Parametric estimation of complex mixed models based on meta-model approach

Complex biological processes are usually experimented along time among a collection of individuals. Longitudinal data are then available and the statistical challenge is to better understand the underlying biological mechanisms. The standard statistical approach is mixed-effects model, with regression functions that are now highly-developed to describe precisely the biological processes (solutions of multi-dimensional ordinary differential equations or of partial differential equation). When there is no analytical solution, a classical estimation approach relies on the coupling of a stochastic version of the EM algorithm (SAEM) with a MCMC algorithm. This procedure needs many evaluations of the regression function which is clearly prohibitive when a time-consuming solver is used for computing it. In this work a meta-model relying on a Gaussian process emulator is proposed to replace this regression function. The new source of uncertainty due to this approximation can be incorporated in the model which leads to what is called a mixed meta-model. A control on the distance between the maximum likelihood estimates in this mixed meta-model and the maximum likelihood estimates obtained with the exact mixed model is guaranteed. Eventually, numerical simulations are performed to illustrate the efficiency of this approach

Parametric estimation of complex mixed models based on meta-model approach

International audienceComplex biological processes are usually experimented along time among a collection of individuals. Longitudinal data are then available and the statistical challenge is to better understand the underlying biological mechanisms. The standard statistical approach is mixed-effects model, with regression functions that are now highly-developed to describe precisely the biological processes (solutions of multi-dimensional ordinary differential equations or of partial differential equation). When there is no analytical solution, a classical estimation approach relies on the coupling of a stochastic version of the EM algorithm (SAEM) with a MCMC algorithm. This procedure needs many evaluations of the regression function which is clearly prohibitive when a time-consuming solver is used for computing it. In this work a meta-model relying on a Gaussian process emulator is proposed to replace this regression function. The new source of uncertainty due to this approximation can be incorporated in the model which leads to what is called a mixed meta-model. A control on the distance between the maximum likelihood estimates in this mixed meta-model and the maximum likelihood estimates obtained with the exact mixed model is guaranteed. Eventually, numerical simulations are performed to illustrate the efficiency of this approach

Effects of reflux laryngitis on laryngeal chemoreflexes in newborn lambs

It has been suggested that reflux laryngitis (RL) is involved in apneas-bradycardias of the newborn. The aim of the present study was to develop a unique RL model in newborn lambs to test the hypothesis that RL enhances the cardiorespiratory components of the laryngeal chemoreflexes (LCR) in the neonatal period. Gastric juice surrogate (2 ml of normal saline solution with HCl pH 2 + pepsin 300 U/ml) (RL group, n = 6) or normal saline (control group, n = 6) was repeatedly injected onto the posterior aspect of the larynx, 3 times a day for 6 consecutive days, via a retrograde catheter introduced into the cervical esophagus. Lambs instilled with gastric juice surrogate presented clinical signs of RL, as well as moderate laryngitis on histological observation. Laryngeal chemoreflexes were thereafter induced during sleep by injection of 0.5 ml of HCl (pH 2), ewe's milk, distilled water or saline into the laryngeal vestibule via a chronic, transcutaneous supraglottal catheter. Overall, RL led to a significantly greater respiratory inhibition compared with the control group during LCR, including longer apnea duration (P = 0.01), lower minimal respiratory rate (P = 0.002), and a more prominent decrease in arterial hemoglobin saturation (SpO(2)) (P = 0.03). No effects were observed on cardiac variables. In conclusion, 1) our unique neonatal ovine model presents clinical and histological characteristics of RL; and 2) the presence of RL in newborn lambs increases the respiratory inhibition observed with LCR, at times leading to severe apneas and desaturations

Effects of reflux laryngitis on non-nutritive swallowing in newborn lambs

Reflux laryngitis in infants may be involved not only in laryngeal disorders, but also in disorders of cardiorespiratory control through its impact on laryngeal function. Our objective was to study the effect of reflux laryngitis on non-nutritive swallowing (NNS) and NNS-breathing coordination. Two groups of six newborn lambs, randomized into laryngitis and control groups, were surgically instrumented for recording states of alertness, swallowing and cardiorespiratory variables without sedation. A mild to moderate reflux laryngitis was induced in lambs from the experimental group. A significant decrease in the number of NNS bursts and apneas was observed in the laryngitis group in active sleep (p=0.03). In addition, lower heart and respiratory rates, as well as prolonged apnea duration (p<0.0001) were observed. No physiologically significant alterations in NNS-breathing coordination were observed in the laryngitis group. We conclude that a mild to moderate reflux laryngitis alters NNS burst frequency and autonomous control of cardiac activity and respiration in lambs

How does Poisson kriging compare to the popular BYM model for mapping disease risks?

