Inferring Multiple Graphical Structures

Gaussian Graphical Models provide a convenient framework for representing dependencies between variables. Recently, this tool has received a high interest for the discovery of biological networks. The literature focuses on the case where a single network is inferred from a set of measurements, but, as wetlab data is typically scarce, several assays, where the experimental conditions affect interactions, are usually merged to infer a single network. In this paper, we propose two approaches for estimating multiple related graphs, by rendering the closeness assumption into an empirical prior or group penalties. We provide quantitative results demonstrating the benefits of the proposed approaches. The methods presented in this paper are embeded in the R package 'simone' from version 1.0-0 and later

Weighted-Lasso for Structured Network Inference from Time Course Data

We present a weighted-Lasso method to infer the parameters of a first-order vector auto-regressive model that describes time course expression data generated by directed gene-to-gene regulation networks. These networks are assumed to own a prior internal structure of connectivity which drives the inference method. This prior structure can be either derived from prior biological knowledge or inferred by the method itself. We illustrate the performance of this structure-based penalization both on synthetic data and on two canonical regulatory networks, first yeast cell cycle regulation network by analyzing Spellman et al's dataset and second E. coli S.O.S. DNA repair network by analysing U. Alon's lab data

Inferring sparse Gaussian graphical models with latent structure

Our concern is selecting the concentration matrix's nonzero coefficients for a sparse Gaussian graphical model in a high-dimensional setting. This corresponds to estimating the graph of conditional dependencies between the variables. We describe a novel framework taking into account a latent structure on the concentration matrix. This latent structure is used to drive a penalty matrix and thus to recover a graphical model with a constrained topology. Our method uses an $\ell_1$ penalized likelihood criterion. Inference of the graph of conditional dependencies between the variates and of the hidden variables is performed simultaneously in an iterative \textsc{em}-like algorithm. The performances of our method is illustrated on synthetic as well as real data, the latter concerning breast cancer.Comment: 35 pages, 15 figure

Intérêt de l anticorps Immunoglobulines G Anti Hsp70.1 dans le diagnostic de toxoplasmose oculaire

La toxoplasmose oculaire est la première cause d uvéite postérieure, dont le retentissement peut conduire à la cécité. L objectif de cette étude était d améliorer le diagnostic des formes atypiques de toxoplasmose oculaire (TO) grâce au dosage sérique d un nouveau marqueur l anticorps Immunoglobulines G Anti Hsp70.1 (Ac IgG Anti Hsp70.1). Cette étude prospective et multicentrique a inclus 21 patients atteints de TO confirmés par la biologie, 30 patients suspects de toxoplasmose présentant une choriorétinite et 42 patients témoins (atteints de cataracte). La confirmation biologique faisait appel au coefficient de Goldmann-Witmer, Western Blot ou la PCR. Les taux d anticorps ont été déterminés par méthode ELISA. La valeur sérique de l Ac IgG anti Hsp70.1 était significativement différente selon la zone de rétine atteinte (p=0.006) ainsi qu en fonction de la taille de la lésion choriorétinienne (p=0.03). La détermination par la méthode de la courbe ROC d un seuil de l Ac IgG anti Hsp70.1 à partir des valeurs des Anticorps anti toxoplasmose dans l humeur aqueuse n a pas montré de différence entre nos 3 groupes (p=0.57). Dans le groupe suspect de toxoplasmose, la mesure de l Ac IgG anti Hsp70.1 a permis de confirmer biologiquement 10 patients sur 18 présentant une TO clinique. En conclusion, l Ac IgG Anti Hsp 70.1 peut être utilisé, en complément des autres méthodes biologiques, pour confirmer l étiologie toxoplasmique d une choriorétinite. Une étude complémentaire de son dosage dans l humeur aqueuse devrait permettre de mieux appréhender la relation entre l Ac IgG Anti Hsp 70.1 et le diagnostic, ainsi que la sévérité de la toxoplasmose oculaire.Laboratory diagnosis of ocular toxoplasmosis (OT) needs to be improved mainly in clinical atypical cases. In a retrospective previous study, infected patients could display serum IgG anti-Hsp70.1 antibodies and that these antibodies could be used to improve the diagnosis of OT. The purpose of this multicentre prospective case-control study was to correlate clinical features with IgG anti-Hsp70 antibodies. We have included patients with confirmed (Group A1) or suspected OT (Group A2), and with cataract (Control Group B). The diagnosis was based on the ocular presentation, Goldmann-Witmer s coefficient, immunoblotting and/or PCR. Serum and aqueous humour (AH) were sampled at the time of uveitis. ELISA was used to measure serum anti-Hsp70.1-antibody levels. The OT patients were clinically followed up to six months and laboratory monitored up to three months. Serum IgG anti-Hsp70.1 antibody levels were related to the affected retinal zone (p=0.006) and were correlated significantly to the retinal lesion size (p<0.05). Serum anti-Hsp70.1 and AH IgG anti-Toxoplasma antibodies were respectively positive in 10 and 5 out of 18 cases of Group A2 that were finally classified as true-clinically suspected OT. Anti-Hsp70 may be involved directly or indirectly in the retinal lesions during ocular Toxoplasma infection and related to the affected retinal zone. Anti-Hsp70.1 antibody may confirm biologically suspected OT with an increasing specificity when associated with the presence of AH IgG anti-Toxoplasma antibodies. The value of AH anti-Hsp-70 antibody levels in the laboratory diagnosis of OT will further evaluated.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Electrorétinogramme multifocal et atteinte anatomofonctionelle dans la maladie de Birdshot

