Les critères de substitution peuvent être utilisés à la place du critère de jugement le plus pertinent pour évaluer l'efficacité d'un nouveau traitement. Dans un contexte de méta-analyse, l'approche classique pour la validation d'un critère de substitution est basée sur une stratégie d'analyse en deux étapes. Pour des critères de jugement à temps d’évènements, cette approche est souvent sujette à des problèmes d'estimations. Nous proposons une approche de validation en une étape s'appuyant sur des modèles conjoints à fragilités et à copules. Ces modèles incluent à la fois des effets aléatoires au niveau essai et au niveau individuel ou des fonctions de copule. Nous considérons des fonctions de risque de base non paramétriquesà l'aide des splines. Les paramètres des modèles et les fonctions de risque de base ont été estimés par une méthode semi-paramétrique, par maximisation de la vraisemblance marginale pénalisée, considérant différentes méthodes d'intégration numérique. La validation des critères de substitution à la fois au niveau individuel et au niveau essai a été faite à partir du tau de Kendall et du coefficient de détermination. Les études de simulation ont été faites pour évaluer les performances de nos modèles. Les modèles ont été appliqués aux données individuelles issues des méta-analyses sur le cancer afin de rechercher de potentiels critères de substitution à la survie globale. Les modèles étaient assez robustes avec réduction des problèmes de convergence et d'estimation rencontrés dans l'approche en deux étapes. Nous avons développé un package R convivial implémentant les nouveaux modèles. / Surrogate endpoint can be used instead of the most relevant clinical endpointto assess the efficiency of a new treatment. In a meta-analysis framework, the classical approach for the validation of surrogate endpoint is based on a two-step analysis. For failure time endpoints, this approach often raises estimation issues.We propose a one-step validation approach based on a joint frailty and a joint frailty-copula model.The models include both trial-level and individual-level random effects or copula functions. We chose a non-parametric form of the baseline hazard functions using splines. We estimated parameters and hazard functions using a semi-parametric penalized marginal likelihood method, considering various numerical integration methods. Both individual level and trial level surrogacy were evaluated using Kendall's tau and coefficient of determination. The performance of the estimators was evaluated using simulation studies. The models were applied to individual patient data meta-analyses in cancer clinical trials for assesing potentiel surrogate endpoint to overall survival.The models were quite robust with a reduction of convergence and model estimation issues encountered in the two-step approach.We developed a user friendly R package implementing the models.

Background: Early efficacy outcome measures in rectal cancer after total neoadjuvant treatment are increasingly investigated. We examined the prognostic role of pathological complete response (pCR), tumor regression grading (TRG) and neoadjuvant rectal (NAR) score for disease-free survival (DFS) in patients with rectal carcinoma treated within the CAO/ARO/AIO-12 randomized phase 2 trial. Methods: Distribution of pCR, TRG and NAR score was analyzed using the Pearson’s chi-squared test. Univariable analyses were performed using the log-rank test, stratified by treatment arm. Discrimination ability of non-pCR for DFS was assessed by analyzing the ROC curve as a function of time. Results: Of the 311 patients enrolled, 306 patients were evaluable (Arm A:156, ArmB:150). After a median follow-up of 43 months, the 3-year DFS was 73% in both groups (HR, 0.95, 95% CI, 0.63–1.45, p = 0.82). pCR tended to be higher in Arm B (17% vs. 25%, p = 0.086). In both treatment arms, pCR, TRG and NAR were significant prognostic factors for DFS, whereas survival in subgroups defined by pCR, TRG or NAR did not significantly differ between the treatment arms. The discrimination ability of non-pCR for DFS remained constant over time (C-Index 0.58) but was slightly better in Arm B (0.61 vs. 0.56). Conclusion: Although pCR, TRG and NAR were strong prognostic factors for DFS in the CAO/ARO/AIO-12 trial, their value in selecting one TNT approach over another could not be confirmed. Hence, the conclusion of a long-term survival benefit of one treatment arm based on early surrogate endpoints should be stated with caution.

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.

The subject of this thesis is presence of endpoints in child-directed speech of Czech native speakers. It is based on researches, which show that czech language prefers holistic perspective. This occur for exemple in description of the motion event; a speaker tends to include the endpoint. Thanks to its holistic perspective, Czech language is unique among other Slavic languages, which use a phasal perspective. The phasal perspective highlights the motion process instead of the endpoint. There are several reasons, why Czech language uses holistic perspective: the most common is the proximity to German langugae, which also uses holistic perspective, and specific category of aspect. My thesis examines whether children can learn one of the feature of the holistic perspective, often referring to endpoints in the description of motion events. Research data consists in transcribing informal conversations between children and parents over incentives made for this purpose. I examine total amount od endpoints and how they are expressed. The analysis of the data proves high concentration of endpoints and also proves, that parents direct child's attention to them.

