la dernière partie de la thèse a mis en application les enseignements de cette étude de simulation au travers de trois méta-analyses sur données individuelles dans le cancer du nasopharynx et dans le cancer du poumon à petites cellules. / The survival benefit restricted up to a certain time horizon has been suggested as an alternative measure to the common relative measures used to estimate the treatment effect, especially in case of non-proportional hazards of death. The restricted survival benefit corresponds to the difference of the two restricted mean survival times estimated for each treatment arm, and is expressed in terms of life years gained. In the literature, this measure is considered as more intuitive than the hazard ratio and many authors have suggested its use for the design and the analysis of clinical trials. However, it is not currently the most used measure in randomized trials. This measure is valid under any distribution of the survival times and is adapted if the proportional hazards assumption does not hold. In addition, the restricted survival benefit can be used in medico-economic evaluation where an absolute measure of the treatment effect is needed (number of [quality adjusted] life years gained). If one wants to estimate the restricted survival benefit from an individual participant data meta-analysis, there is a need to take into account the trial effect due to the hierarchical structure of the data. The aim of this thesis was to compare statistical methods to estimate the restricted survival benefit from an individual participant data meta-analysis of randomized trials. The starting point was a case study (cost-effectiveness analysis) using data from the Meta-Analysis of Radiotherapy in Lung Cancer. This study showed that the five investigated methods yielded different estimates for the restricted survival benefit and its confidence interval. The choice of a method to estimate the survival benefit also impacted on cost-effectiveness results. Our second project consisted in a simulation study to have a better understanding of the properties of the investigated methods in terms of bias and standard error. Finally, the last part of the thesis illustrated the lessons learned from the simulation study through three examples of individual participant data meta-analysis in nasopharynx cancer and in small cell lung cancer.

The Master’s Thesis is focused to introduction MES systems and factory information systems. Describes main advantages of applying MES systems and describes concept of Six Big Losses, which characterise main losses in production. For quantification of losses are used indicators like OEE. Next part is simulation data of Filler Machine and producing via OPC Server. Main application made in software SIMATIC IT by Siemens is collecting, processing and archiving data to PPA database due to rules and setups. Presentation of data is powered by Data Report which provides overview of efficiency and main losses in production.

Background: In the ‘Arimidex’, Tamoxifen Alone or in Combination (ATAC) trial, the aromatase inhibitor (AI) anastrozole had a ignificantly better efficacy and safety profile than tamoxifen as initial adjuvant therapy for hormone receptor-positive (HR+) early breast cancer (EBC) in postmenopausal patients. To compare the combined long-term clinical and economic benefits, we carried out a cost-effectiveness analysis (CEA) of anastrozole versus tamoxifen based on the data of the 100- month analysis of the ATAC trial from the perspective of the German public health insurance. Patients and Methods: A Markov model with a 25-year time horizon was developed using the 100-month analysis of the ATAC trial as well as data obtained from published literature and expert opinion. Results: Adjuvant treatment of EBC with anastrozole achieved an additional 0.32 quality-adjusted life-years (QALYs) gained per patient compared with tamoxifen, at an additional cost of D 6819 per patient. Thus, the incremental cost effectiveness of anastrozole versus tamoxifen at 25 years was D 21,069 ($ 30,717) per QALY gained. Conclusions: