Risk of Drug-Drug Interactions in Out-Hospital Drug Dispensings in France: Results From the DRUG-Drug Interaction Prevalence Study

Introduction: Drug interactions could account for 1% of hospitalizations in the general population and 2-5% of hospital admissions in the elderly. However, few data are available on the drugs concerned and the potential severity of the interactions encountered. We thus first aimed to estimate the prevalence of dispensings including drugs Contraindicated or Discommended because of Interactions (CDI codispensings) and to identify the most frequently involved drug pairs. Second, we aimed to investigate whether the frequency of CDI codispensings appeared higher or lower than the expected for the drugs involved. Methods: We carried out a study using a random sample of all drugs dispensings registered in a database of the French Health Insurance System between 2010 and 2015. The distribution of the drugs involved was described considering active principles, detailing the 20 most frequent ones for both contraindicated or discommended codispensings (DCs). To investigate whether the frequency of CDI codispensings appeared higher or lower than the expected for the drugs involved, we developed a specific indicator, the Drug-drug interaction prevalence study-score (DIPS-score), that compares for each drug pair the observed frequency of codispensing to its expected probability. The latter is determined considering the frequencies of dispensings of the individual drugs constituting a pair of interest. Results: We analyzed 6,908,910 dispensings: 13,196 (0.2%) involved contraindicated codispensings (CCs), and 95,410 (1.4%) DCs. For CCS, the most frequently involved drug pair was "bisoprolol+flecainide" = 5,036); four out of five of the most represented pairs involved cardiovascular drugs. For DCS, the most frequently involved drug pair was "ramipril+spironolactone" = 4,741); all of the five most represented pairs involved cardiovascular drugs. The drug pair involved in the CC with the highest score value was "citalopram+hydroxyzine" (DIPS-score: 3.7; 2.9-4.6); that with the lowest score was "clarithromycin+simvastatin" (DIPS-score: 0.2; 0.2-0.3). DIPS-score median value was 0.4 for CCs and 0.6 for DCs. Conclusion: This high prevalence of CDI codispensings enforces the need for further risk-prevention actions regarding drug-drug interactions (DDIs), especially for arrhythmogenic or anti-arrhythmic drugs. In this perspective, the DIPS-score we develop could ease identifying the interactions that are poorly considered by clinicians/pharmacists and targeting interventions

Risk of Drug-Drug Interactions in Out-Hospital Drug Dispensings in France: Results From the DRUG-Drug Interaction Prevalence Study

Introduction: Drug interactions could account for 1% of hospitalizations in the general population and 2–5% of hospital admissions in the elderly. However, few data are available on the drugs concerned and the potential severity of the interactions encountered. We thus first aimed to estimate the prevalence of dispensings including drugs Contraindicated or Discommended because of Interactions (CDI codispensings) and to identify the most frequently involved drug pairs. Second, we aimed to investigate whether the frequency of CDI codispensings appeared higher or lower than the expected for the drugs involved.Methods: We carried out a study using a random sample of all drugs dispensings registered in a database of the French Health Insurance System between 2010 and 2015. The distribution of the drugs involved was described considering active principles, detailing the 20 most frequent ones for both contraindicated or discommended codispensings (DCs). To investigate whether the frequency of CDI codispensings appeared higher or lower than the expected for the drugs involved, we developed a specific indicator, the Drug-drug interaction prevalence study-score (DIPS-score), that compares for each drug pair the observed frequency of codispensing to its expected probability. The latter is determined considering the frequencies of dispensings of the individual drugs constituting a pair of interest.Results: We analyzed 6,908,910 dispensings: 13,196 (0.2%) involved contraindicated codispensings (CCs), and 95,410 (1.4%) DCs. For CCS, the most frequently involved drug pair was “bisoprolol+flecainide” (n = 5,036); four out of five of the most represented pairs involved cardiovascular drugs. For DCS, the most frequently involved drug pair was “ramipril+spironolactone” (n = 4,741); all of the five most represented pairs involved cardiovascular drugs. The drug pair involved in the CC with the highest score value was “citalopram+hydroxyzine” (DIPS-score: 3.7; 2.9–4.6); that with the lowest score was “clarithromycin+simvastatin” (DIPS-score: 0.2; 0.2–0.3). DIPS-score median value was 0.4 for CCs and 0.6 for DCs.Conclusion: This high prevalence of CDI codispensings enforces the need for further risk-prevention actions regarding drug-drug interactions (DDIs), especially for arrhythmogenic or anti-arrhythmic drugs. In this perspective, the DIPS-score we develop could ease identifying the interactions that are poorly considered by clinicians/pharmacists and targeting interventions

