Resting Behaviour of Deltamethrin-Resistant Malaria Vectors, Anopheles arabiensis and Anopheles coluzzii, from North Cameroon: Upshots from a Two-Level Ordinary Logit Model

The current study was conducted in Garoua, Pitoa, and Mayo-Oulo health districts of north Cameroon, in order to investigate the resting behaviour of deltamethrin-resistant Anopheles (An.) gambiae s.l. populations and build a model of their response to the use of Permanet 2.0 long-lasting insecticidal nets (LLINs). Adult mosquitoes were collected in October and November 2011, using spray catches and window exit traps in 29 clusters with LLINs in use. Sampled An. gambiae s.l. were identified down to species and analysed for blood-meal origin, physiological and circumsporozoite protein status. Deltamethrin resistance was assessed using World Health Organization’s (WHO’s) standard protocol. A two-level ordinary logit model was used to relate the resting behaviour and deltamethrin resistance. Identified species of the An. gambiae complex included An. arabiensis (90.6%), An. coluzzii (7.1%) and An. gambiae s.s. (2.3%). They displayed 1.1–4.8% infection rates, 80% indoor-resting density and 56–80% human blood index. Eleven An. gambiae s.l. populations over the 15 tested were resistant to deltamethrin (51–89.5% mortality rates). Model results showed a significant dependence of indoor vector density on increasing deltamethrin resistance (p-value of <0.01). These behavioural and resistance patterns may lead to increasing malaria transmission in study health districts

Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon

Background: Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon. Methods: A retrospective cohort study was conducted among HIV-1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine. Results: Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm(3) (interquartile range [IQR] 67 218), 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 x 107 IU/mL for HBV (IQR 3680-1.59 x 10(8)) and 928 000 IU/mL for HCV (IQR 178 400-2.06 x 10(6)). Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p < 0.01). The response to antiretroviral therapy was however comparable between monoinfected and coinfected patients in terms of CD4 cell count increase (p = 0.8), HIV-1 viral load below 400 copies/mL (p = 0.9), death (p = 0.3) and death or new AIDS-defining event (p = 0.1). Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity. Conclusion: This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be a decisive argument for testing when hepatitis status is unknown

Sélection de variable (structure génétique d'une population et transmission de Plasmodium à travers le moustique)

Dans cette thèse, nous considérons la question de sélection de variable dans deux deux problèmes pratiques. Le premier concerne une préoccupation très récurrente en génétique des populations qui consiste à regrouper les individus d'un échantillon d'organismes vivants dans des classes génétiquement homogènes sur la base d'informations procurées par un certain nombre de marqueurs génétiques. Nous supposons ne disposer d'aucune information a priori sur la population cible: il s'agit alors d'un problème de classification non supervisée. Par ailleurs, certaines variables peuvent ajouter du bruit à la classification. Nous proposons de résoudre simultanément le problème de sélection de variable et celui de sélection du nombre de composants du mélange dans une procédure de sélection de modèle. La sélection est ensuite faite via pénalisation du maximum de vraisemblance pénalisé. Sous des hypothèses faibles sur la fonction de pénalité, nous montrons que la procédure de sélection est consistante. Nous construisons ensuite une fonction de pénalité garantissant une inégalité oracle non-asymptotique. Bien que ce deuxième résultat ne soit pas directement utilisable, il suggère une pénalité de la forme du produit de la dimension des modèles en compétition et d'un paramètre données-dépendant que nous calibrons grâce à l'heuristique de la pente. Nous montrons sur des données simulées que cette calibration répond en partie au problème du choix du critère de sélection en fonction de la taille de l'échantillon. Le deuxième problème est motivé par le contrôle de la transmission de Plasmodium à travers son vecteur moustique. Nous disposons de données décrites par des variables diverses dont le nombre est de l'ordre de la taille de l'échantillon. Nous appliquons tout d'abord une procédure de sélection de variable qui repose sur l'importance des variables obtenues des forêts aléatoires. Les variables sélectionnées sont ensuite évaluées dans le modèle binomial négatif modifié en zéro.This thesis is concerned with variable selection in two practical problems. The first one is the identification of genetically homogeneous populations without prior information on the target population. The structure of interest may be contained in only a subset of available genetic markers. We propose a model selection procedure to simultaneously solve the two-fold problem of selection of the number of populations and the relevant subset of variable. The models in competition are compared using penalized maximum likelihood criteria. Under weak assumptions on the penalty function, we proved the consistency of the selection procedure. We also proposed a new penalty function with an associated non-asymptotic oracle inequality. ln practice, this result suggests a penalty function defined up to a multiplicative parameter which is calibrated thanks to the slope heuristics. Using simulated data, we found that the calibration of the penalty term improves the perforrnances of the selection procedure with respect to classical asymptotic criteria such as AIC and BlC. ln addition, we proposed a stand alone C++ package implementing our proposed selection procedure. The second problem is motivated by malaria control strategies aiming at reducing disease transmission intensity. The data we have at hand are described by variables of different types. ln addition their number is of the order of the sample size. We considered a variable selection procedure based on the variable importances from random forests to face the variable selection problem. The selected variables are assessed in Zero Inflated Negative Binomial model.ORSAY-PARIS 11-BU Sciences (914712101) / SudocORSAY-PARIS 11-Bib. Maths (914712203) / SudocSudocFranceF