This is the first CEA of an AI that is based on extended follow-up data, taking into account the carryover effect of anastrozole, which maintains the efficacy benefits beyond therapy completion after 5 years. Adjuvant treatment with anastrozole for postmenopausal women with HR+ EBC is a cost-effective alternative to tamoxifen. / Hintergrund: Bei der adjuvanten Therapie von postmenopausalen Patientinnen mit Hormonrezeptor-positivem (HR+) Mammakarzinom belegen die ATAC-100-Monatsdaten (ATAC-Studie: ‘Arimidex’, Tamoxifen Alone or in Combination) einen signifikanten Vorteil von Anastrozol gegenüber Tamoxifen in Bezug auf Rezidivrisiko und Verträglichkeit. Es wurde eine Kosten-Nutzwert-Analyse von Anastrozol im Vergleich zu Tamoxifen aus der Sicht des deutschen Gesundheitssystems durchgeführt. Material und Methoden: Als Berechnungsbasis wurde ein Markov- Modell zur Abschätzung der Kosteneffektivität entwickelt. Der Modellierungszeitraum umfasste 25 Jahre. Die Daten wurden anhand der ATAC-100-Monatsdaten, vorliegender Literatur und durch ein interdisziplinäres Expertenteam ermittelt. Ergebnisse: Eine adjuvante Therapie mit Anastrozol erzielte 0,32 quality-adjusted life-years (QALYs) pro Patientin mehr, verglichen mit einer adjuvanten Tamoxifentherapie. Die zusätzlichen Kosten der Therapie mit Anastrozol lagen bei 6819 D pro Patientin. Im Vergleich mit Tamoxifen erzielte Anastrozol einen ICER (Incremental Cost-Effectiveness Ratio) von 21 069 D (30 717 $)/QALY über den gesamten Modellierungszeitraum. Schlussfolgerung: Diese Kosten- Nutzwert-Analyse eines Aromatasehemmers basiert erstmals auf einer Datenanalyse, die auch das Follow-Up und den sogenannten Carryover- Effekt nach einer abgeschlossenen 5-Jahres-Therapie beinhaltet. Anastrozol ist auch nach dieser Analyse aus der Sicht des deutschen Gesundheitssystems eine kosteneffektive Therapieoption für postmenopausale Patientinnen mit einem HR+ frühen Mammakarzinom. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Aims: To assess effectiveness and economic benefit of the psychological treatment of anxiety disorders in order to compare them with the consumed resources of the treatment. Methods: Assessment of specific and non-specific symptoms and impairments in N=493 anxiety patients (DSM-IV) receiving cognitive behavior therapy pre, post, and one year after treatment with various measures. Additional analyses of costs of the treatment and the benefits due to reduced work disability and health care utilization after therapy (including a pilot study using a willingness-to-pay approach). The treatment setting can be characterised as clinically typical for everyday practice. Core results: a) effectiveness: Effect sizes ranged from 0.9 to 1.9. All improvements were significant and lasted until 1-year-follow-up. Rates of clinically significant therapy success ranged from 63% to 79% depending on outcome measure and success criteria. b) cost-effectiveness analysis: Cost-effectiveness-indices ranged from DM 8338.- to DM 10456.- for one successful treatment (average costs taking also the costs of unsuccessful treatments into account). c) cost-benefit-analysis: Cost reduction in the year after therapy was remarkable (inpatient costs about 25%, other cost factors 87%-100%), resulting in a benefit of DM 3026.- per patient and a cost-benefit-ratio of 1:0.58 in the first year after treatment. Assuming that the improvements are stable, the cost-benefit-ratio after five years would be estimated as 1:2.63. Discussion: The present study shows exemplarily for CBT of anxiety disorders that modern psychotherapy can produce remarkable results at reasonable costs. Furthermore, clinical-psychological treatment methods show an additional economic benefit. Clinical Psychology can benefit from focusing not only the promising developments in classification, etiology, and treatment but also taking over the cost perspective (which is relatively new in scientific evaluation of psychotherapy). (Appendix: Cost-Benefit-Calculator.htm; 8,97 KB -- Usage: Referat Informationsvermittlung/ SLUB) / Fragestellungen: Ermittlung von Effektivität