Assignment of PolyProline II Conformation and Analysis of Sequence – Structure Relationship

International audienceBACKGROUND: Secondary structures are elements of great importance in structural biology, biochemistry and bioinformatics. They are broadly composed of two repetitive structures namely α-helices and β-sheets, apart from turns, and the rest is associated to coil. These repetitive secondary structures have specific and conserved biophysical and geometric properties. PolyProline II (PPII) helix is yet another interesting repetitive structure which is less frequent and not usually associated with stabilizing interactions. Recent studies have shown that PPII frequency is higher than expected, and they could have an important role in protein - protein interactions. METHODOLOGY/PRINCIPAL FINDINGS: A major factor that limits the study of PPII is that its assignment cannot be carried out with the most commonly used secondary structure assignment methods (SSAMs). The purpose of this work is to propose a PPII assignment methodology that can be defined in the frame of DSSP secondary structure assignment. Considering the ambiguity in PPII assignments by different methods, a consensus assignment strategy was utilized. To define the most consensual rule of PPII assignment, three SSAMs that can assign PPII, were compared and analyzed. The assignment rule was defined to have a maximum coverage of all assignments made by these SSAMs. Not many constraints were added to the assignment and only PPII helices of at least 2 residues length are defined. CONCLUSIONS/SIGNIFICANCE: The simple rules designed in this study for characterizing PPII conformation, lead to the assignment of 5% of all amino as PPII. Sequence - structure relationships associated with PPII, defined by the different SSAMs, underline few striking differences. A specific study of amino acid preferences in their N and C-cap regions was carried out as their solvent accessibility and contact patterns. Thus the assignment of PPII can be coupled with DSSP and thus opens a simple way for further analysis in this field

Analyse d'un grand jeu de données en épidémiologie : problématiques et perspectives méthodologiques

The increasing size of datasets is a growing issue in epidemiology. The CoPanFlu-France cohort(1450 subjects), intended to study H1N1 pandemic influenza infection risk as a combination of biolo-gical, environmental, socio-demographic and behavioral factors, and in which hundreds of covariatesare collected for each patient, is a good example. The statistical methods usually employed to exploreassociations have many limits in this context. We compare the contribution of data-driven exploratorymethods, assuming the absence of a priori hypotheses, to hypothesis-driven methods, requiring thedevelopment of preliminary hypotheses.Firstly a data-driven study is presented, assessing the ability to detect influenza infection determi-nants of two data mining methods, the random forests (RF) and the boosted regression trees (BRT), ofthe conventional logistic regression framework (Univariate Followed by Multivariate Logistic Regres-sion - UFMLR) and of the Least Absolute Shrinkage and Selection Operator (LASSO), with penaltyin multivariate logistic regression to achieve a sparse selection of covariates. A simulation approachwas used to estimate the True (TPR) and False (FPR) Positive Rates associated with these methods.Between three and twenty-four determinants of infection were identified, the pre-epidemic antibodytiter being the unique covariate selected with all methods. The mean TPR were the highest for RF(85%) and BRT (80%), followed by the LASSO (up to 78%), while the UFMLR methodology wasinefficient (below 50%). A slight increase of alpha risk (mean FPR up to 9%) was observed for logisticregression-based models, LASSO included, while the mean FPR was 4% for the data-mining methods.Secondly, we propose a hypothesis-driven causal analysis of the infection risk, with a structural-equation model (SEM). We exploited the SEM specificity of modeling latent variables to study verydiverse factors, their relative impact on the infection, as well as their eventual relationships. Only thelatent variables describing host susceptibility (modeled by the pre-epidemic antibody titer) and com-pliance with preventive behaviors were directly associated with infection. The behavioral factors des-cribing risk perception and preventive measures perception positively influenced compliance with pre-ventive behaviors. The intensity (number and duration) of social contacts was not associated with theinfection.This thesis shows the necessity of considering novel statistical approaches for the analysis of largedatasets in epidemiology. Data mining and LASSO are credible alternatives to the tools generally usedto explore associations with a high number of variables. SEM allows the integration of variables des-cribing diverse dimensions and the explicit modeling of their relationships ; these models are thereforeof major interest in a multidisciplinary study as CoPanFlu.L'augmentation de la taille des jeux de données est une problématique croissante en épidémiologie. La cohorte CoPanFlu-France (1450 sujets), proposant une étude du risque d'infection par la grippe H1N1pdm comme une combinaison de facteurs très divers en est un exemple. Les méthodes statistiques usuelles (e.g. les régressions) pour explorer des associations sont limitées dans ce contexte. Nous comparons l'apport de méthodes exploratoires data-driven à celui de méthodes hypothesis-driven.Une première approche data-driven a été utilisée, évaluant la capacité à détecter des facteurs de l'infection de deux méthodes de data mining, les forêts aléatoires et les arbres de régression boostés, de la méthodologie " régressions univariées/régression multivariée" et de la régression logistique LASSO, effectuant une sélection des variables importantes. Une approche par simulation a permis d'évaluer les taux de vrais et de faux positifs de ces méthodes. Nous avons ensuite réalisé une étude causale hypothesis-driven du risque d'infection, avec un modèle d'équations structurelles (SEM) à variables latentes, pour étudier des facteurs très divers, leur impact relatif sur l'infection ainsi que leurs relations éventuelles. Cette thèse montre la nécessité de considérer de nouvelles approches statistiques pour l'analyse des grands jeux de données en épidémiologie. Le data mining et le LASSO sont des alternatives crédibles aux outils conventionnels pour la recherche d'associations. Les SEM permettent l'intégration de variables décrivant différentes dimensions et la modélisation explicite de leurs relations, et sont dès lors d'un intérêt majeur dans une étude multidisciplinaire comme CoPanFlu

