Les maladies rares sont celles qui touchent un nombre restreint de personnes. Par conséquent, des problèmes spécifiques sont dus par cette rareté.Pour cette raison nous avons systématiquement recherché dans la littérature les publications concernant les caractéristiques des différentes méthodes mathématiques qui ont été utilisées pour l'étude des maladies rares. L'objectif est d'identifier des approches novatrices pour la recherche qui ont été, ou peuvent être, utilisées afin de surmonter les difficultés méthodologiques inhérentes à l'étude des maladies rares.Les méthodes bayésiennes sont recommandées par plusieurs auteurs et dans le cas de ces méthodes il faut introduire une loi informative a priori sur l'effet inconnu du traitement.La détermination de la loi a priori dans le modèle bayésien est difficile. Nous avons travaillé sur les méthodes qui permettent de déterminer de la loi a priori en incluant la possibilité de considérer des informations provenant des études historiques et/ou des données provenant d'autres études "voisines".D'une part, on décrit un modèle bayésien qui a pour but de vérifier l'hypothèse de non-infériorité de l'essai qui repose sur l'hypothèse que le méthotrexate est plus efficace que le corticostéroïde seul.D'autre part, notre travail de thèse se repose sur la méthode epsilon- contamination, qui se base sur le principe de contaminer une loi a priori pas entièrement satisfaisante par une série de lois provenant des informations d'autres études ayant même pathologie de maladie, même traitement ou même population.Enfin, toutes les informations a priori peuvent être résumées par la distribution a priori déterminer à partir des opinions d'experts, leur avis sont recueillis lors d'une réunion où ils ont répondu à un questionnaire qui montre leurs a priori sur les paramètres du modèle bayésien. / In recent years, scientists have difficulties to study rare diseases by conventional methods, because the sample size needed in such studies to meet a conventional frequentist power is not adapted to the number of available patients. After systemically searching in literature and characterizing different methods used in the contest of rare diseases, we remarked that most of the proposed methods are deterministic and are globally unsatisfactory because it is difficult to correct the insufficient statistical power.More attention has been placed on Bayesian models which through a prior distribution combined with a current study enable to draw decisionsfrom a posterior distribution. Determination of the prior distribution in a Bayesian model is challenging, we will describe the process of determining the prior including the possibility of considering information from some historical controlled trials and/or data coming from other studies sufficiently close to the subject of interest.First, we describe a Bayesian model that aims to test the hypothesis of the non-inferiority trial based on the hypothesis that methotrexate is more effective than corticosteroids alone.On the other hand, our work rests on the use of the epsilon-contamination method, which is based on contaminating an a priori not entirely satisfactory by a series of distributions drawn from information on other studies sharing close conditions,treatments or even populations. Contamination is a way to include the proximity of information provided bythese studies.

Esta dissertação é composta por dois ensaios sobre economia da saúde. O primeiro ensaio tem como objetivo analisar o ambiente regulatório no mercado de medicamentos para doenças raras. Essas doenças são caracterizadas por afetar um pequeno número de indivíduos em uma determinada população e por serem crônicas, progressivas, degenerativas, 80% são de origem genética, 50% afetam as crianças, das quais 30% morrem antes dos 5 anos de idade. Elas representam risco de morte e um custo socioeconômico alto para o paciente e sua família. Devido à raridade, a indústria farmacêutica tem não demonstra interesse em desenvolver novos medicamentos órfãos. Apesar de individualmente raras, estima-se que o número de casos de alcançar 420 a 560 milhões de pessoas. Para a referida análise foi utilizado o modelo econômico desenvolvido por DeBrock (1985), que consiste na determinação simultânea de esforço de inovação e extensão de patentes, estabelecendo a trajetória ótima de proteção como resultado de um jogo não cooperativo entre o regulador e a empresa inovadora. Foram identificados individualmente os principais incentivos e instrumentos de regulação econômica. Eles são compostos por assistência à protocolos, procedimento centralizado de análise, reduções de taxas, o acesso de pesquisa financiado e exclusividade de mercado. Conclui-se que o instrumento regulatório mais importante foi a exclusividade de mercado, pois garante lucros extraordinários para a empresa inovadora, tornando o desenvolvimento de novas drogas tornou-se economicamente viável. No entanto, ressalta-se que todos os mecanismos tem um papel importante no sistema de incentivos e que cada um deles deve ser considerado para o desenvolvimento de políticas públicas para doenças raras. O segundo ensaio tem como objetivo medir o impacto do Diabete Melito nos rendimentos dos trabalhadores brasileiros no ano de 2008. Essa doença é caracterizada