Accelerating Monte Carlo power studies through parametric power estimation

Estimating the power for a non-linear mixed-effects model-based analysis is challenging due to the lack of a closed form analytic expression. Often, computationally intensive Monte Carlo studies need to be employed to evaluate the power of a planned experiment. This is especially time consuming if full power versus sample size curves are to be obtained. A novel parametric power estimation (PPE) algorithm utilizing the theoretical distribution of the alternative hypothesis is presented in this work. The PPE algorithm estimates the unknown non-centrality parameter in the theoretical distribution from a limited number of Monte Carlo simulation and estimations. The estimated parameter linearly scales with study size allowing a quick generation of the full power versus study size curve. A comparison of the PPE with the classical, purely Monte Carlo-based power estimation (MCPE) algorithm for five diverse pharmacometric models showed an excellent agreement between both algorithms, with a low bias of less than 1.2 % and higher precision for the PPE. The power extrapolated from a specific study size was in a very good agreement with power curves obtained with the MCPE algorithm. PPE represents a promising approach to accelerate the power calculation for non-linear mixed effect models

Market size, competition, and the product mix of exporters

We build a theoretical model of multi-product firms that highlights how market size and ge- ography (the market sizes of and bilateral economic distances to trading partners) affect both a firm's exported product range and its exported product mix across market destinations (the dis- tribution of sales across products for a given product range). We show how tougher competition in an export market induces a firm to skew its export sales towards its best performing products. We find very strong confirmation of this competitive effect for French exporters across export market destinations. Trade models based on exogenous markups cannot explain this strong sig- nificant link between destination market characteristics and the within-firm skewness of export sales (after controlling for bilateral trade costs). Theoretically, this within firm change in prod- uct mix driven by the trading environment has important repercussions on firm productivity and how it responds to changes in that trading environment

Optimizing the design of a pharmacokinetic trial to evaluate the dosing scheme of a novel tuberculosis drug in children living with or without HIV

Pharmacokinetic (PK) studies in children are usually small and have ethical constraints due to the medical complexities of drawing blood in this special population. Often, population PK models for the drug(s) of interest are available in adults, and these models can be extended to incorporate the expected deviations seen in children. As a consequence, there is increasing interest in the use of optimal design methodology to design PK sampling schemes in children that maximize information using a small sample size and limited number of sampling times per dosing period. As a case study, we use the novel tuberculosis drug delamanid, and show how applications of optimal design methodology can result in highly efficient and model-robust designs in children for estimating PK parameters using a limited number of sampling measurements. Using developed population PK models based on available data from adults living with and without HIV, and limited data on children without HIV, competing designs for children living with HIV were derived and assessed based on robustness to model uncertainty

Schools are open during the coronavirus outbreak but should I voluntarily keep my kids home anyway, if I can? We asked 5 experts

We asked five experts to answer the question: schools are staying open but should I voluntarily keep my kids home anyway, if I can

Maturation of Oxycodone Pharmacokinetics in Neonates and Infants : a Population Pharmacokinetic Model of Three Clinical Trials

Purpose The aim of the current population pharmacokinetic study was to quantify oxycodone pharmacokinetics in children ranging from preterm neonates to children up to 7 years of age. Methods Data on intravenous or intramuscular oxycodone administration were obtained from three previously published studies (n = 119). The median [range] postmenstrual age of the subjects was 299 days [170 days-7.8 years]. A population pharmacokinetic model was built using 781 measurements of oxycodone plasma concentration. The model was used to simulate repeated intravenous oxycodone administration in four representative infants covering the age range from an extremely preterm neonate to 1-year old infant. Results The rapid maturation of oxycodone clearance was best described with combined allometric scaling and maturation function. Central and peripheral volumes of distribution were nonlinearly related to bodyweight. The simulations on repeated intravenous administration in virtual patients indicated that oxycodone plasma concentration can be kept between 10 and 50 ng/ml with a high probability when the maintenance dose is calculated using the typical clearance and the dose interval is 4 h. Conclustions Oxycodone clearance matures rapidly after birth, and between-subject variability is pronounced in neonates. The pharmacokinetic model developed may be used to evaluate different multiple dosing regimens, but the safety of repeated doses should be ensured.Peer reviewe