Analysis of a large dataset in epidemiology : issues and methodological perspectives

L'augmentation de la taille des jeux de données est une problématique croissante en épidémiologie. La cohorte CoPanFlu-France (1450 sujets), proposant une étude du risque d'infection par la grippe H1N1pdm comme une combinaison de facteurs très divers en est un exemple. Les méthodes statistiques usuelles (e.g. les régressions) pour explorer des associations sont limitées dans ce contexte. Nous comparons l'apport de méthodes exploratoires data-driven à celui de méthodes hypothesis-driven.Une première approche data-driven a été utilisée, évaluant la capacité à détecter des facteurs de l'infection de deux méthodes de data mining, les forêts aléatoires et les arbres de régression boostés, de la méthodologie " régressions univariées/régression multivariée" et de la régression logistique LASSO, effectuant une sélection des variables importantes. Une approche par simulation a permis d'évaluer les taux de vrais et de faux positifs de ces méthodes. Nous avons ensuite réalisé une étude causale hypothesis-driven du risque d'infection, avec un modèle d'équations structurelles (SEM) à variables latentes, pour étudier des facteurs très divers, leur impact relatif sur l'infection ainsi que leurs relations éventuelles. Cette thèse montre la nécessité de considérer de nouvelles approches statistiques pour l'analyse des grands jeux de données en épidémiologie. Le data mining et le LASSO sont des alternatives crédibles aux outils conventionnels pour la recherche d'associations. Les SEM permettent l'intégration de variables décrivant différentes dimensions et la modélisation explicite de leurs relations, et sont dès lors d'un intérêt majeur dans une étude multidisciplinaire comme CoPanFlu.The increasing size of datasets is a growing issue in epidemiology. The CoPanFlu-France cohort(1450 subjects), intended to study H1N1 pandemic influenza infection risk as a combination of biolo-gical, environmental, socio-demographic and behavioral factors, and in which hundreds of covariatesare collected for each patient, is a good example. The statistical methods usually employed to exploreassociations have many limits in this context. We compare the contribution of data-driven exploratorymethods, assuming the absence of a priori hypotheses, to hypothesis-driven methods, requiring thedevelopment of preliminary hypotheses.Firstly a data-driven study is presented, assessing the ability to detect influenza infection determi-nants of two data mining methods, the random forests (RF) and the boosted regression trees (BRT), ofthe conventional logistic regression framework (Univariate Followed by Multivariate Logistic Regres-sion - UFMLR) and of the Least Absolute Shrinkage and Selection Operator (LASSO), with penaltyin multivariate logistic regression to achieve a sparse selection of covariates. A simulation approachwas used to estimate the True (TPR) and False (FPR) Positive Rates associated with these methods.Between three and twenty-four determinants of infection were identified, the pre-epidemic antibodytiter being the unique covariate selected with all methods. The mean TPR were the highest for RF(85%) and BRT (80%), followed by the LASSO (up to 78%), while the UFMLR methodology wasinefficient (below 50%). A slight increase of alpha risk (mean FPR up to 9%) was observed for logisticregression-based models, LASSO included, while the mean FPR was 4% for the data-mining methods.Secondly, we propose a hypothesis-driven causal analysis of the infection risk, with a structural-equation model (SEM). We exploited the SEM specificity of modeling latent variables to study verydiverse factors, their relative impact on the infection, as well as their eventual relationships. Only thelatent variables describing host susceptibility (modeled by the pre-epidemic antibody titer) and com-pliance with preventive behaviors were directly associated with infection. The behavioral factors des-cribing risk perception and preventive measures perception positively influenced compliance with pre-ventive behaviors. The intensity (number and duration) of social contacts was not associated with theinfection.This thesis shows the necessity of considering novel statistical approaches for the analysis of largedatasets in epidemiology. Data mining and LASSO are credible alternatives to the tools generally usedto explore associations with a high number of variables. SEM allows the integration of variables des-cribing diverse dimensions and the explicit modeling of their relationships ; these models are thereforeof major interest in a multidisciplinary study as CoPanFlu

