A population-based registry as a source of health indicators for rare diseases: the ten-year experience of the Veneto Region’s rare diseases registry

The Italian health-care system is a universal, regionally-based public system. A law defining Italian policy on rare diseases was issued in 2001 [28]. The key elements of this legislation are: the establishment of a list of rare diseases, the identification of regional/inter-regional Centers of expertise for rare diseases responsible for patient diagnosis and follow-up, and the creation of area-based rare disease registries.

The list of rare diseases attached to the Italian Law establishes which patients are entitled to benefits and facilitated access to care. The list contains 331 single diseases or groups of disorders divided into 14 nosological categories, based on the ICD9-CM [see Additional file 1]. For the groups, only a few examples of the relevant diseases are mentioned in the law. As a preliminary step, the medical team developing the registry properly identified all the diseases to consider (for which patients are eligible for benefits) in the light of the medical literature and existing databases. This also involved dealing with synonyms and eponyms. In addition, corresponding codes as used in international classifications (i.e. ICD9-CM, ICD-10, MIM and ORPHA-code) were assigned to each disease. The resulting list is continuously updated as new forms are described and new classifications are adopted. Considering the diseases included in all the groups and the disease sub-types, nearly 3,000 conditions have been identified, although some diseases, or groups of diseases, that qualify as rare are not currently covered by our monitoring system. Excluding rare cancers (which are recorded in the regional cancer registry), the conditions monitored by the rare disease registry represent 58% of all the rare diseases included in the Orphanet list.

In 2002 the Veneto Regional Authority officially identified the Centers dedicated to the diagnosis and treatment of patients with rare diseases. In 2004 a formal collaboration agreement between four neighboring regions and provinces in the north-east of Italy (including the Veneto) led to the identification of a shared inter-regional network of Centers of expertise for specific groups of rare diseases (e.g. rare hematological conditions, rare neurological disorders, etc.); each Center has at least one clinical ward. These Centers were identified officially on the grounds of indicators and criteria established by the Regional Health Authorities signing the collaboration agreement and they are monitored continuously. The Centers of expertise are closely linked to the territorial network of public health services providing primary and specialized care, as well as non-medical services for patients with rare diseases. All health care providers involved in caring for patients with rare diseases use a common information system (IS) to share clinical data and support the delivery of benefits and services to patients. At the same time, the system provides the foundations for an area-based registry recording data on patients with rare diseases.

The system collects a set of patients’ socio-demographic details, such as name, date and place of birth, gender, fiscal code, place of residence and, where applicable, place and time of death. The core element in the information system is the diagnosis of a rare disease included in a list shared by all users and regularly updated, as mentioned earlier. Specific forms have been developed over the years to manage the drug and dietary prescriptions, medical devices and prosthetics provision, and to collect each patient’s medical history. Several technical solutions have been developed to ensure a high-quality data input (with the completion of mandatory fields, data validation by checks on data format and plausibility, dropdown lists, provisional and final data-saving options, etc.). Reported errors or modifications are managed centrally. Double entries are prevented by the system, except when the same patient is diagnosed with two different rare diseases.

To access the system, every user is assigned a personal user name and password. The system assures a high standard of security. It is accessible to users via a standard browser using encrypted log-in sessions, in compliance with the Italian legislation on personal data protection [29].

The system is accessible to: (1) clinicians working at the Centers of expertise who input patients’ data (demographic details, diagnosis, prescribed treatments, clinical data, etc.); (2) health-care providers working in the primary care setting (local public health districts), who can view information they are entitled to see and input patient data that are monitored by the Centers of expertise located outside the Veneto and collaborating regions; (3) pharmacists working in the local health districts and in hospitals who view prescriptions directly and issue medications to patients according to the treatment plan formulated by clinicians at the Centers of expertise; (4) other clinicians working in hospitals and directly involved in the patients’ care.