La Survie globale (SG) est le critère de jugement de référence dans les essais cliniques en oncologie mais les critères de jugement dit intennédiaires centrés sur la tumeur qui sont évalués plus précocement sont de plus en plus utilisés comme critères substitutifs de la survie globale La qualité de vie (QdV) constitue un critère de jugement pour évaluer un bénéfice clinique direct pour le patient. Nos résultats ont montré que 32% des critères de jugement dans les essais de phase III de CBNPC avancés étaient pas du tout définis et seulement 43% était clairement défini et qu'aucun critère intermédiaire n'a démontré sa substitutivité sur la SG. Nous avons montré que la mesure, l'analyse et le report des données de QdV étaient hétérogènes entre les essais de phase III de CBNPC avancés d'où la nécessité de recommandations. Nous avons comparé longitudinalement la QdV chez 451 patients âgés de 70-89 ans atteints de CBNPC avancés randomisés entre une bichimiothérapie et une monochimiothérapie selon la technique du temps jusqu'à détérioration définitive (TJD) d'un score de QdV. Cette étude a montré : sur le plan clinique, le bénéfice du doublet de chimiothérapie pour les patients est renforcé par les données de QdV; sur le plan méthodologique: le TJD est une technique d'analyse faisable dans les essais de phase III de CBNPC et fournit des résultats faciles d'interprétation. Nous avons proposé l'utilisation de co-critères de jugement principaux associant QdV et critère centré sur la tumeur. Enfin, nous avons démontré la valeur pronostique de la dimension santé globale de QdV à baseline du questionnaire sur la SG chez les patients âgés atteints de CBNPC avancés. / Overall survival (OS) is the gold standard endpoint in oncology clinical trials. Nevertheless, intermediate tumor-centered endpoints which are assessed earlier are more and more used as surrogate of OS. Health-related quality of life is an endpoint which assesses a direct benefit for the patient. We demonstrated that 32% of endpoints in advanced non-small-cell lung phase III clinical trials were not defined at all, 43% were not clearly defined and none ofthem has demonstrated its surrogacy on OS. We demonstrated the weakness and the heterogeneity of the measurement, analysis, and reporting of HRQoL in phase III advanced NSCLC trials. Precise and uniform recommendations are needed. We longitudinally compared HRQoL using tüne until definitive deterioration (TUDD) method in 451 patients aged 70-89 years with advanced NSCLC randomly assigned to receive a doublet of chemotherapy or a monochemotherapy. We demonstrated the benefit of the doublet chemotherapy in terms ofHRQoL. On a methodological point ofview TUDD method is feasible and provide clinically meaningful results. We proposed another approach which would be to combine intermediate endpoint• with HRQoL as co-primary endpoints. Finally, we demonstrated the additional prognostic value of HRQoL data at baseline to identify vulnerable subpopulations in elderly NSCLC patients.

Med dagens snabba utveckling av informationsteknologin och med ökningen av antalet människor som är uppkopplade mot Internet, blir utvecklingen av webbtjänster allt viktigare. Eftersom webbtjänster har en betydande roll för utvecklingen av Internet, uppstår frågan om vilka verktyg som bör användas för att uppnå den prestanda som dagens användare kräver. Ett vanligt tillvägagångssätt för implementering av webbtjänster är med arkitekturen REST. Dock har REST prestandasvagheter som overfetching, underfetching och hantering av slutpunkter som uppstår i fall där flera slutpunkter nås. Ett alternativ till REST är frågespråket GraphQL som utvecklades för att utesluta de svagheter som REST har och således förbättra prestanda vid datahämtning. I detta arbete utfördes prestandamätningar där latens och datavolym mättes vid olika typer av frågor för respektive GraphQL, REST utan cache och REST med cache. Latens är tidsintervallet från att en klient skickar en förfrågan till att klienten mottar svaret, och datavolym avser storleken på data i ett svarspaket som överförs från en server till en klient. REST med cache togs med i prestandamätningarna då det inte har undersökts i tidigare arbeten som jämfört prestanda mellan GraphQL och REST. Resultaten visade att GraphQL presterar bättre med avseende på både latens och datavolym, i jämförelse med de övriga systemen i fall där förfrågningar ställs mot två eller flera slutpunkter i REST. GraphQL presterade sämre än övriga system, med avseende på latens, när endast en slutpunkt i REST kontaktades. Däremot presterade GraphQL bättre än de övriga systemen, med avseende