pelo elevado nível de glicose no sangue, problema que pode desencadear desencadeia má cicatrização, ataque cardíaco, acidente vascular cerebral, insuficiência renal, problemas de visão e amputação de membros. Dados do Ministério da Saúde indicam que, no Brasil, em 2010, havia cerca de 10 milhões de casos da doença, sendo a quarta principal causa de morte no país. Dados da WHO estimam que a prevalência da doença no Brasil é de 10,2% da população, cerca de 20 milhões de pessoas. A hipótese a ser testada é que o estado de saúde interfere nos rendimentos por meio de três mecanismos distintos: (i) na decisão de participar no mercado de trabalho, mensurado por meio de um Probit binário, (ii) na quantidade de horas trabalhadas e (iii) a produtividade por hora, ambos mensurados por meio do método de dois estágios de Heckman. Cada modelo é estimado separadamente para indivíduos com e sem doenças, sendo tomada a diferença do valor esperado de ambos para capturar o efeito contrafactual. Os resultados obtidos indicaram a existência de perdas progressivas, que incidem com maior intensidade entre a população feminina e que, no agregado, podem chegar ao valor de R$ 8.064.408.441.99 (USD 3.450.709.518,02 e EUR 2.490.436.905,56), correspondendo a cerca de 0,54% dos rendimentos totais e 0,20% do PIB do referido ano. Concluiu-se que o Diabete Melito gera perdas significativas na renda dos trabalhadores brasileiros, especialmente em relação à sua participação no mercado de trabalho. Os resultados indicam que as políticas públicas devem ser direcionadas para a prevenção da doença, uma vez que o desenvolvimento de comorbidades amplifica o efeito de perdas. Por fim, visando a manter a inter-relação entre os temas e a estabelecer a unidade do trabalho, foram abordadas na última seção as conclusões a respeito da dissertação. / This dissertation consists of two essays on health economics. The aim of the first essay is to analyze the regulatory environment for medicinal products for rare diseases. These diseases are characterized by to affect a small number of individuals in a given population and to be chronic, progressive, degenerative, 80% are genetic in origin, 50% affect children, of which 30% die before the age of 5. They represent death risk and a high socioeconomic cost to the patient and his family. Due to the rarity, pharmaceutical industry has not shown interest in developing new orphan drugs. Although individually rare, estimatives show that the number of cases to reach 420 million to 560 million people. For this analysis the economic model developed by DeBrock (1985), which consists of the simultaneous determination of innovation effort and extension of patents, establishing the optimal path protection as a result of a non-cooperative game between the regulator and the innovator was used. The main incentives and instruments of economic regulation were individually identified. They are protocols assistance, centralized analysis procedure, fee reductions, access to funded research and market exclusivity. We conclude that the most important regulatory tool was market exclusivity, because it ensures extraordinary profits for the innovator, making the development of new drugs become economically viable. However, it is noteworthy that all the mechanisms have an important role in the incentive system and that each of them should be considered for the development of public policies for rare diseases. The second essay aims to measure the impact of diabetes mellitus on the income of Brazilian workers in 2008. The main disease characteristic is high blood glucose, a problem that can trigger scarring troubles, heart attack, stroke, failure kidney, vision problems and limbs amputation. Ministry of Health data indicate that, in Brazil, in 2010, there were about 10 million cases of the disease, making it the fourth leading cause of death in the country. WHO data estimate that the disease prevalence is 10.2% of the Brazilian population, about 20 million people. The hypothesis to be tested is that the health status interfere in worker income through three distinct mechanisms: (i) in the decision to participate in the labor market, measured by means of a binary Probit, (ii) in the amount of hours worked and (iii) in the productivity per hour, both measured by the Heckman two-stage method. Each model is estimated separately for individuals with and without disease, and taking the difference of the expected value of both to capture the counterfactual effect. The results indicated the existence of progressive losses, which focus more strongly among women and that, in the aggregate, may reach R$ 8.064.408.441.99 (3,450,709,518.02 USD and EUR 2,490,436,905, 56), corresponding to about 0.54% of the total income and 0.20% of GDP in that year. It was concluded that diabetes mellitus causes significant losses in Brazilian workers income, especially in relation to their participation in the labor market. The results indicate that public policies should be directed to the prevention of disease, since the development of comorbidities amplifies the losses effect. Finally, to keep the inter-relationship between the issues and to establish the unity of the work, have been addressed in the last section the conclusions regarding the dissertation.

