Study Design and Data Source
The study was conducted in a retrospective cohort design. Source of data was the German Pharmacoepidemiological Research Database (GePaRD) which has been described elsewhere [20]. The GePaRD is a database of more than 14 million insurees of all ages (approximately 17% of the German population) and covers all geographical regions of Germany. The database consists of records of four large statutory health insurance companies (SHI). The data is not publicly available but other institutions could apply for the data of the respecitve SHIs and years. Statutory health insurance is mandatory in Germany for all persons below a certain income threshold. Above this threshold persons are permitted to choose private insurance companies instead. However, given the relatively high threshold and the fact, that some persons with a high income still elect statutory health insurance, about 90% of the German population remain in statutory health insurance. When this project started, the database contained data for the years 2004-2006 for the different insurance companies. Since then, the database has been extended to include data from more recent years.
The GePaRD contains demographic information, information on hospital admissions, ambulatory physician visits and prescriptions. The hospital data contains information on admission and discharge dates and on diagnostic and therapeutic procedures carried out in hospital with the respective date. Ambulatory physician visit claims data include ambulatory treatments, procedures, and diagnoses. Since ambulatory physician visits are reimbursed quarterly, ambulatory diagnoses can only be allocated to a quarter of the year. All diagnoses, inpatient and ambulatory diagnoses, are coded according to the German Modification of the International Classification of Diseases, 10th Revision (ICD-10-GM) [21]. Preliminary analyses regarding the age and sex distribution, the number of hospital admissions, and drug use demonstrated that the database is generally representative of information published in official statistics [20]. Since the proportion of the population included in the database varies across German federal states, regional weights are necessary to obtain an estimate representative for the whole of Germany. The utilisation of health insurance data for scientific research is regulated by the Code of Social Law in Germany (SGB X). Approval for the use of the data used in this study was granted by all SHIs that contributed data to the study and the Federal Ministry of Health. A detailed data protection concept was approved by the Federal Ministry of Health which precludes the use of data outside of the Bremen Institute for Prevention Research and Social Medicine. Informed consent was not required by law, since the study was based on pseudonymous data.
Definitions
Case identification
Diagnoses of AGW were ascertained by using the ICD-10-GM (version valid in 2006) code A63.0, a specific code for anogenital (venereal) warts. In order to estimate incidence rates, we only considered newly diagnosed cases for this analysis. Each insuree had to have an AGW free period of 12 months preceding the diagnosis. Cases were only considered from 2005 onwards, since the year 2004 served to exclude prevalent cases of AGW. In case of several diagnoses of AGW in the same patient in different quarters, these were counted as a single episode of AGW when the time interval between two diagnoses of AGW was less than 12 months. Since ambulatory data are only available by quarter, the date of the ambulatory diagnosis was set to be at the middle of each quarter. Some insurees could have had more than one episode, thus persons could be counted as incident cases more than once.
Cohort entry and exit
Cohort entry was on 1st of January 2005 or on the first date afterwards, when patients had been continuously insured 12 months preceding cohort entry and not had a diagnosis of anogenital warts during this time period. Cohort members had to be between 10 and 79 years of age at cohort entry and remained in the cohort until the first of the following dates: reaching of age 80, the day of the first diagnosis of AGW, end or interruption of insurance, death or end of the study period (31.12.2006).
Regional analysis
To investigate regional differences, we estimated incidence rates by federal state. A specific characteristic of the German federal states is that three major cities (Berlin, Hamburg and Bremen) are federal states themselves, so called city-states. These three city-states present densely populated areas and can serve as a proxy for urban regions. For the purpose of description of regional differences regarding predominantly rural and urban regions on the one side and west-east comparison on the other side, federal states were classified into three groups: city-states, other former West-German federal states, and other former East-German federal states.
Specialty of medical practitioners
For the descriptive analysis of the specialty of the medical practitioner who initially diagnosed AGW, only the first episode for each patient was considered. The specialty of the medical practitioner was only available for doctors not practicing in group practices. In the coding system, general practitioners can not be distinguished from group practices and therefore built a common category. The specialties of medical practitioners included in the analysis were gynaecologists, dermatologists, urologists, general practitioners/group practices, surgeons, and internists. As no exact date, but only the quarter was known for ambulatory diagnoses, it was not possible to establish which medical practitioner diagnosed anogenital warts first in cases where more than one ambulatory diagnosis was made in the same quarter. In these cases, the specialty of the medical practitioner was classified as "not identifiable".
Statistical analysis
Estimation of incidence rates
The crude incidence rate and incidence rates stratified by age, sex and region were calculated for the time period 2005 to 2006. The number of incident cases of the respective stratum was divided by the total person time of the respective stratum, expressed per 100,000 person-years (py). Confidence intervals for incidence rates were obtained from the Poisson distribution [22]. For comparison purposes with incidence rates reported in the literature, incidence rates for the age group 14 to 65 years were calculated.
Incidence estimates were validated by independent programming by a second programmer and all other analyses by independent code review. All statistical analyses were conducted using SAS statistical software version 8.2.
Standardisation of incidence rates
The incidence was stratified by sex, five year age groups and the 16 federal states. An estimate of incidence for Germany was obtained using population weights taking age (14 categories), sex (2 categories) and federal state (16 categories) into account. For each of the resulting 448 strata, population weights were obtained for the German population in 2006 based on data from the German Federal Statistical Office [23]. In order to account for differences in regional age structure, incidence rates for federal states were directly standardised for the German population aged 10 to 79 years in 2006.
Assessment of the specialty of the medical practitioner
For the assessment of the specialty of the medical practitioner who initially diagnosed AGW, only the first diagnosis of AGW during the time in the cohort was considered for each insuree.
Geographical distribution of incidence rates
The graphical presentation of the incidence rates in a geographical map was conducted with ESRI® ArcMap™, version 9.3. The classification of incidence rates for this geographical mapping was performed using natural breaks, where classes are based on natural groupings inherent in the data and not on equal intervals. This grouping method is based on the ArcGIS implementation of the Fisher-Jenks algorithm and minimizes differences between data values within classes and maximises differences between classes [24, 25].