Contribution of Genome-Wide Association Studies to Scientific Research: A Bibliometric Survey of the Citation Impacts of GWAS and Candidate Gene Studies Published during the Same Period and in the Same Journals

<div><p>In genetic epidemiology, genome-wide association studies (GWAS) are used to rapidly scan a large set of genetic variants and thus to identify associations with a particular trait or disease. The GWAS philosophy is different to that of conventional candidate-gene-based approaches, which directly test the effects of genetic variants of potentially contributory genes in an association study. One controversial question is whether GWAS provide relevant scientific outcomes by comparison with candidate-gene studies. We thus performed a bibliometric study using two citation metrics to assess whether the GWAS have contributed a capital gain in knowledge discovery by comparison with candidate-gene approaches. We selected GWAS published between 2005 and 2009 and matched them with candidate-gene studies on the same topic and published in the same period of time. We observed that the GWAS papers have received, on average, 30±55 citations more than the candidate gene papers, 1 year after their publication date, and 39±58 citations more 2 years after their publication date. The GWAS papers were, on average, 2.8±2.4 and 2.9±2.4 times more cited than expected, 1 and 2 years after their publication date; whereas the candidate gene papers were 1.5±1.2 and 1.5±1.4 times more cited than expected. While the evaluation of the contribution to scientific research through citation metrics may be challenged, it cannot be denied that GWAS are great hypothesis generators, and are a powerful complement to candidate gene studies.</p> </div

Boxplots of the citation count and of the crown index.

<p>Distributions of the citation count and of the crown index are depicted on panel A and panel B, respectively, 1 year (Year 1) and 2 years (Year 2) after the publication dates. Blue boxes refer to GWAS and orange boxes to candidate-gene studies. The boxplots depict five statistics: the sample minimum, the lower quartile, the median, the upper quartile, and the sample maximum.</p

Study flow diagram.

<p>Study flow diagram.</p

Summary statistics of the citation metrics of the “GWAS” and “candidate-gene study” papers.

<p>Mean±sd.</p

Ann Fam Med

We evaluated the impact of the implementation of a requirement that zolpidem prescriptions be obtained via secured forms (April 2017) on zolpidem and other hypnotics use in France. We conducted a time-series analysis on data from the French national health care system, from January 1, 2015 to January 3, 2018, for all reimbursed hypnotics. An important and immediate decrease in zolpidem use (−161,873 defined daily doses [DDD]/month; −215,425 to −108,323) was evidenced, with a concomitant raise in zopiclone use (+64,871; +26,925 to +102,817). These findings suggest that the change in zolpidem prescribing policies was effective, but has resulted in a shift from zolpidem to zopiclone. Further interventions are needed to decrease hypnotics’ overuse in France