på datavolym, i samtliga fall. Vid jämförelse av REST med och utan cache visade det sig att ju fler slutpunkter som kontaktades, desto bättre presterade REST utan cache med avseende på datavolym medan REST med cache presterade bättre med avseende på latens. / With today’s rapid development of information technology and with the increase in the number of people connected to the Internet, the development of web services is becoming more important. As web services play a significant role in the development of the Internet, the question arises as to which tools should be used to achieve the performance required by today’s users. A common approach for implementing web services is with the architecture REST. However, REST has performance weaknesses such as overfetching, underfetching, and maintenance of endpoints, that arise in cases where multiple endpoints are accessed. An alternative to REST is the GraphQL query language, which was developed to exclude the weaknesses that REST has and thus improve performance in data retrieval. In this work, performance measurements were conducted where latency and data volume were measured for different types of queries for GraphQL, REST without cache and, REST with cache. Latency is the time interval between a client sending a request and the client receiving the response, and data volume refers to the size of data in a response packet that is transmitted from a server to a client. REST with cache was included in the experiment as it has not been investigated in previous work comparing performance between GraphQL and REST. The results showed that GraphQL performs better, in terms of both latency and data volume, compared to the other systems in cases where requests are made to two or more endpoints in REST. GraphQL performed worse than the other systems, in terms of latency, when only one endpoint in REST was contacted. However, GraphQL performed better than the other systems in terms of data volume in all cases. When comparing REST with and without cache, it turned out that the more endpoints that were contacted, the better REST without cache performed in terms of data volume, while REST with cache performed better in terms of latency.

Submitted by Anderson Silva (avargas@icict.fiocruz.br) on 2012-09-30T16:24:14Z No. of bitstreams: 1 edna_m_queiroz_ipec_pesquisaclinicadi_0001_2008.pdf: 1325959 bytes, checksum: fdbb83407bcd934e88f394e837a9b759 (MD5) / Made available in DSpace on 2012-09-30T16:24:14Z (GMT). No. of bitstreams: 1 edna_m_queiroz_ipec_pesquisaclinicadi_0001_2008.pdf: 1325959 bytes, checksum: fdbb83407bcd934e88f394e837a9b759 (MD5) Previous issue date: 2008 / Fundação Oswaldo Cruz. Instituto de Pesquisa Clínica Evandro Chagas. Rio de Janeiro, RJ, Brasil / A tuberculose é uma doença antiga e curável que permanece como um dos maiores problema de saúde pública no mundo. Um aumento na incidência coincidiu com a pandemia de HIV/AIDS. Como conseqüência, observou-se um aumento das formas extrapulmonares e disseminadas, mais freqüentes em indivíduos HIV+. Esse estudo visa descrever as formas exclusivamente extrapulmonares de tuberculose, suas características clínicas e desfechos terapêuticos em pacientes com e sem a infecção pelo HIV. A coleta de dados foi retrospectiva, longitudinal, baseada na revisão dos protocolos de atendimento do ambulatório de tuberculose do Instituto de Pesquisa Evandro Chagas - FIOCRUZ. Todos os pacientes com diagnóstico de tuberculose extrapulmonar no período de janeiro de 2003 até dezembro de 2006 foram incluídos. Foram excluídos os pacientes com mais de dois sítios extrapulmonares não contíguos e as formas disseminadas clássicas. A análise dos dados foi descritiva e em algumas situações foram comparados subgrupos através do teste do λ2 ou Mann-Whitney. Foram selecionados 89 pacientes sendo 56,2% HIV negativo, com predomínio do sexo masculino, solteiros, idade <40 anos, raça não branca, baixa escolaridade, renda até 3 salários mínimos, habitantes de casas de alvenaria, sem presença de aglomeração no domicílio, moradores da baixada fluminense e sem fatores de risco aparentes para tuberculose, porém relatavam relações sexuais desprotegidas. Nenhum paciente relatou tratamento anterior para a infecção latente ou tuberculose. O tabagismo foi revelado por 20,7% dos indivíduos, o uso de drogas intravenosas por 2,2 e o alcoolismo por 11%. As doenças pregressas mais freqüentes foram as alergias (21,1%), doenças digestivas (14%), cirurgias (26,7%) câncer/terapia com imunossupressores (5,6%). As co-morbidades mais freqüentes foram: hipertensão arterial (15,5), hepatite (9,8%), diabetes mellitus (4,2%), e doença