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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Evaluation of Repeated Biomarkers: Non-parametric Comparison of Areas under the Receiver Operating Curve Between Correlated Groups Using an Optimal Weighting Scheme

Xu, Ping 01 January 2012 (has links)
Receiver Operating Characteristic (ROC) curves are often used to evaluate the prognostic performance of a continuous biomarker. In a previous research, a non-parametric ROC approach was introduced to compare two biomarkers with repeated measurements. An asymptotically normal statistic, which contains the subject-specific weights, was developed to estimate the areas under the ROC curve of biomarkers. Although two weighting schemes were suggested to be optimal when the within subject correlation is 1 or 0 by the previous study, the universal optimal weight was not determined. We modify this asymptotical statistic to compare AUCs between two correlated groups and propose a solution to weight optimization in non-parametric AUCs comparison to improve the efficiency of the estimator. It is demonstrated how the Lagrange multiplier can be used as a strategy for finding the weights which minimize the variance function subject to constraints. We show substantial gains of efficiency by using the novel weighting scheme when the correlation within group is high, the correlation between groups is high, and/or the disease incidence is small, which is the case for many longitudinal matched case-control studies. An illustrative example is presented to apply the proposed methodology to a thyroid function dataset. Simulation results suggest that the optimal weight performs well with a sample size as small as 50 per group.
2

Méthodologie de l’évaluation des biomarqueurs prédictifs quantitatifs et de la détermination d’un seuil pour leur utilisation en médecine personnalisée / Treatment selection markers in precision medicine : methodology of use and estimation of marker threshold

Blangero, Yoann 13 September 2019 (has links)
En France, la recherche contre le cancer est un enjeu majeur de santé publique. On estime notamment que le nombre de nouveaux cas de cancer a plus que doublé entre 1980 et 2012. L’hétérogénéité des caractéristiques tumorales, pour un même cancer, impose des défis complexes dans la recherche de traitements efficaces. Dans ce contexte, des espoirs importants sont placés dans la recherche de biomarqueurs prédictifs reflétant les caractéristiques des patients ainsi que de leur tumeur afin d’orienter le choix de la stratégie thérapeutique. Par exemple, pour les cancers colorectaux métastatiques, il est maintenant reconnu que l’ajout de cetuximab (un anti-EGFR) à la chimiothérapie classique (ici le FOLFOX4), n’apporte un bénéfice qu’aux patients dont le gène KRAS est non muté. Le gène KRAS est ici un biomarqueur prédictif binaire, mais de nombreux biomarqueurs sont le résultat d’une quantification ou d’un dosage. L’objectif de cette thèse est dans un premier temps, de quantifier la capacité globale d’un biomarqueur quantitatif à guider le choix du traitement. Après une revue de la littérature, une nouvelle méthode basée sur une extension des courbes ROC est proposée, et comparée aux méthodes existantes. Son principal avantage est d’être non paramétrique, et d’être indépendante de l’efficacité moyenne des traitements. Dans un second temps, lorsqu’un biomarqueur prédictif quantitatif est étudié, la définition d’un seuil de marqueur au-delà duquel la première option de traitement sera préférée, et en-deçà duquel la deuxième option de traitement sera préférée se pose. Une approche reposant sur la définition d’une fonction d’utilité est proposée permettant alors de tenir compte de l’efficacité des traitements ainsi que de leur impact sur la qualité de vie des patients. Une méthode Bayésienne d’estimation de ce seuil optimal est proposée / In France, the cancer research is a major public health issue. The number of new cancer cases nearly doubled between 1980 and 2012. The heterogeneity of the tumor characteristics, for a given cancer, presents a great challenge in the research of new effective treatments. In this context, much hope is placed in the research of predictive (or treatment selection) biomarkers that reflect the patients’ characteristics in order to guide treatment choice. For example, in the metastatic colorectal cancer setting, it is admitted that the addition of cetuximab (an anti-EGFR) to classical chemotherapy (the FOLFOX4), only improve the outcome of patients with KRAS wild-type tumors. In that context, the KRAS gene is a binary treatment selection marker, but plenty of biomarkers result from some quantifications or dosage measurements. The first aim of this thesis is to quantify the global treatment selection ability of a biomarker. After a review of the existing litterature, a method based on an extension of ROC curves is proposed and compared to existing methods. Its main advantage is that it is non-parametric, and that it does not depend on the mean risk of event in each treatment arm. In a second time, when a quantitative treatment selection biomarker is assessed, there is a need to estimate a marker thereshold value above which one treatment is preferred, and below which the other treatment is recommended. An approach that relies on the definition of a utility function is proposed in order to take into account both efficacy and toxicity of treatments when estimating the optimal threshold. A Bayesian method for the estimation of the optimal threshold is proposed

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