Esta dissertação é composta por dois ensaios sobre economia da saúde. O primeiro ensaio tem como objetivo analisar o ambiente regulatório no mercado de medicamentos para doenças raras. Essas doenças são caracterizadas por afetar um pequeno número de indivíduos em uma determinada população e por serem crônicas, progressivas, degenerativas, 80% são de origem genética, 50% afetam as crianças, das quais 30% morrem antes dos 5 anos de idade. Elas representam risco de morte e um custo socioeconômico alto para o paciente e sua família. Devido à raridade, a indústria farmacêutica tem não demonstra interesse em desenvolver novos medicamentos órfãos. Apesar de individualmente raras, estima-se que o número de casos de alcançar 420 a 560 milhões de pessoas. Para a referida análise foi utilizado o modelo econômico desenvolvido por DeBrock (1985), que consiste na determinação simultânea de esforço de inovação e extensão de patentes, estabelecendo a trajetória ótima de proteção como resultado de um jogo não cooperativo entre o regulador e a empresa inovadora. Foram identificados individualmente os principais incentivos e instrumentos de regulação econômica. Eles são compostos por assistência à protocolos, procedimento centralizado de análise, reduções de taxas, o acesso de pesquisa financiado e exclusividade de mercado. Conclui-se que o instrumento regulatório mais importante foi a exclusividade de mercado, pois garante lucros extraordinários para a empresa inovadora, tornando o desenvolvimento de novas drogas tornou-se economicamente viável. No entanto, ressalta-se que todos os mecanismos tem um papel importante no sistema de incentivos e que cada um deles deve ser considerado para o desenvolvimento de políticas públicas para doenças raras. O segundo ensaio tem como objetivo medir o impacto do Diabete Melito nos rendimentos dos trabalhadores brasileiros no ano de 2008. Essa doença é caracterizada pelo elevado nível de glicose no sangue, problema que pode desencadear desencadeia má cicatrização, ataque cardíaco, acidente vascular cerebral, insuficiência renal, problemas de visão e amputação de membros. Dados do Ministério da Saúde indicam que, no Brasil, em 2010, havia cerca de 10 milhões de casos da doença, sendo a quarta principal causa de morte no país. Dados da WHO estimam que a prevalência da doença no Brasil é de 10,2% da população, cerca de 20 milhões de pessoas. A hipótese a ser testada é que o estado de saúde interfere nos rendimentos por meio de três mecanismos distintos: (i) na decisão de participar no mercado de trabalho, mensurado por meio de um Probit binário, (ii) na quantidade de horas trabalhadas e (iii) a produtividade por hora, ambos mensurados por meio do método de dois estágios de Heckman. Cada modelo é estimado separadamente para indivíduos com e sem doenças, sendo tomada a diferença do valor esperado de ambos para capturar o efeito contrafactual. Os resultados obtidos indicaram a existência de perdas progressivas, que incidem com maior intensidade entre a população feminina e que, no agregado, podem chegar ao valor de R$ 8.064.408.441.99 (USD 3.450.709.518,02 e EUR 2.490.436.905,56), correspondendo a cerca de 0,54% dos rendimentos totais e 0,20% do PIB do referido ano. Concluiu-se que o Diabete Melito gera perdas significativas na renda dos trabalhadores brasileiros, especialmente em relação à sua participação no mercado de trabalho. Os resultados indicam que as políticas públicas devem ser direcionadas para a prevenção da doença, uma vez que o desenvolvimento de comorbidades amplifica o efeito de perdas. Por fim, visando a manter a inter-relação entre os temas e a estabelecer a unidade do trabalho, foram abordadas na última seção as conclusões a respeito da dissertação. / This dissertation consists of two essays on health economics. The aim of the first essay is to analyze the regulatory environment for medicinal products for rare diseases. These diseases are characterized by to affect a small number of individuals in a given population and to be chronic, progressive, degenerative, 80% are genetic in origin, 50% affect children, of which 30% die before the age of 5. They represent death risk and a high socioeconomic cost to the patient and his family. Due to the rarity, pharmaceutical industry has not shown interest in developing new orphan drugs. Although individually rare, estimatives show that the number of cases to reach 420 million to 560 million people. For this analysis the economic model developed by DeBrock (1985), which consists of the simultaneous determination of innovation effort and extension of