und monetärem Nutzen psychologischer Behandlung von Angststörungen, die dann den für die Therapie aufgewendeten Ressourcen gegenübergestellt werden. Methoden: N=493 Patienten mit Angststörungen (DSM-IV), die eine ambulante störungsspezifische kognitive Verhaltenstherapie absolviert haben, wurden prä, post und zur 1-Jahres-Katamnese untersucht. Das Spektrum der Erhebungen umfasste störungsspezifische und störungsübergreifende Symptombelastung und Beeinträchtigungen in verschiedenen Lebensbereichen, sowie eine globale Therapieerfolgseinschätzung von Patienten und Therapeuten. In einer zweiten Studie wurden zusätzlich an einer Teilstichprobe Kosten-Nutzen-Aspekte untersucht (Einsparungen durch Reduktion von Gesundheitsleistungen und Arbeitsunfähigkeit; außerdem Pilotstudie zu willingness-to-pay-Ansatz). Das Behandlungssetting der Studie ist charakterisiert durch klinisch relevante Rahmenbedingungen und Praxisnähe. Zentrale Ergebnisse: a) Effektivität: Die Effektstärken reichten in Abhängigkeit von der Meßmethode von 0.9 bis 1.9. Die Verbesserungen waren durchgängig signifikant und blieben bis zur 1-Jahres-Katamnese stabil. Die Raten klinisch bedeutsamer Besserungen betrugen 63% - 79% in Abhängigkeit von Mess- und Auswertungsmethode. b) Kosten-Effektivitäts-Analyse: Die Kosten-Effektivitätivitäts-Indices betrugen DM 8338.- bis DM 10456.- (dieser Index gibt an, was eine erfolgreiche Behandlung durchschnittlich kostet, also unter Einbezug der nicht erfolgreichen Behandlungen in die Gesamtkosten). c) Kosten-Nutzen-Analyse: Im Jahr nach Therapie reduzierten sich die Kostenfaktoren der Störungen vor Therapie beträchtlich (stationäre Kosten um 25%, restliche Kostenfaktoren 87% - 100%). Die dadurch erzielten Einsparungen betrugen durchschnittlich DM 3026.- (Kosten-Nutzen-Verhältnis im ersten Jahr: 1 : 0.58). Unter der Annahme, dass die Auswirkungen der Therapie auch über die 1-Jahres-Katamnese hinaus stabil bleiben, kann man abschätzen, dass sich die Therapie innerhalb des zweiten Jahres amortisiert und das Kosten-Nutzen-Verhältnis nach fünf Jahren (diskontiert) 1 : 2.63 beträgt. Diskussion: Wie in dieser Arbeit anhand der kognitiven Verhaltenstherapie für Angststörungen gezeigt wird, kann moderne Psychotherapie bei vertretbarem Aufwand beachtliche Erfolge verbuchen. Klinisch-psychologische Behandlungsmethoden sind darüber hinaus auch wirtschaftlich, derart, dass sie über den reinen Behandlungserfolg hinaus zu Kosteneinsparungen beitragen könnten. Es ist erstaunlich, dass die Kosten-Perspektive der wissenschaftlichen Bewertung von Psychotherapie noch recht neu ist. Die Klinische Psychologie kann davon profitieren, diese Dimension (neben den beachtlichen Erkenntnisfortschritten in bezug auf Klassifikation, Ätiologie, Verlaufsforschung und Behandlungsverfahren) mehr herauszustellen. (Anlage: Cost-Benefit-Calculator.htm; 8,97 KB -- Nutzung: Referat Informationsvermittlung der SLUB)

Objectives: The Dental and Pharmaceutical Benefits Agency (TLV) is responsible for deciding which prescription pharmaceuticals should be subsidized in Sweden. Cost-effectiveness analyses are fundamental to its decision-making, but future price reductions following patent expiry are excluded from these analyses. The purpose of this study is to investigate and illustrate the economic and strategic aspects of including these future price changes in reimbursement decisions for prescription pharmaceuticals. Methods: We construct a Markov model in R to serve as a laboratory and evaluate the cost-effectiveness of a completely fictional drug, Liunek, under eight sets of assumptions and study differences in incremental cost-effectiveness ratios. Results: Including future price changes in TLV's reimbursement decisions will lead to increased healthcare expenditures if producers respond by raising prices, but may strengthen incentives to develop new pharmaceuticals. Policy implications: Sweden needs to decide whether it is TLV's responsibility to incentivize the development of new pharmaceuticals, and to what extent this should be done.

<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.