Application of mixed-effects models to study the country-specific outpatient antibiotic use in Europe: a tutorial on longitudinal data analysis

Resistance to antibiotics is a major public health problem and antibiotic use is being increasingly recognized as the main selective pressure driving this resistance. Yearly and quarterly data on outpatient antibiotic use were collected by the European Surveillance of Antimicrobial Consumption (ESAC) project for the period 1997-2009 from 33 and 27 European countries, respectively, and expressed in defined daily doses per 1000 inhabitants per day. Since repeated measures were taken for the countries, correlation has to be taken into account when analysing the data. This paper illustrates the application of mixed-effects models to the study of country-specific outpatient antibiotic use in Europe. Mixed models are useful in a wide variety of disciplines in the biomedical, physical and social sciences. In this application for outpatient antibiotic use, the linear mixed model is extended to a non-linear mixed model, allowing analysis of seasonal variation on top of a global trend, with country-specific effects for global mean use and amplitude, and trends over time in use and in amplitude.