patents, establishing the optimal path protection as a result of a non-cooperative game between the regulator and the innovator was used. The main incentives and instruments of economic regulation were individually identified. They are protocols assistance, centralized analysis procedure, fee reductions, access to funded research and market exclusivity. We conclude that the most important regulatory tool was market exclusivity, because it ensures extraordinary profits for the innovator, making the development of new drugs become economically viable. However, it is noteworthy that all the mechanisms have an important role in the incentive system and that each of them should be considered for the development of public policies for rare diseases. The second essay aims to measure the impact of diabetes mellitus on the income of Brazilian workers in 2008. The main disease characteristic is high blood glucose, a problem that can trigger scarring troubles, heart attack, stroke, failure kidney, vision problems and limbs amputation. Ministry of Health data indicate that, in Brazil, in 2010, there were about 10 million cases of the disease, making it the fourth leading cause of death in the country. WHO data estimate that the disease prevalence is 10.2% of the Brazilian population, about 20 million people. The hypothesis to be tested is that the health status interfere in worker income through three distinct mechanisms: (i) in the decision to participate in the labor market, measured by means of a binary Probit, (ii) in the amount of hours worked and (iii) in the productivity per hour, both measured by the Heckman two-stage method. Each model is estimated separately for individuals with and without disease, and taking the difference of the expected value of both to capture the counterfactual effect. The results indicated the existence of progressive losses, which focus more strongly among women and that, in the aggregate, may reach R$ 8.064.408.441.99 (3,450,709,518.02 USD and EUR 2,490,436,905, 56), corresponding to about 0.54% of the total income and 0.20% of GDP in that year. It was concluded that diabetes mellitus causes significant losses in Brazilian workers income, especially in relation to their participation in the labor market. The results indicate that public policies should be directed to the prevention of disease, since the development of comorbidities amplifies the losses effect. Finally, to keep the inter-relationship between the issues and to establish the unity of the work, have been addressed in the last section the conclusions regarding the dissertation.

Au cours de la dernière décennie, la recherche biomédicale et la pratique médicale ont été révolutionné par l'ère post-génomique et l'émergence des « Big Data » en biologie. Il existe toutefois, le cas particulier des maladies rares caractérisées par la rareté, allant de l’effectif des patients jusqu'aux connaissances sur le domaine. Néanmoins, les maladies rares représentent un réel intérêt, car les connaissances fondamentales accumulées en temps que modèle d'études et les solutions thérapeutique qui en découlent peuvent également bénéficier à des maladies plus communes. Cette thèse porte sur le développement de nouvelles solutions bioinformatiques, intégrant des données Big Data et des approches guidées par la connaissance pour améliorer l'étude des maladies rares. En particulier, mon travail a permis (i) la création de PubAthena, un outil de criblage de la littérature pour la recommandation de nouvelles publications pertinentes, (ii) le développement d'un outil pour l'analyse de données exomique, VarScrut, qui combine des connaissance multiniveaux pour améliorer le taux de résolution. / Over the last decade, biomedical research and medical practice have been revolutionized by the post-genomic era and the emergence of Big Data in biology. The field of rare diseases, are characterized by scarcity from the patient to the domain knowledge. Nevertheless, rare diseases represent a real interest as the fundamental knowledge accumulated as well as the developed therapeutic solutions can also benefit to common underlying disorders. This thesis focuses on the development of new bioinformatics solutions, integrating Big Data and Big Data associated approaches to improve the study of rare diseases. In particular, my work resulted in (i) the creation of PubAthena, a tool for the recommendation of relevant literature updates, (ii) the development of a tool for the analysis of exome datasets, VarScrut, which combines multi-level knowledge to improve the resolution rate.