Objectif : Caractériser les paramètres ERG multifocal (ERGm) chez les patients atteints de maladie de birdshot (BSCR ). Méthodes: L' ERGm a été évalué de façon prospective chez 28 patients à l'aide de l appareil Métrovision . Un œil a été randomisé pour l'analyse statistique. Les corrélations entre les paramètres ERG et l'acuité visuelle (AV), le champ visuel, la vision des couleurs (VC), l angiographie et l OCT ont été étudiés. 27 sujets sains ont été appariés aux patients birdshot, pour l âge, la longueur axiale et le statut cristallinien. Résultats: La population étudiée avait un âge moyen de 56,7 +- 9,7 ans ; représentant 46,4% d hommes. On retrouvait chez les patients BSCR : une diminution significative de la moyenne RMS (- 24,7%), des amplitudes P1 (-17.3 %), N2 (-27.5 %), et P1/N1 (-26.3 %) et une augmentation significative des temps implicites (TI) de N1 (8,7%), P1 (5,4%). Un effet du degré d excentricité (5 zones) a été trouvé pour le RMS, les amplitudes P1 et N2, et le TI P1. Le RMS, P1/N1, les amplitudes P1 et N2; les TI P1 et N1 étaient significativement corrélées avec l AV, le seuil fovéolaire, et le score de VC. Au niveau des 5 centraux, le RMS, les amplitudes P1, N1 et N2, étaient significativement associés à l AV, au seuil fovéolaire. Le RMS, les amplitudes N1 et P1 étaient significativement corrélée avec les scores angiographiques. Conclusion : On retrouve des altérations des amplitudes et des TI des différents paramètres ERGm chez les patients BSCR. Ces paramètres ERGm sont bien corrélés avec les tests anatomiques et fonctionnels classiquement utilisés. La contribution de l ERGm pour la prise en charge thérapeutique des patients reste à déterminer.Purpose: to characterize multifocal ERG parameters in patients with birdshot disease (BSCR). Methods: The mfERG was prospectively evaluated in 28 patients using Vision Monitor, Métrovision , France (2006-2011). One eye was randomized for the statistical analysis. The correlations between mfERG parameters and visual acuity, visual field, color vision, fluorescein and indocyanine green angiography, and optical coherence tomography were studied. Twenty seven healthy subjects were matched to BSCR patients for age, axial length and lens status. Results: The mean age of the patients was 56.7 +-9.7 years, and 46.4% of the patients were male. BSCR eyes differed significantly from healthy eyes by a decrease in mean RMS (- 24.7%), amplitude of P1 (-17.3%), N2 (-27.5%), and P1/N1 ratio (-26.3%) and an increase in implicit time of N1 (8.7%), P1 (5.4%). An effect of the degree of eccentricity (5 zones, figure 1) was found for RMS (p<0.001), amplitude of P1 (p<0.001) and N2 (p<0.001), and implicit times of P1 (p<0.001). RMS, P1N1 ratio, amplitudes of P1 and N2; implicit times of P1 and N1 were significantly correlated with VA, mean defect, foveal threshold, and colour vision score. When the central zone (5: ring 1+2) was considered, RMS, amplitudes of P1, N1 and N2, and not implicit time, were significantly associated with VA, and foveal threshold ; RMS, amplitudes of N1 and P1 were significantly correlated with the FA and ICG score. Conclusion: Amplitudes and implicit times of mfERG parameters are impaired in BSCR patients and are well correlated with other anatomical and functional tests. The contribution of mfERG for the therapeutic management of patients remains to be determined.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Electrorétinogramme multifocal et atteinte anatomofonctionelle dans la maladie de Birdshot

