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The incubation period is of paramount importance in infectious disease epidemiology as it informs about the transmission potential of a pathogenic organism and helps to plan public health strategies to keep an epidemic outbreak under control. Estimation of the incubation period distribution from reported exposure times and symptom onset times is challenging as the underlying data is coarse. We develop a new Bayesian methodology using Laplacian-P-splines that provides a semi-parametric estimation of the incubation density based on a Langevinized Gibbs sampler. A finite mixture density smoother informs a set of parametric distributions via moment matching and an information criterion arbitrates between competing candidates. Algorithms underlying our method find a natural nest within the EpiLPS package, which has been extended to cover estimation of incubation times. Various simulation scenarios accounting for different levels of data coarseness are considered with encouraging results. Applications to real data on COVID-19, MERS and Mpox reveal results that are in alignment with what has been obtained in recent studies. The proposed flexible approach is an interesting alternative to classic Bayesian parametric methods for estimation of the incubation distribution., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

The use of social contact rates is widespread in infectious disease modeling since it has been shown that they are key driving forces of important epidemiological parameters. Quantification of contact patterns is crucial to parameterize dynamic transmission models and to provide insights on the (basic) reproduction number. Information on social interactions can be obtained from population-based contact surveys, such as the European Commission project POLYMOD. Estimation of age-specific contact rates from these studies is often done using a piecewise constant approach or bivariate smoothing techniques. For the latter, typically, smoothness is introduced in the dimensions of the respondent's and contact's age (i.e., the rows and columns of the social contact matrix). We propose a smoothing constrained approach-taking into account the reciprocal nature of contacts-introducing smoothness over the diagonal (including all subdiagonals) of the social contact matrix. This modeling approach is justified assuming that when people age their contact behavior changes smoothly. We call this smoothing from a cohort perspective. Two approaches that allow for smoothing over social contact matrix diagonals are proposed, namely (i) reordering of the diagonal components of the contact matrix and (ii) reordering of the penalty matrix ensuring smoothness over the contact matrix diagonals. Parameter estimation is done in the likelihood framework by using constrained penalized iterative reweighted least squares. A simulation study underlines the benefits of cohort-based smoothing. Finally, the proposed methods are illustrated on the Belgian POLYMOD data of 2006. Code to reproduce the results of the article can be downloaded on this GitHub repository https://github.com/oswaldogressani/Cohort_smoothing., (© The Author 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Corona Virus Disease (COVID-19) pandemic has increased mortality in countries worldwide. To evaluate the impact of the pandemic on mortality, the use of excess mortality rather than reported COVID-19 deaths has been suggested. Excess mortality, however, requires estimation of mortality under nonpandemic conditions. Although many methods exist to forecast mortality, they are either complex to apply, require many sources of information, ignore serial correlation, and/or are influenced by historical excess mortality. We propose a linear mixed model that is easy to apply, requires only historical mortality data, allows for serial correlation, and down-weighs the influence of historical excess mortality. Appropriateness of the linear mixed model is evaluated with fit statistics and forecasting accuracy measures for Belgium and the Netherlands. Unlike the commonly used 5-year weekly average, the linear mixed model is forecasting the year-specific mortality, and as a result improves the estimation of excess mortality for Belgium and the Netherlands., (© 2021 The International Biometric Society.)

A decade ago, a statistics-based method was introduced to count the number of atoms from annular dark-field scanning transmission electron microscopy (ADF STEM) images. In the past years, this method was successfully applied to nanocrystals of arbitrary shape, size, and composition (and its high accuracy and precision has been demonstrated). However, the counting results obtained from this statistical framework are so far presented without a visualization of the actual uncertainty about this estimate. In this paper, we present three approaches that can be used to represent counting results together with their statistical error, and discuss which approach is most suited for further use based on simulations and an experimental ADF STEM image.

In this tutorial, statistical methods for studying outpatient use of antibiotics in Europe are described, using data provided by IMS Health. The methods are applied to two related research questions, namely the assessment of changes in the relative volume of use of different antibiotic subclasses over time and changes in the absolute volume of antibiotic use.

