Historically, Swedish health care has generally been population-based, since it is mainly funded by taxes and private health-care providers have been scarce.
Since January 1, 1947, all inhabitants of Sweden have been assigned a 10-digit national registration number, which is a unique personal identifier. Since it is used in most registries it provides an opportunity to unambiguously link information from different sources.
Sweha-Reg is a population-based census of HAE in Sweden, established to achieve a baseline epidemiological description, and to provide a framework to study quality of life, and to further characterize the disease. The registry attempts to capture data on all individuals with diagnosed or suspected HAE type I and II in Sweden by using multiple recruitment channels, and to record enough clinical information, including biochemical diagnostic markers to assure a case definition with high sensitivity and specificity, accurately excluding those with non-hereditary angioedema. Sweha-Reg is a nation-wide registry that serves the entirety of Sweden, which is estimated to have a population of 9.1 million people.
Cases are prospectively followed over time for disease course, efficacy, safety and outcome of different treatments, for co-morbidities and quality of life. Furthermore, we have used the Swedish Population Registry to identify a set of control subjects matched to the first 100 adult cases (> 18 yrs old) enrolled during early 2007. The controls are selected from the Stockholm County as a stratified random sample, taking age and sex into consideration. Three control subjects are selected per adult case.
Additionally, biological specimens, including serum, plasma and whole-blood are collected for studying the biochemical, immunological and genetical background of the patients. Data obtained from this biobank (Sweha-Bank) can be useful for describing common polymorphisms in Sweden, establishing a basis for biobank-based post-genome studies, integrating phenotype and genotype data. The stored biological specimens are useful also for other pertinent research.
Case definition and recruitment
In brief, the cases comprise individuals at any age with a diagnosis and/or treatment of HAE type I and II, and who live in Sweden. Diagnosis and classification of HAE is made using established criteria and terminology . Only subjects with a convincing clinically and laboratory diagnosis of HAE are included. In situations in which the diagnosis is uncertain, additional previous medical records are requested to determine an accurate diagnosis.
Patients are recruited nationwide. In order to enroll as many cases as possible, multiple recruitment sources are used, such as physicians and clinics specialized in HAE, hospital discharge databases and periodic correspondence with all medical directors of dermatologic, pediatric, allergologic and internal medicine clinics at Swedish hospitals, as well as the immunologic HAE-laboratories in Lund and Uppsala. Additional cases are recruited through advertisements, campaigns on the website and magazine of the Primary Immunodeficiency Organization (PIO) in Sweden.
Once a potential case is identified, informed consent to approach the patient to join the registry and to release medical information is obtained via the treating physician. This process is most straightforward for patients treated by the registry investigators. To enlist cases handled by other physicians, the registry sends the survey information to the treating physician to pass on to patients. Thus, all patients are contacted through their treating physicians. Unlike some other population-based registries, such as The Swedish Cancer Registry, there is no requirement on the part of hospitals or treating physicians to report HAE cases. Moreover, the Sweha-Reg requires consent for patient participation. These issues add to the challenge of completeness of case-participation. In order to optimize participation, there is no absolute requirement for patients to provide blood samples. In addition self referral is possible through contacting the survey's telephone hotline or e-mail service. By means of these services patients and physicians are also able to receive advice and counsel with regard to any question related to the Sweha-project and/or HAE in general.
Moreover, close collaboration within the Sweha study group, involving HAE-leading physicians in Sweden, plays a crucial role in the recruitment process. This study group also disseminates information on Sweha-Reg and fosters a constructive collaboration between investigators and treating physicians.
Participation involves answering a mailed questionnaire, followed by attending a standardized telephone interview by a physician, and for those who live near one of the survey's qualified laboratory centers, to provide blood samples for laboratory analyses and for storage in Sweha-Bank.
Written informed consent is obtained from the study participants or their parents (for individuals aged < 18 yrs) prior to the telephone interview. Parental interviews are conducted for patients with an age less than 12 yrs of age. Control individuals answer an identical questionnaire as cases, but do not attend the telephone interview.
Blood samples, a total amount of approximately 40 ml (less in young children), are collected at one of the qualified laboratories, assuring the appropriate systems for biological specimen collection, processing and storage. The labs are located in 4 different areas in Sweden (Lund, Jönköping, Göteborg and Stockholm). The Sweha-survey, including the registry and biobank, is approved by the ethics committee of the Karolinska Institutet, Sweden. The survey is performed according to the Declaration of Helsinki Principles.
Registry participants are mailed a questionnaire with up to 3 reminder follow-up letters if it is not returned. For patient's convenience the questionnaire is in paper format. However Sweha-Reg, consisting of data from the questionnaire and the telephone interview, exists in digital format which could easily be adapted as a web-based register, if such a design is found beneficial. Once the questionnaire is returned it is transferred to the digital format.
Information on demographic data, social, educational, economical, and health status, quality of life, family history of HAE, co-morbidities, potentially predisposing trigger factors surrounding onset and new attacks, previous and ongoing medication and attacks characterization and severity of symptoms are obtained by answering 38 questions.
The telephone interview is structured to capture the natural course of HAE and the efficacy, safety and outcome of different treatments in patients and the extent of usage of health and social services. Furthermore, information about potential precipitating factors and co-morbidities, provided through the mailed questionnaire, is verified and missing or unclear data are completed. Additional information includes family history of HAE. Besides, the telephone interview provides patients with the opportunity to raise questions related to their disease and its treatment.
Confidentiality of Patient Records
Due to patient confidentiality requirements, all subjects receive a unique study-identification code, which anonymizes the records. Only the registry's main investigators (CFW and LM) know the code and are able to link an individual report to an individual patient. Access to data will initially be restricted to the Sweha study group physicians participating in the concerted action but will eventually be open, on request, to any HAE-treating physician. Also, clinicians contributing to the register will have access to the data of their own patients, and will obtain (by request) feedback such as individual or group reports.
The survey board, consisting of the authors of the present manuscript, manages the anonymized database and may access aggregated reports but not individual data sets. No single member of the board can use or publish the data without the consent of the board and the contributors as a whole.
Cross-linking of registries
One of the Sweha-Reg's objectives is to be able to share and compare data with other similar HAE-registries in other nations. In this context, some of the questions are designed to be compatible with data in the European HAE registry . Moreover, by using the unique Swedish personal identification number, we are able to crosslink Sweha-Reg to other population-based registries, such as The Swedish Cancer Registry, Hospital Discharge Patient Registry, National database for Acute Myocardial Infarction and Cause-of-death Register.