Objectif : Caractériser les paramètres ERG multifocal (ERGm) chez les patients atteints de maladie de birdshot (BSCR ). Méthodes: L' ERGm a été évalué de façon prospective chez 28 patients à l'aide de l appareil Métrovision . Un œil a été randomisé pour l'analyse statistique. Les corrélations entre les paramètres ERG et l'acuité visuelle (AV), le champ visuel, la vision des couleurs (VC), l angiographie et l OCT ont été étudiés. 27 sujets sains ont été appariés aux patients birdshot, pour l âge, la longueur axiale et le statut cristallinien. Résultats: La population étudiée avait un âge moyen de 56,7 +- 9,7 ans ; représentant 46,4% d hommes. On retrouvait chez les patients BSCR : une diminution significative de la moyenne RMS (- 24,7%), des amplitudes P1 (-17.3 %), N2 (-27.5 %), et P1/N1 (-26.3 %) et une augmentation significative des temps implicites (TI) de N1 (8,7%), P1 (5,4%). Un effet du degré d excentricité (5 zones) a été trouvé pour le RMS, les amplitudes P1 et N2, et le TI P1. Le RMS, P1/N1, les amplitudes P1 et N2; les TI P1 et N1 étaient significativement corrélées avec l AV, le seuil fovéolaire, et le score de VC. Au niveau des 5 centraux, le RMS, les amplitudes P1, N1 et N2, étaient significativement associés à l AV, au seuil fovéolaire. Le RMS, les amplitudes N1 et P1 étaient significativement corrélée avec les scores angiographiques. Conclusion : On retrouve des altérations des amplitudes et des TI des différents paramètres ERGm chez les patients BSCR. Ces paramètres ERGm sont bien corrélés avec les tests anatomiques et fonctionnels classiquement utilisés. La contribution de l ERGm pour la prise en charge thérapeutique des patients reste à déterminer.Purpose: to characterize multifocal ERG parameters in patients with birdshot disease (BSCR). Methods: The mfERG was prospectively evaluated in 28 patients using Vision Monitor, Métrovision , France (2006-2011). One eye was randomized for the statistical analysis. The correlations between mfERG parameters and visual acuity, visual field, color vision, fluorescein and indocyanine green angiography, and optical coherence tomography were studied. Twenty seven healthy subjects were matched to BSCR patients for age, axial length and lens status. Results: The mean age of the patients was 56.7 +-9.7 years, and 46.4% of the patients were male. BSCR eyes differed significantly from healthy eyes by a decrease in mean RMS (- 24.7%), amplitude of P1 (-17.3%), N2 (-27.5%), and P1/N1 ratio (-26.3%) and an increase in implicit time of N1 (8.7%), P1 (5.4%). An effect of the degree of eccentricity (5 zones, figure 1) was found for RMS (p<0.001), amplitude of P1 (p<0.001) and N2 (p<0.001), and implicit times of P1 (p<0.001). RMS, P1N1 ratio, amplitudes of P1 and N2; implicit times of P1 and N1 were significantly correlated with VA, mean defect, foveal threshold, and colour vision score. When the central zone (5: ring 1+2) was considered, RMS, amplitudes of P1, N1 and N2, and not implicit time, were significantly associated with VA, and foveal threshold ; RMS, amplitudes of N1 and P1 were significantly correlated with the FA and ICG score. Conclusion: Amplitudes and implicit times of mfERG parameters are impaired in BSCR patients and are well correlated with other anatomical and functional tests. The contribution of mfERG for the therapeutic management of patients remains to be determined.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Inference of gene regulatory networks from non independently and identically distributed transcriptomic data