Background: Data on 13 years (1997-2009) of outpatient penicillin use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project and analysed in detail., Methods: For the period 1997-2009, data on outpatient use of systemic penicillins aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011) and expressed in DDD per 1000 inhabitants per day (DID). For detailed analysis of trends over time, seasonal variation and composition of outpatient penicillin use in 33 European countries, we distinguished between narrow-spectrum penicillins (NSP), broad-spectrum penicillins (BSP), penicillinase-resistant penicillins (PRP) and combinations with β-lactamase inhibitors (COP)., Results: Total outpatient penicillin (ATC group J01C) use in 2009 varied by a factor of 3.8 between the countries with the highest (16.08 DID in France) and lowest (4.23 DID in the Russian Federation) use. COP represented 45.8%, BSP 40.7%, NSP 10.8% and PRP 2.6% of total European outpatient penicillin use. Total outpatient penicillin use significantly increased over time by 1.53 (SD 0.71) DID between 1997 and 2009. COP (mainly co-amoxiclav) increased by 2.17 (SD 0.40) DID, which was the result of its absolute increase as well as the observed shift from NSP and BSP towards COP. This increase exceeded 10% in 20 countries, where it coincided with a similar decrease in either BSP (15 countries) or NSP (5 countries)., Conclusions: Penicillins represented the most widely used antibiotic subgroup in all 33 participating countries, albeit with considerable variation in their use patterns. For Europe, a continuous increase in overall penicillin use and of COP use was observed during the period 1997-2009.

Background: Data on more than a decade of outpatient quinolone use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC)., Methods: For the period 1997-2009, data on outpatient use of systemic quinolones aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011), and expressed in DDD and packages per 1000 inhabitants per day (DID and PID, respectively). Using a classification based on pharmacokinetic and in vitro potency profiles, quinolone use was analysed with regard to trends over time, seasonal variation and composition., Results: Total outpatient quinolone use in 2009 varied by a factor of 7.5 between the country with the highest (Italy, 3.61 DID) and the country with the lowest (the UK, 0.48 DID) quinolone use. The second-generation quinolones accounted for >50% of quinolone use (mainly ciprofloxacin), except for Croatia, where first-generation quinolones (mainly norfloxacin) were mostly used. A significant increase in outpatient quinolone use was found for Europe, as well as a large seasonal variation, which increased significantly over time from 1997 to 2009. Relative use of third-generation quinolones significantly increased over time with respect to the use of second-generation quinolones, while the relative use of both significantly increased with respect to the first-generation quinolones. Levofloxacin and moxifloxacin (respiratory quinolones) represented >10% of quinolone outpatient use in 17 countries, with extreme seasonal variation in all countries., Conclusions: There was a substantial increase and change in the pattern of quinolone use between 1997 and 2009, a period during which quinolones that are effective for the treatment of respiratory tract infections were introduced. These quinolones are not the first-line antibiotics for this indication and their use should generally be limited, and quinolones should ideally show no substantial seasonal variation in terms of their use.

Objectives: To describe total outpatient systemic antibiotic use in Europe from 1997 to 2009 and to analyse statistically trends of total use and composition of use over time., Methods: For the period 1997-2009, data on outpatient use of systemic antibiotics aggregated at the level of the active substance were collected and expressed in defined daily doses (WHO, version 2011) and packages per 1000 inhabitants per day (DID and PID, respectively). Outpatient antibiotic (ATC J01) use in DID in the 33 European countries able to deliver valid data was analysed using longitudinal and compositional data analyses., Results: Total outpatient antibiotic use in 2009 varied by a factor of 3.8 between the countries with the highest (38.6 DID in Greece) and lowest (10.2 DID in Romania) use. For Europe, a significant increase was found in total outpatient antibiotic use, as well as a significant seasonal variation, which decreased over time from 1997 to 2009. Relative use of penicillins and quinolones significantly increased over time with respect to sulphonamides and trimethoprim, and relative use of quinolones increased with respect to macrolide/lincosamide/streptogramin as well. More detailed analyses of these major antibiotic subgroups will be described in separate papers., Conclusions: Outpatient antibiotic use in Europe measured as DID has increased since 1997, whereas seasonal variation has decreased over time. European Surveillance of Antimicrobial Consumption (ESAC) data on outpatient antibiotic use in Europe enable countries to audit their antibiotic use. Complemented by longitudinal and compositional data analyses, these data provide a tool for assessing public health strategies aimed at reducing antibiotic resistance and optimizing antibiotic prescribing.