Problématiques statistiques rencontrées dans l'étude du traitement antirétroviral des adultes infectés par le VIH en Afrique subsaharienne

Partant de problématiques statistiques rencontrées dans l'étude du traitement antirétroviral des adultes infectés par le virus de l'immunodéficience humaine (VIH) en Afrique subsaharienne, cette thèse cherche, d'une part, à favoriser la vulgarisation d'outils méthodologiques relativement récents auprès d'un public d'utilisateurs moins avertis et, d'autre part, à participer au développement de nouveaux outils. Le premier chapitre présente différentes méthodes de modélisation des données longitudinales dont des méthodes d'analyse de l'évolution d'un critère au cours du temps (les modèles linéaires mixtes généralisés et les modèles d'équations d'estimation généralisées) ou de la survenue d'un évènement au cours du temps (le modèle semi-paramétrique de Cox et ses extensions à la prise en compte des covariables dépendantes du temps et de la censure informative). Le deuxième chapitre s'intéresse aux tests de non-infériorité et propose deux développements de la procédure classique de ces tests pour les cas où la marge de non-infériorité est relative. Enfin, le troisième chapitre aborde la question des données manquantes et propose une extension de la méthode d'imputation multiple par les distributions conditionnelles univariées qui consiste à prendre en compte des effets non-linéaires des covariables dans les modèles d'imputation par des fonctions B-splines. Ces méthodes sont illustrées par des études sur le VIH au Cameroun et au Sénégal.On the basis of statistical challenges encountered in study of antiretroviral treatment of adults infected with human immunodeficiency virus (HIV) in sub-Saharan Africa, this thesis aims to promote the dissemination of relatively recent methodological tools of less aware audience of users on one hand and to participate to development of new tools on the other hand. The first chapter presents various methods for modeling longitudinal data of which analysis methods for changing of a criterion over time (the generalized linear mixed models and models of generalized estimating equations) or the occurrence of an event over time (the semi-parametric Cox model and its extensions to take into account time-dependent covariates and informative censoring). The second chapter focuses on non-inferiority test and provides two developments of the classical procedure of these tests in cases where the non-inferiority margin is relative. The third chapter addresses the question of missing data and proposes an extension of the multiple imputation method based on fully conditional specification, to take into account nonlinear effects of covariates in the imputation models using B-splines functions. These methods are illustrated by studies on HIV in Cameroon and Senegal.MONTPELLIER-BU Médecine UPM (341722108) / SudocSudocFranceF

Fuzzy implication operators for difference operations for fuzzy sets and cardinality-based measures of comparison

International audienceIn this paper, we determine by means of fuzzy implication operators, two classes of difference operations for fuzzy sets and two classes of symmetric difference operations for fuzzy sets which preserve properties of the classical difference operation for crisp sets and the classical symmetric difference operation for crisp sets respectively. The obtained operations allow us to construct as in [B. De Baets, H. De Meyer, Transitivity-preserving fuzzification schemes for cardinality-based similarity measures, European Journal of Operational Research 160 (2005) 726–740], cardinality-based similarity measures which are reflexive, symmetric and transitive fuzzy relations and, to propose two classes of distances (metrics) which are fuzzy versions of the well-known distance of cardinality of the symmetric difference of crisp sets