Cette thèse étudie l'inférence de modèles graphiques Gaussiens en grande dimension à partir de données du transcriptome non indépendamment et identiquement distribuées dans l'objectif d'estimer des réseaux de régulation génétique. Dans ce contexte de données en grande dimension, l'hétérogénéité des données peut être mise à profit pour définir des méthodes de régularisation structurées améliorant la qualité des estimateurs. Nous considérons tout d'abord l'hétérogénéité apparaissant au niveau du réseau, fondée sur l'hypothèse que les réseaux biologiques sont organisés, ce qui nous conduit à définir une régularisation l1 pondérée. Modélisant l'hétérogénéité au niveau des données, nous étudions les propriétés théoriques d'une méthode de régularisation par bloc appelée coopérative-Lasso, définie dans le but de lier l'inférence sur des jeux de données distincts mais proches en un certain sens. Pour finir, nous nous intéressons au problème central de l'incertitude des estimations, définissant un test d'homogénéité pour modèle linéaire en grande dimension.This thesis investigates the inference of high-dimensional Gaussian graphical models from non identically and independently distributed transcriptomic data in the objective of recovering gene regulatory networks. In the context of high-dimensional statistics, data heterogeneity paves the way to the definition of structured regularizers in order to improve the quality of the estimator. We first consider heterogeneity at the network level, building upon the assumption that biological networks are organized, which leads to the definition of a weighted l1 regularization. Modelling heterogeneity at the observation level, we provide a consistency analysis of a recent block-sparse regularizer called the cooperative-Lasso designed to combine observations from distinct but close datasets. Finally we address the crucial question of uncertainty, deriving homonegeity tests for high-dimensional linear regression.EVRY-Bib. électronique (912289901) / SudocSudocFranceF

Comparing Measurements of Vascular Diameter Using Adaptative Optics Imaging and Conventional Fundus Imaging

The aim of this prospective study was to compare retinal vascular diameter measurements taken from standard fundus images and adaptive optics (AO) images. We analysed retinal images of twenty healthy subjects with 45-degree funduscopic colour photographs (CR-2 Canon fundus camera, Canon™) and adaptive optics (AO) fundus images (rtx1 camera, Imagine Eyes(®)). Diameters were measured using three software applications: the VAMPIRE (Vessel Assessment and Measurement Platform for Images of the REtina) annotation tool, IVAN (Interactive Vessel ANalyzer) for funduscopic colour photographs, and AO_Detect_Artery™ for AO images. For the arterial diameters, the mean difference between AO_Detect_Artery™ and IVAN was 9.1 µm (−27.4 to 9.2 µm, p = 0.005) and the measurements were significantly correlated (r = 0.79). The mean difference between AO_Detect_Artery™ and VAMPIRE annotation tool was 3.8 µm (−34.4 to 26.8 µm, p = 0.16) and the measurements were poorly correlated (r = 0.12). For the venous diameters, the mean difference between the AO_Detect_Artery™ and IVAN was 3.9 µm (−40.9 to 41.9 µm, p = 0.35) and the measurements were highly correlated (r = 0.83). The mean difference between the AO_Detect_Artery™ and VAMPIRE annotation tool was 0.4 µm (−17.44 to 25.3 µm, p = 0.91) and the correlations were moderate (r = 0.41). We found that the VAMPIRE annotation tool, an entirely manual software, is accurate for the measurement of arterial and venular diameters, but the correlation with AO measurements is poor. On the contrary, IVAN, a semi-automatic software tool, presents slightly greater differences with AO imaging, but the correlation is stronger. Data from arteries should be considered with caution, since IVAN seems to significantly under-estimate arterial diameters