renal (4,2%). As formas clínicas mais freqüentes foram: ganglionar (56,2%), pleural (12,4%), oftálmica (10,1%), cutânea (7,9%). A sintomatologia variou segundo o sítio. O teste tuberculínico foi positivo na maioria dos pacientes,e os HIV negativos apresentaram menos reação ao teste que os demais nas formas ganglionares (χ2, p=0,03). O diagnóstico de tuberculose foi baseado em critério histopatológico em 59,5%, O diagnóstico por cultura foi possível em 34% dos casos. A carga bacilar foi pequena (< 1+) em 18% das realizadas e observamos a cultura negativa em 72%. O HbsAg foi evidenciado em 18,3% dos casos e a sorologia para hepatite C foi positiva em 6,4%. A maioria dos pacientes (95,6%) foi tratada com esquema I ou I-R. O tempo de tratamento foi mais longo nos casos de tuberculose cutânea que nos demais (M-W, p=0,07). A resistência às drogas anti-tuberculose foi observada em 2 casos. Os eventos adversos foram freqüentes (88,7%) e 22,1% dos casos precisaram interromper o tratamento da tuberculose. A cura foi obtida na maioria dos casos e foi limitada pelo abandono (18%) principalmente em pacientes soronegativos. Um óbito ocorreu em paciente co-infectado com o HIV. As formas exclusivamente extrapulmonares apresentam características demográficas e epidemiológicas diferentes das formas pulmonares, são paucibacilares e de difícil diagnóstico, a cura foi obtida na maioria dos casos e foi limitada pelo abandono. O percentual de óbitos foi baixo. / Tuberculosis is an old curable disease that still is the biggest health problem in the world. An increase in the incidence was concurrent with the HIV/AIDS pandemia. As a consequence an increase in extrapulmonary and disseminated forms was observed, that were frequent in HIV+ individuals. The aim of this study is to describe the strictly extrapulmonary forms of tuberculosis, its clinical, characteristics and therapeutic endpoints in patients with and without HIV infection. Data collection was retrospective, longitudinal, based in the revision of clinical protocols of the tuberculosis outpatients clinics of Instituto de Pesquisa Clínica Evandro Chagas, Fiocruz. All patients with diagnosis of extrapulmonary tuberculosis during of January 2003 to December 2006 were included. All patients with more than two extrapulmonary sites or disseminated tuberculosis were excluded. Data analysis was descriptive and in some situations subgroups were compared using the λ2 or Mann-Whitney tests. Were selected 89 patients from these 56,2% were HIV negative, the occurrence was more frequent in male sex, not married , age <40 years, non white race, low schooling, monthly income of more than 3 salaries, living in brick homes, no evident, risk factors for tuberculosis, however they reported sex without protection. No patients reported previous therapy to latent infection or tuberculosis. Tobacco use was revealed in 20,7% of the individuals, injection of drugs by 2,2% and alcohol abuse by 11%. The more prevalents previous pathologies were allergy (21,1%), Gastrointestinal diseases (14%), surgery (26,7%) cancer or therapy with immunossupressors (5,6%). The more frequents co-morbidities were: hypertension (15,5), hepatitis (9,8%), diabetes mellitus (4,2%), and renal disease (4,2%). The more frequents clinical forms were: lymph nodes (56,2%), pleural (12,4%), ophthalmic (10,1%) and cutaneous (7,9%). Symptoms varied according to the site. Tuberculin test was positive in the majority of patients, and the HIV negative presented less reaction to the test than the others in the lymph nodes forms (χ2, p=0,03). Tuberculosis diagnose was based on histopatologic criteria in 59,5% of cases, Isolation in culture was possible in 34% of cases. The bacillus load was small (<1+) in 18% of the performed exams and were negative in 72%. The HbsAg was detected in 18, 3% of cases and hepatitis C serology was positive in 6,4%. Most of the patients (95, 6%) were treated with regimen I or I-R. The length of therapy was longer among cases of cutaneous tuberculosis (M-W,p=0,07). Resistance to anti-tuberculosis drugs was observed in two cases. Adverse events were frequent (88, 7%) and 22, 1% of cases needed tuberculosis treatment interruption. The cure was obtained in most of cases and was affected by the abandonment (18%), mainly in seronegative patients. A death occurred in a patient co-infected with HIV. Strictly extrapulmonary forms present different demographic and epidemiological characteristics from pulmonary forms, are paucibacillary and the diagnose is difficult. The cure was obtained in the majority of cases and was limited by abandonment. The proportion of deaths was low.