La santé se digitalise et de multiples projets d’e-santé se développent. Dans le contexte des maladies rares (MR), un champ qui est devenu parmi les priorités de la stratégie de santé publique en France, l’e-santé pourrait constituer une solution pour améliorer les connaissances sur l’épidémiologie des MR. La Banque Nationale de Données Maladies Rares (BNDMR) propose de centraliser la conduite de ces études épidémiologiques pour toutes les MR et tous les patients, atteints de ces maladies, suivis dans le système de soin français. La BNDMR doit se développer au sein d’un paysage numérique dense et hétérogène. Développer l’interopérabilité de la BNDMR constitue l’objectif des travaux de cette thèse. Comment identifier les patients, incluant les fœtus ? Comment fédérer les identités des patients? Comment chainer des données pour permettre la conduite des études ? En réponse à ces questions, nous proposons une méthode universelle d’identification des patients qui respecte les contraintes de protection des données de santé. Quelles données recueillir dans la BNDMR ? Comment améliorer l’interopérabilité entre ces données et celles issues du large éventail des systèmes existants ? En réponse à ces questions, nous proposons de standardiser le recueil d’un set minimal de données pour toutes les MR. L’implémentation de standards internationaux assure un premier pas vers l’interopérabilité. Nous proposons aussi d’aller à la découverte de correspondances. Minimiser l’intervention humaine en adoptant des techniques d’alignement automatisé et rendre fiables et exploitables les résultats de ces alignements ont constitué les principales motivations de notre proposition. / The digitalization of healthcare is on and multiple e-health projects are unceasingly coming up. In the rare diseases context, a field that has become a public health policy priority in France, e-health could be a solution to improve rare diseases epidemiology and to propose a better care for patients. The national data bank for rare diseases (BNDMR) offers the centralization of these epidemiological studies conduction for all rare diseases and all affected patients followed in the French healthcare system. The BNDMR must grow in a dense and heterogeneous digital landscape. Developing the BNDMR interoperability is the objective of this thesis’ work. How to identify patients, including fetuses? How to federate patients’ identities to avoid duplicates creation? How to link patients’ data to allow studies’ conduction? In response to these questions, we propose a universal method for patients’ identification that meets the requirements of health data protection. Which data should be collected in the national data bank? How to improve and facilitate the development of interoperability between these data and those from the wide range of the existing systems? In response to these questions, we first propose the collection of a standardized minimum data set for all rare diseases. The implementation of international standards provides a first step toward interoperability. We then propose to move towards the discovery of mappings between heterogeneous data sources. Minimizing human intervention by adopting automated alignment techniques and making these alignments’ results reliable and exploitable were the main motivations of our proposal.