A Binary Intuitionistic Fuzzy Relation: Some New Results, a General Factorization, and Two Properties of Strict Components

We establish, by means of a large class of continuous t-representable intuitionistic fuzzy t-conorms, a factorization of an intuitionistic fuzzy relation (IFR) into a unique indifference component and a family of regular strict components. This result generalizes a previous factorization obtained by Dimitrov (2002) with the (max,min) intuitionistic fuzzy t-conorm. We provide, for a continuous t-representable intuitionistic fuzzy t-norm , a characterization of the -transitivity of an IFR. This enables us to determine necessary and sufficient conditions on a -transitive IFR under which a strict component of satisfies pos-transitivity and negative transitivity

Méthodologies d'évaluation de l'efficacité thérapeutique des antipaludiques (application à des données du Cameroun)

Le sujet de cette thèse s'inscrit dans un contexte commun aux pays d'Afrique sub-saharienne, celui des évaluations des stratégies thérapeutiques et des choix des politiques de santé publique dans la lutte contre le paludisme. Il concerne les méthodes d'évaluation globale de l'efficacité thérapeutique des antipaludiques qui s'attachent aux techniques de méta-analyse de comparaisons mixtes de traitements. D'une part, le critère principal préconisé par l'OMS dans les essais d'antipaludiques est un critère ordinal. D'autre part, les différents bras thérapeutiques dans les essais ne concernent pas toujours les mêmes bras de combinaisons thérapeutiques et la durée totale d'évaluation entre essais a changé au cours des années. Enfin, le critère ordinal d'évaluation préconisé entraine des répartitions déséquilibrées dans les réponses. Nous avons travaillé sur un jeu de données correspondant à une série d'essais menés entre 2003 et 2007, chez l'enfant de moins de 5 ans au Cameroun, suivant les recommandations OMS. La première étape du travail a emprunté des techniques d'analyse classique de meta-analyse sur un critère binaire pour comparer l'ensemble des traitements de tous les essais. Le caractère ordinal de la réponse dans des essais à plus de 2 bras de traitement et temps unique d'évaluation de ce critère a été ensuite analysé, en s'appuyant sur une étude par simulation pour évaluer les risques associés de première et seconde espèces en fonction de l'amplitude de l'effet traitement. La méthode a été étendue aux données répétées dans le temps à 14, 21 et 28 jours de traitement.La prise en compte de l'ordinalité du critère a permis d'obtenir des résultats significatifsThis work was motivated by a health context which is common to all subsaharian African countries. It is directly related to the evaluation of the therapeutical strategies and the public health decisions in the fight against malaria. It concerns the quantitative methods for pooling randomised trials and estimating the efficacy of the various antimalarial drugs.First, the primary outcome developed by the WHO is an ordinal one. Second, the different treatment arms between the trials are not always the same combined treatments and, the follow up durations changed over the years. Third, the observed counts between the different categories of responses are highly unbalanced. In the first step method, a global classical meta-analysis pooling all the trials was carried out using as primary outcome a binarised WHO outcome. In a second step, the primary outcome was analysed as an ordinal outcome at a fixed time endpoint in a single three- arm randomised clinical trial. A simulation study was performed to assess the type- 1 and type-2 errors in relation to the treatment effect. In a third step, the 28- day trials were pooled by extending the previous methodology to the repeated measurements on days 14, 21 and 28. Significant results were obtained when analyzing the WHO outcome as ordinal.PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon

Abstract Background Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon. Methods A retrospective cohort study was conducted among HIV-1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine. Results Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm3 (interquartile range [IQR] 67-218), 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 × 107 IU/mL for HBV (IQR 3680-1.59 × 108) and 928 000 IU/mL for HCV (IQR 178 400-2.06 × 106). Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p p = 0.8), HIV-1 viral load below 400 copies/mL (p = 0.9), death (p = 0.3) and death or new AIDS-defining event (p = 0.1). Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity. Conclusion This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be a decisive argument for testing when hepatitis status is unknown.</p