Methods

Background: Rare diseases are a set of disorders that individually affect a small fraction of the population. While each specific disease is rare, when taken collectively, they are estimated to affect approximately 6-8% of the global population. Historically, very little was known about rare diseases in childhood and adolescence due to their low prevalence and the limited attention they received in medical research and clinical studies. This lack of data led to inadequacies in both diagnostic and therapeutic techniques and strategies for the affected children and adolescents. As a result, many of these patients went undiagnosed or received suboptimal or no treatment. 

History: In response to this shortcoming, the GPSU was established in 1992 in Düsseldorf, modelled after the British Paediatric Surveillance Unit. The GPSU operates according to international standards within the International Network of Paediatric Surveillance Units (INOPSU) and is affiliated to the German Society for Paediatrics and Adolescent Medicine. Since 2021, GPSU is housed at the Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI) at University Medical Centre Mainz.

Objectives: GPSU aims to record the frequency and clinical characteristics of rare paediatric diseases, new unknown symptoms, rare complications of common diseases, and the outcomes of rare or novel medical procedures. This information is used to describe the status quo of the epidemiology and the clinical course of the condition, support hypothesis generation for innovative diagnostic, therapeutic, and preventive approaches, and improve the care for affected patients.

Definition of an GPSU survey: A survey is the temporary inclusion of a rare, predefined entity (disease, syndrome, complication, or procedure) into the GPSU surveillance. Typically, these surveys run for one to two years, but can be extended if necessary. Up to 12 surveys on different entities are conducted at the same time; a 13th survey may be added for acute emerging health problems.

Survey requirements: A survey is considered if the condition being studied is rare enough in childhood and adolescence to require a nationwide survey to collect a sufficient number of cases. Only inpatient admissions at paediatric hospitals are included. Regional surveys of more common entities may be considered within GPSU under certain circumstances.

Setting: GPSU seeks participation of all public and private hospitals for paediatric and adolescent medicine in Germany. Currently, about 90% of eligible hospitals participate.

Inclusion and exclusion criteria: Any inpatient admission for the condition of interest at a participating hospital is eligible for inclusion. Disease-specific inclusion and exclusion criteria (e.g., age, gender, diagnosis) are defined for each survey separately.

Design: GPSU operates as a hospital-based clustered cross-sectional surveillance study with monthly follow-up. Data collection is retrospective, with participating hospitals transmitting data to GPSU after discharge. The data are cleaned and coarsened, undergo quality checks, and are then forwarded to the respective survey's study management for analysis.

Data collection: GPSU contacts the participating hospitals on a monthly basis to inquire about newly diagnosed and existing patients with the conditions of interest; if this is not the case, a zero entry is made for the respective conditions. In case of a positive response, a link to a survey-specific web-based questionnaire is sent to the reporting hospital. This questionnaire collects anonymized data on demographics, medical history, diagnostic results, therapies and prognosis.

Advantages: GPSU unique features include validation of reported cases through clinical questionnaires and in-depth clinical characterization of cases. This allows for hypothesis generation on disease causes, pathophysiology, clinical course, and prognosis, and provides more comprehensive information than is currently available through, e.g., billing information from health insurance companies.

Outcomes and statistics: Primary and secondary outcomes are determined by the study directors and depend on the specific condition being surveyed. The primary outcome is commonly the incidence or prevalence of the condition in the German paediatric population; the denominator is determined by the number of children who are currently registered in Germany and who are at risk of developing the disease (e.g., depending on gender and age). Due to incomplete coverage, estimates may be adjusted using inverse probability weighting to obtain population-based estimates. Secondary outcomes may include -depending on the survey- clinical symptoms, comorbidities, results of diagnostic testing, details of the selected therapies, and prognosis.

Reports and publications: The data are evaluated annually by the study directors and published both in the GPSU annual report and in a short form in the journal Monatsschrift Kinderheilkunde. The study directors are also required to publish the results in a peer-reviewed scientific journal as soon as possible.

Privacy and confidentiality: As a fundamental principle, the collected data will not be shared with any persons or institutions not involved in the research process. The data are collected by physicians in hospitals, passed on to the GPSU office, and from there forwarded to the study director at a hospital or public research institution (e.g., Robert Koch Institute). GPSU surveys are based on a centralised web-based reporting portal that capture anonymised data (i.e., without directly identifying information) from hospitals. The data are stored at the GPSU office and then securely transmitted to the respective study director for analysis. Before transmission, identifying details such as the reporting hospital, birth and admission dates, and residential postal code are coarsened or removed to reduce the risk of disclosure. Details can be found the the GPSU data protection guidelines.

Application and role of the study director: Any researcher in Germany with expertise in the respective area can apply to GPSU to conduct a survey. The study director is fully responsible for defining the study objectives, determining the data to collect, conducting the analysis, and publishing the results. Detailed application instructions can be found HERE.

Role of the GPSU office: The GPSU office supports new applicants by providing methodological consulting, IT infrastructure, a portal and a database for data collection, data storage and cleaning, as well as ensuring compliance with data protection regulations, and transferring the collected data upon completion of the survey.

Role of the Scientific Advisory Board: GPSU surveys are guided by a Scientific Advisory Board made up of experts in paediatrics, epidemiology, and public health. Members are appointed by the German Society for Paediatric and Adolescent Medicine. The Board regulates the number and type of surveys, reviews objectives and methods, evaluates suitability of new surveys, and decides on extensions to ongoing surveys. The Advisory Board meets two to three times a year and may consult independent experts as necessary.