Background: Data on more than a decade of outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 33 countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC), using the WHO Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) methodology., Methods: For the period 1997-2009, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2011) per 1000 inhabitants per day (DID). Using a classification based on mean plasma elimination half-life, macrolide use was analysed for trends over time, seasonal variation and composition., Results: Total outpatient MLS use in 2009 varied by a factor of 18 between the countries with highest (11.5 DID in Greece) and lowest (0.6 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediate- and long-acting macrolides were the most commonly used agents in 2, 25 and 5 countries, respectively (mainly erythromycin, clarithromycin and azithromycin, respectively). In Sweden, mainly lincosamides (clindamycin) were used. Lincosamide use was observed in all countries, while substantial use of a streptogramin was only seen in France (pristinamycin). For Europe, a significant increase in outpatient MLS use was found, as well as a significant seasonal variation, which increased over time from 1997 to 2009. Relative use of long-acting macrolides and lincosamides significantly increased over time with respect to intermediate-acting macrolides, and relative use of the latter increased with respect to short-acting macrolides., Conclusions: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this subgroup of antibiotics is still prescribed inappropriately in many countries.

Background: Data on more than a decade of outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe were collected from 33 countries as part of the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC)., Methods: For the period 1997-2009, data on outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials aggregated at the level of the active substance were collected and expressed in defined daily doses (DDD; WHO, version 2011) per 1000 inhabitants per day (DID). Using the Anatomical Therapeutic Chemical (ATC) classification, trends in the use of tetracyclines (J01A), sulphonamides and trimethoprim (J01E) and other antibacterials (J01X) over time, seasonal variation and composition of use were analysed., Results: In 2009, the variations in outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials between countries, and also in the composition of use over time, were huge. For tetracyclines a significant and for sulphonamides and trimethoprim a non-significant decrease in use was observed between 1997 and 2009 in Europe. The seasonal variation in their use significantly decreased over time. For the other antibacterials, no significant changes in the volume of use or its seasonal variation were seen., Conclusions: As for all other major antibiotic subgroups, a striking variation in use and composition of use between countries in Europe was observed for outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials. In combination with the decreasing use, especially of recommended substances, this represents an opportunity not only to reduce antibiotic use but also to improve its quality.

Background: Data on 13 years of outpatient cephalosporin use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC), and analysed in detail., Methods: For the period 1997-2009, data on outpatient use of systemic cephalosporins aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011) and expressed in DDD per 1000 inhabitants per day (DID). For detailed analysis of trends over time, seasonal variation and composition of outpatient cephalosporin use in 33 European countries, we distinguished between first-generation (J01DB), second-generation (J01DC), third-generation (J01DD) and fourth-generation (J01DE) cephalosporins., Results: Total outpatient cephalosporin use in 2009 varied from 8.7 DID in Greece to 0.03 DID in Denmark. In general, use was higher in Southern and Eastern European countries than in Northern European countries. Total outpatient cephalosporin use increased over time by 0.364 (SD 0.473) DID between 1997 and 2009. Cephalosporin use increased for half of the countries. Low-consuming Northern European countries and the UK further decreased their use. Second-generation cephalosporins increased by >20% in seven countries (mainly cefuroxime), coinciding with a decrease in first-generation cephalosporins. Substantial parenteral use of third-generation substances (mainly ceftriaxone) was observed in France, Italy and the Russian Federation., Conclusions: Since 1997, the use of the older (narrow-spectrum) cephalosporins decreased in favour of the newer (i.e. broad-spectrum) cephalosporins in most countries. Extreme variations between European countries in cephalosporin use over time suggest that they are to a large extent inappropriately used.

Background: To determine the denominator or the 'population at risk' is a problem which has long been encountered in general practice-based epidemiological research. It is important for calculating epidemiological figures., Objectives: The aim of this article is to demonstrate how in the absence of a patient list, a reliable denominator can be calculated, starting from the number of patients who contacted their GP in the period of one year. Therefore a brief overview will be given from known approaches, then the new approach will be illustrated on a database named Intego, with data from 43 general practices in Belgium., Methods: The Intego database contains information about patient contacts, diagnoses, laboratory results and drug prescriptions, extracted from the participants' structured electronic medical record system. The number of patients who contacted the practice in a year can be calculated from the Intego data. On the other hand, the percentage of the population that consults a GP during a particular period was obtained from the reimbursement claims data available from the sickness funds. By combining these two datasets, stratified by age, gender and district, a correction factor was calculated. An estimate of the real size of the Intego practice populations was obtained by extrapolating the yearly contact group by this factor., Results: In 2003 according the Intego-register, 64,161 patients contacted their family practice and this correlated with an estimated practice population of 80,094 patients. The absence of the socio-economic status in the estimation is irrelevant in our model of estimating the practice population., Conclusion: The availability of a denominator in general practice-based research is essential to calculate epidemiological figures. This method using a correction factor makes it possible to calculate a reliable practice population. A similar approach will probably also be applicable in other European countries.