<p>Abstract</p> <p>Background</p> <p>Geostatistical techniques are now available to account for spatially varying population sizes and spatial patterns in the mapping of disease rates. At first glance, Poisson kriging represents an attractive alternative to increasingly popular Bayesian spatial models in that: 1) it is easier to implement and less CPU intensive, and 2) it accounts for the size and shape of geographical units, avoiding the limitations of conditional auto-regressive (CAR) models commonly used in Bayesian algorithms while allowing for the creation of isopleth risk maps. Both approaches, however, have never been compared in simulation studies, and there is a need to better understand their merits in terms of accuracy and precision of disease risk estimates.</p> <p>Results</p> <p>Besag, York and Mollie's (BYM) model and Poisson kriging (point and area-to-area implementations) were applied to age-adjusted lung and cervix cancer mortality rates recorded for white females in two contrasted county geographies: 1) state of Indiana that consists of 92 counties of fairly similar size and shape, and 2) four states in the Western US (Arizona, California, Nevada and Utah) forming a set of 118 counties that are vastly different geographical units. The spatial support (i.e. point versus area) has a much smaller impact on the results than the statistical methodology (i.e. geostatistical versus Bayesian models). Differences between methods are particularly pronounced in the Western US dataset: BYM model yields smoother risk surface and prediction variance that changes mainly as a function of the predicted risk, while the Poisson kriging variance increases in large sparsely populated counties. Simulation studies showed that the geostatistical approach yields smaller prediction errors, more precise and accurate probability intervals, and allows a better discrimination between counties with high and low mortality risks. The benefit of area-to-area Poisson kriging increases as the county geography becomes more heterogeneous and when data beyond the adjacent counties are used in the estimation. The trade-off cost for the easier implementation of point Poisson kriging is slightly larger kriging variances, which reduces the precision of the model of uncertainty.</p> <p>Conclusion</p> <p>Bayesian spatial models are increasingly used by public health officials to map mortality risk from observed rates, a preliminary step towards the identification of areas of excess. More attention should however be paid to the spatial and distributional assumptions underlying the popular BYM model. Poisson kriging offers more flexibility in modeling the spatial structure of the risk and generates less smoothing, reducing the likelihood of missing areas of high risk.</p

The Logarithmic Sobolev Constant of The Lamplighter

We give estimates on the logarithmic Sobolev constant of some finite lamplighter graphs in terms of the spectral gap of the underlying base. Also, we give examples of application

Valeur médiatrice des traits de la personnalité dans l'association entre l'agression sexuelle à l'enfance et les symptômes psychologiques, conjugaux et sexuels à l'âge adulte

Les victimes d'agression sexuelle à l'enfance (ASE) sont à risque de développer une multitude de symptômes dans diverses sphères du fonctionnement à l'âge adulte, notamment sur le plan psychologique, conjugal et sexuel. De plus, la survenue d'un traumatisme interpersonnel précoce, comme une ASE, pourrait moduler les caractéristiques de la personnalité à l'âge adulte. La présente étude a pour but d'examiner le rôle intermédiaire des cinq traits de la personnalité du modèle de personnalité en cinq facteurs, dans l'association entre l'agression sexuelle à l'enfance (ASE) et la détresse psychologique, la satisfaction conjugale et la satisfaction sexuelle à l'âge adulte. Un échantillon de 767 participants a été recruté au Service de Consultation de l'École de psychologie de l'université Laval, afin de répondre aux questionnaires portant sur l'ASE, la personnalité, la détresse psychologique, la satisfaction conjugale et la satisfaction sexuelle. Parmi l'échantillon, 24,5% (n = 188) ont rapporté avoir vécu une ASE. L'échantillon est composé de 61,3% (n = 470) de femmes et 38,7% (n = 297) d'hommes. Des analyses acheminatoires indiquent que les traits de névrosisme et d'extraversion ont un rôle intermédiaire dans l'association entre l'ASE et les répercussions vécues à l'âge adulte. Plus précisément, un effet indirect est observé dans l'association entre l'ASE, le névrosisme et la détresse psychologique. De plus, pour les hommes uniquement, un effet indirect est observé dans l'association entre l'ASE, l'extraversion et la satisfaction conjugale, ainsi qu'avec la satisfaction sexuelle. Ces résultats démontrent le rôle intermédiaire de la personnalité entre l'ASE et les répercussions observées à l'âge adulte. Ils contribueront à guider les pratiques en matière d'évaluation et de traitement des victimes d'agression sexuelle à l'enfance maintenant devenues adultes

Increased acetylcholinesterase expression in bumble bees during neonicotinoid-coated corn sowing

While honey bee exposure to systemic insecticides has received much attention, impacts on wild pollinators have not been as widely studied. Neonicotinoids have been shown to increase acetylcholinesterase (AChE) activity in honey bees at sublethal doses. High AChE levels may therefore act as a biomarker of exposure to neonicotinoids. This two-year study focused on establishing whether bumble bees living and foraging in agricultural areas using neonicotinoid crop protection show early biochemical signs of intoxication. Bumble bee colonies (Bombus impatiens) were placed in two different agricultural cropping areas: 1) control (≥3 km from fields planted with neonicotinoid-treated seeds) or 2) exposed (within 500 m of fields planted with neonicotinoid-treated seeds) and maintained for the duration of corn sowing. As determined by Real Time qPCR, AChE mRNA expression was initially significantly higher in bumble bees from exposed sites, then decreased throughout the planting season to reach a similar endpoint to that of bumble bees from control sites. These findings suggest that exposure to neonicotinoid seed coating particles during the planting season can alter bumble bee neuronal activity. To our knowledge, this is the first study to report in situ that bumble bees living in agricultural areas exhibit signs of neonicotinoid intoxication

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients.: Effectiveness of triple therapy in cirrhotic patients

International audienceTriple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day(-1)) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients