Etude de consistance et applications du modèle Poisson-gamma : modélisation d'une dynamique de recrutement multicentrique

Abstract : A clinical trial is a biomedical research which aims to consolidate and improve the biological and medical knowledges. The number of patients required il the minimal number of patients to include in the trial in order to insure a given statistical power of a predefined test. The constitution of this patients' database is one of the fundamental issues of a clinical trial. To do so several investigation centres are opened. The duration between the first opening of a centre and the last recruitment of the needed number of patients is called the recruitemtn duration that we aim to model. The fisrt model goes back 50 years ago with the work of Lee, Williford et al. and Morgan with the idea to model the recruitment dynamic using Poisson processes. One problem emerge, that is the lack of caracterisation of the variabliity of recruitment between centers that is mixed with the mean of the recruitment rates. The most effective model is called the Poisson-gamma model which is based on Poisson processes with random rates (Cox process) with gamma distribution. This model is at the very heart of this project. Different objectives have motivated the realisation of this thesis. First of all the validity of the Poisson-gamma model is established asymptotically. A simulation study that we made permits to give precise informations on the model validity in specific cases (function of the number of centers, the recruitement duration and the mean rates). By studying database, one can observe that there can be breaks during the recruitment dynamic. A question that arise is : How and must we take into account this phenomenon for the prediction of the recruitment duration. The study made tends to show that it is not necessary to take them into account when they are random but their law is stable in time. It also veered around to measure the impact of these breaks on the estimations of the model, that do not impact its validity under some stability hypothesis. An other issue inherent to a patient recruitment dynamic is the phenomenon of screening failure. An empirical Bayesian technique analogue to the one of the recruitment process is used to model the screening failure issue. This hierarchical Bayesian model permit to estimate the duartion of recruitment with screening failure consideration as weel as the probability to drop out from the study using the data at some interim time of analysis, giving predictions on the randomisation dynamic. The recruitment dynamic can be studied in many different ways than just the duration of recruitment. These fundamental aspects coupled with the Poisson-gamma model give relevant indicators for the study follow-up. Multiples applications in this sense are computed. It is therefore possible to adjust the number of centers according to predefined objectives, to model the drug's supply chain per region or center and to predict the effect of the randomisation on the power of the test's study. It also allows to model the folow-up period of the patients by means of transversal or longitudinal methods, that can serve to adjust the number of patients if too many quit during the foloww-up period, or to stop the study if dangerous side effects or no effects are observed on interim data. The problematic of the recruitment dynamic can also be coupled with the dynamic of the study itself when it is longitudinal. The independance between these two processes allows easy estimations of the different parameters. The result is a global model of the patient pathway in the trail. Two key examples of such situations are survival data - the model permit to estimate the duration of the trail when the stopping criterion is the number of events observed, and the Markov model - the model permit to estimate the number of patients in a certain state for a given duartion of analysis.
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Nathan Minois. Etude de consistance et applications du modèle Poisson-gamma : modélisation d'une dynamique de recrutement multicentrique. Statistiques [math.ST]. Université Paul Sabatier - Toulouse III, 2016. Français. ⟨NNT : 2016TOU30396⟩. ⟨tel-02275009⟩

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