Pourquoi les politiques publiques sont-elles si peu suivies d’effets ?:Quelques interrogations

L’insertion des femmes sur le marché du travail a connu à la fois des avancées et des reculs. Si davantage de femmes accèdent à l’éducation supérieure et aux emplois qualifiés, d’autres sont touchées par la précarité et connaissent une dégradation de leurs conditions de travail et de vie. Face à ce constat ambivalent, on peut questionner la mise en œuvre et l’efficacité des politiques qui visent à promouvoir l’égalité entre les femmes et les hommes. Cet article a pour objectif de soulever quelques débats. Le plus souvent, les politiques publiques au sens large (y compris la protection sociale) sont définies en termes de compensation et de correction des inégalités et des discriminations. Mais elles ne concernent pas les causes effectives de l’extension du sous-emploi des femmes, qui relèvent du fonctionnement même du marché du travail. C’est donc la définition des politiques publiques qu’il faut interroger, en dépassant une vision binaire qui oppose d’une part un champ économique extérieur, d’autre part un champ social, juridique et culturel qui, seul, pourrait être l’objet d’inflexions. En réalité, le champ économique est aussi le produit des politiques publiques : la libre-concurrence et la prééminence du marché sont le résultat d’une action volontaire des États. Il faut donc réintégrer les politiques économiques dans le champ de la réflexion sur les moyens de combattre les discriminations à l’encontre des femmes.The integration of women into the labour market has gone through both upswings and downturns. In view of this ambivalent result, we can question the efficiency of public policies set up to overcome gender inequality and fight gender discrimination. Does a real will exist, and if so why is it so inefficient or so poorly implemented? What forms do individual and collective resistance take? Most of the time, public policies are defined in terms of compensation and correction. But they don’t deal with the actual causes of women’s underemployment resulting from labour market adjustments. It is therefore the definition of the public policies that we need to examine, going beyond a binary view that opposes economic issues, on the one hand, to social, juridical and cultural concerns on the other

Enhanced He-alpha emission from "smoked" Ti targets irradiated with 400nm, 45 fs laser pulses

We present a study of He-like 1s(2)-1s2p line emission from solid and low-density Ti targets under similar or equal to 45 fs laser pulse irradiation with a frequency doubled Ti: Sapphire laser. By varying the beam spot, the intensity on target was varied from 10(15) W/cm(2) to 10(19) W/cm(2). At best focus, low density "smoked" Ti targets yield similar to 20 times more He-alpha than the foil targets when irradiated at an angle of 45 degrees with s-polarized pulses. The duration of He-alpha emission from smoked targets, measured with a fast streak camera, was similar to that from Ti foils

Methods for non-proportional hazards in clinical trials: A systematic review

For the analysis of time-to-event data, frequently used methods such as the log-rank test or the Cox proportional hazards model are based on the proportional hazards assumption, which is often debatable. Although a wide range of parametric and non-parametric methods for non-proportional hazards (NPH) has been proposed, there is no consensus on the best approaches. To close this gap, we conducted a systematic literature search to identify statistical methods and software appropriate under NPH. Our literature search identified 907 abstracts, out of which we included 211 articles, mostly methodological ones. Review articles and applications were less frequently identified. The articles discuss effect measures, effect estimation and regression approaches, hypothesis tests, and sample size calculation approaches, which are often tailored to specific NPH situations. Using a unified notation, we provide an overview of methods available. Furthermore, we derive some guidance from the identified articles. We summarized the contents from the literature review in a concise way in the main text and provide more detailed explanations in the supplement (page 29)