La réutilisation des données de soins pour la recherche s’est largement répandue avec le développement d’entrepôts de données cliniques. Ces entrepôts de données sont modélisés pour intégrer et explorer des données structurées liées à des thesaurus. Ces données proviennent principalement d’automates (biologie, génétique, cardiologie, etc) mais aussi de formulaires de données structurées saisies manuellement. La production de soins est aussi largement pourvoyeuse de données textuelles provenant des comptes rendus hospitaliers (hospitalisation, opératoire, imagerie, anatomopathologie etc.), des zones de texte libre dans les formulaires électroniques. Cette masse de données, peu ou pas utilisée par les entrepôts classiques, est une source d’information indispensable dans le contexte des maladies rares. En effet, le texte libre permet de décrire le tableau clinique d’un patient avec davantage de précisions et en exprimant l’absence de signes et l’incertitude. Particulièrement pour les patients encore non diagnostiqués, le médecin décrit l’histoire médicale du patient en dehors de tout cadre nosologique. Cette richesse d’information fait du texte clinique une source précieuse pour la recherche translationnelle. Cela nécessite toutefois des algorithmes et des outils adaptés pour en permettre une réutilisation optimisée par les médecins et les chercheurs. Nous présentons dans cette thèse l'entrepôt de données centré sur le document clinique, que nous avons modélisé, implémenté et évalué. À travers trois cas d’usage pour la recherche translationnelle dans le contexte des maladies rares, nous avons tenté d’adresser les problématiques inhérentes aux données textuelles: (i) le recrutement de patients à travers un moteur de recherche adapté aux données textuelles (traitement de la négation et des antécédents familiaux), (ii) le phénotypage automatisé à partir des données textuelles et (iii) l’aide au diagnostic par similarité entre patients basés sur le phénotypage. Nous avons pu évaluer ces méthodes sur l’entrepôt de données de Necker-Enfants Malades créé et alimenté pendant cette thèse, intégrant environ 490 000 patients et 4 millions de comptes rendus. Ces méthodes et algorithmes ont été intégrés dans le logiciel Dr Warehouse développé pendant la thèse et diffusé en Open source depuis septembre 2017. / The repurposing of clinical data for research has become widespread with the development of clinical data warehouses. These data warehouses are modeled to integrate and explore structured data related to thesauri. These data come mainly from machine (biology, genetics, cardiology, etc.) but also from manual data input forms. The production of care is also largely providing textual data from hospital reports (hospitalization, surgery, imaging, anatomopathologic etc.), free text areas in electronic forms. This mass of data, little used by conventional warehouses, is an indispensable source of information in the context of rare diseases. Indeed, the free text makes it possible to describe the clinical picture of a patient with more precision and expressing the absence of signs and uncertainty. Particularly for patients still undiagnosed, the doctor describes the patient's medical history outside any nosological framework. This wealth of information makes clinical text a valuable source for translational research. However, this requires appropriate algorithms and tools to enable optimized re-use by doctors and researchers. We present in this thesis the data warehouse centered on the clinical document, which we have modeled, implemented and evaluated. In three cases of use for translational research in the context of rare diseases, we attempted to address the problems inherent in textual data: (i) recruitment of patients through a search engine adapted to textual (data negation and family history detection), (ii) automated phenotyping from textual data, and (iii) diagnosis by similarity between patients based on phenotyping. We were able to evaluate these methods on the data warehouse of Necker-Enfants Malades created and fed during this thesis, integrating about 490,000 patients and 4 million reports. These methods and algorithms were integrated into the software Dr Warehouse developed during the thesis and distributed in Open source since September 2017.

No description available.

Acute Myeloid Leukemia (AML) is a potentially fatal disease, more common in an elderly population. The American Cancer Society estimates 21,450 new cases of AML and 10,920 deaths from AML in the United States in 2019. This malignancy originating in the Bone Marrow (BM), usually presents with peripheral blood (PB) abnormalities. Rarely, AML, particularly monoblastic variants can present with extramedullary disease. Here we describe a case of AML presenting with diffuse lymphadenopathy and a biopsy revealing myeloid sarcoma. A 53 years old male developed diffuse lymphadenopathy. Failure of outpatient empiric antibiotic treatment prompted right cervical lymph node biopsy. Lymph node architecture was distorted by the presence of malignant monocytic myeloid cells. Both the peripheral blood and bone marrow were involved by AML with monocytic features. The monoblasts count was 14% in PB and 24% in BM and the promonocyte count was 12% in PB and 26% in BM. Complete Blood Count showed total white blood cell count of 31,700, hemoglobin 11.8, monocytes 22.5% and platelets 122,000. Flow cytometry of the bone marrow demonstrated a blast population with positive expression of cMPO, CD33, CD13, CD11b, HLA-DR, CD64, CD14 and CD4; and negative for CD34, CD117, nTdT, cCD3, cCD79a. Fluorescence in situ hybridization study was positive for MLL gene rearrangement. Molecular study was positive for IDH1 mutation, and negative for IDH2, RUNX1, FLT3 mutations. Further laboratory analysis was significant for lactate dehydrogenase 346, uric acid 8.6, prothrombin time 13.6, INR 1.2, partial thromboplastin time 33.5 and fibrinogen 293. Computed tomography of chest, abdomen, pelvis with contrast revealed extensive adenopathy with enlarged bilateral supraclavicular, bilateral axillary, mediastinal, bilateral hilar, upper abdominal, periaortic retroperitoneal, pelvic and inguinal lymph nodes. Hepatosplenomegaly was also reported. The term Myeloid Sarcoma (MS) is used when leukemic cells are present outside the bone marrow and peripheral blood. MS tends to oocur more commonly in middle aged males (male-to-female ratio, 2:1, median age, 56 years). The Mayo Clinic Experience of 96 cases demonstrated 27% of patients had no bone marrow involvement, and 69% of patients had primary bone marrow disease. Extramedullary involvement can occur prior to, simultaneously, or after bone marrow involvement. Just as in our case this is an important feature for clinicians to remember so that they may recognize this rare entity early.

L'approche Bayésienne permet d’enrichir l'information apportée par l'essai clinique, en intégrant des informations externes à l'essai. De plus, elle permet d’exprimer les résultats directement en termes de probabilité d’un certain effet du traitement, plus informative et interprétable qu’une p-valeur et un intervalle de confiance. Par ailleurs, la réduction fréquente d’une analyse à une interprétation binaire des résultats (significatif ou non) est particulièrement dommageable dans les maladies rares. L’objectif de mon travail était d'explorer la faisabilité, les contraintes et l'apport de l'approche Bayésienne dans les essais cliniques portant sur des cancers rares lorsque le critère principal est censuré. Tout d’abord, une revue de la littérature a confirmé la faible implémentation actuelle des méthodes Bayésiennes dans l'analyse des essais cliniques avec critère de survie.Le second axe de ce travail a porté sur le développement d’un essai Bayésien avec critère de survie, intégrant des données historiques, dans le cadre d’un essai réel portant sur une pathologie rare (ostéosarcome). Le prior intégrait des données historiques individuelles sur le bras contrôle et des données agrégées sur l’effet relatif du traitement. Une large étude de simulations a permis d’évaluer les caractéristiques opératoires du design proposé, de calibrer le modèle, tout en explorant la problématique de la commensurabilité entre les données historiques et actuelles. Enfin, la ré-analyse de trois essais cliniques publiés a permis d’illustrer l'apport de l'approche Bayésienne dans l'expression des résultats et la manière dont cette approche permet d’enrichir l’analyse fréquentiste d’un essai. / Bayesian approach augments the information provided by the trial itself by incorporating external information into the trial analysis. In addition, this approach allows the results to be expressed in terms of probability of some treatment effect, which is more informative and interpretable than a p-value and a confidence interval. In addition, the frequent reduction of an analysis to a binary interpretation of the results (significant versus non-significant) is particularly harmful in rare diseases.In this context, the objective of my work was to explore the feasibility, constraints and contribution of the Bayesian approach in clinical trials in rare cancers with a primary censored endpoint. A review of the literature confirmed that the implementation of Bayesian methods is still limited in the analysis of clinical trials with a censored endpoint.In the second part of our work, we developed a Bayesian design, integrating historical data in the setting of a real clinical trial with a survival endpoint in a rare disease (osteosarcoma). The prior incorporated individual historical data on the control arm and aggregate historical data on the relative treatment effect. Through a large simulation study, we evaluated the operating characteristics of the proposed design and calibrated the model while exploring the issue of commensurability between historical and current data. Finally, the re-analysis of three clinical trials allowed us to illustrate the contribution of Bayesian approach to the expression of the results, and how this approach enriches the frequentist analysis of a trial.

Submitted by Ana Lúcia Torres (bfmhuap@gmail.com) on 2018-01-18T12:47:36Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) IACINETE CRUZ.pdf: 1225738 bytes, checksum: a273218629d7c4fe0b7b4833801d177a (MD5) / Approved for entry into archive by Ana Lúcia Torres (bfmhuap@gmail.com) on 2018-01-18T12:47:46Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) IACINETE CRUZ.pdf: 1225738 bytes, checksum: a273218629d7c4fe0b7b4833801d177a (MD5) / Made available in DSpace on 2018-01-18T12:47:46Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) IACINETE CRUZ.pdf: 1225738 bytes, checksum: a273218629d7c4fe0b7b4833801d177a (MD5) Previous issue date: 2016 / Distrito Sanitário Especial Indígena do Alto Rio Negro / O modo como uma informação sobre medicamentos é comunicada produz efeitos de configuração que podem impactar na saúde tanto no âmbito do indivíduo como no coletivo. Pacientes com doenças raras são mais vulneráveis uma vez que as informações sobre a doença e o tratamento são mais limitadas. Portanto, efeitos de configuração podem ser ainda mais relevante na percepção de risco de pacientes com doenças raras em razão da escassez de informações. Esta pesquisa analisa a presença de efeitos de configuração na comunicação de risco sobre medicamentos em websites de associações de pacientes com doenças raras no Brasil. Os resultados obtidos foram posteriormente discutidos a partir da perspectiva da bioética principialista. Foram observados websites de associações brasileiras de pacientes para 44 doenças raras selecionadas, em fevereiro e março de 2016. Os conteúdos sobre tratamento medicamentoso foram selecionados como corpus desta pesquisa. Foram definidos os marcadores linguísticos e as unidades de contexto para pautar a análise da configuração de risco. Foram identificadas 76 associações brasileiras de pacientes com doenças raras diretamente relacionadas a 33 diferentes doenças. Foi identificado efeito de configuração da informação sobre tratamento medicamentoso em 16 destas, na seguinte dimensão: 12,5% do tipo risco relativo, 6,2% do tipo de ganho, 12,5% do tipo de perda, 18,8% do tipo positivo, 25,0% do tipo representação numérica e 56,3% do tipo representação verbal. Esta distribuição indica ser mais comum o uso de efeitos de configuração persuasivos do que informativos. Posterior análise bioética sugere que os princípios prima facie de respeito à autonomia, beneficência, não-maleficência e justiça são desafiados. Conclui-se haver a necessidade, tanto técnica quanto ética, de melhorar a comunicação de risco atrelado ao uso de medicamentos em websites de associações brasileiras de pacientes com doenças raras / The way information about medicines is communicated produces framings effects that may impact the health of individuals as well as public health. Patients with rare diseases are increasingly more vulnerable given that information about disease and pharmacological treatment is more limited. Therefore, framing effects may be even more important in risk perception of patients with rare diseases due to the scarcity of information. This study analyzes the presence of framing effects in drug risk communication on websites of associations of patients with rare diseases in Brazil. Those results are further discussed through a principlist lens. We evaluated websites of Brazilian associations of patients with 44 rare diseases, between February and March 2016. Contents about pharmacological treatment were selected as the research corpus. Linguistic markers and content units were defined to guide framing effect analysis. We identified 76 Brazilian associations of patients with rare diseases directly related to thirty-three different diseases. Framing effects were observed in websites relative to sixteen of these rare diseases, in the following types: 12.5% relative risk, 6.2% gain framing, 12.5% loss framing, 18.8% positive framing, 25.0% numerical presentation, and 56.3% verbal presentation. This distribution indicates that persuasive framing effects are more common than informative framing effects. Further bioethical analysis suggests that the prima facie principles of respect for autonomy, beneficence, non-maleficence, and justice are challenged. We conclude that there is both a technical and an ethical need to improve drug risk communication in websites of Brazilian associations of patients with rare diseases