For the moment, general practitioners do not have access to the system for security reasons (because most GPs do not have direct access to the protected regional intranet system). There are plans to find technical solutions in the near future to enable them to connect to the platform and share information with the clinicians at the Centers of expertise in charge of their patients.

All users received training before the system was implemented and updates when new modules were added to the core system. A help line is managed by trained registry personnel and can be contacted to deal with any questions.

Currently, more than 3,484 health-care professionals access the system (1,224 in the Veneto Region, and 2,260 in the other regions where the system is used); those in the Veneto Region include 508 clinicians working at the Centers of expertise, 450 users at the local public health districts, and 233 pharmacists.

In practical terms, a patient is referred to a given Center of the network for a complete assessment (which is free of charge when a rare disease is suspected). If a rare disease is diagnosed, this implicitly involves the clinician at the Center issuing a certificate and, at the same time, the local public health authority of the patient’s place of residence issuing an exemption document. Patients can thus receive the benefits to which they are legally entitled, including specific drugs or medical devices indicated in the treatment plan drawn up at the Center of expertise. In this way, the case is registered in the information system, thus providing the foundations for an area-based registry of patients with rare diseases.

The population monitored includes all residents in the Veneto Region, i.e. a population of 4,853,657 as at 2012 (source: Italian National Institute of Statistics).

Eligible cases are all patients diagnosed with one of the rare diseases on the list in the Italian law (see Additional file 1) and registered in the information system from May 1, 2002 to December 31, 2012.

Cases are identified using two possible alternative sources of input data, i.e. the clinicians working at the Centers of expertise in the Veneto and the other regions sharing the same IS, or health professionals working at the local public health districts who input data on patients diagnosed and followed up by Centers of expertise outside the inter-regional area being monitored. This ensures a good coverage of the Veneto’s resident population.

To ensure that almost all patients diagnosed with one of the monitored diseases are enrolled in the registry, cross-referencing with other regional data sources is done at regular intervals. These other sources include the registry of hospital discharge records, the birth registry, the records of outpatient rehabilitation services, and the death registry.

The following indicators were calculated with a 95% confidence interval from registry data, by age group (0–12 months; 1–14 years, 15–17 years; 18–64 years; over 65 years old) and by nosological group: prevalence, incidence, mortality rate and fatality rate. Here we report the results for the interval between 1 May 2002 and 31 December 2012, estimating the point prevalence as at 31 December 2012.

To calculate the years of life lost (YLLs) we considered life expectancies by age and gender based on life tables by age and gender referring to the Veneto population (source: Italian National Institute of Statistics, year 2010).

Our statistical analysis was performed using the SAS package, rel. 9.1 (SAS Institute Inc., Cary, NC, USA).

Although this descriptive population-based study provides insight into the epidemiology of a sizable group of rare diseases being monitored by a unique web-based population registry, it has some limitations that need to be mentioned. First, the data presented here could underestimate the phenomenon because the registry may not have enrolled all the individuals living in the area monitored. This could be the case of patients with a rare disease that has yet to be diagnosed (diagnostic delays are known to be common for these rare conditions) [53, 54], or patients with severe forms of disease who were not registered due to early mortality. Elderly cases may have been overlooked because their shorter life expectancy and risk of death from other diseases would make them less likely to be referred to Centers of expertise. Having said as much, we can assume that our figures might be only slightly underestimated because the registration system has been in use since 2002, because patient enrolment is linked with exemption from health care costs, and specialized diagnostic facilities are only available at Centers of expertise - all aspects that facilitate a more comprehensive patient capture. The use of multiple sources to identify cases (Centers of expertise, local public health authorities and pharmaceutical services) also helps to assure a good coverage of the population.

Another limitation may relate to the contention that clearly-defined diagnostic criteria are not available for all the rare diseases monitored. We can assume, however, that the diagnoses registered in our system are highly accurate because they are established by clinicians at Centers of expertise for rare diseases, identified on the strength of highly-standardized criteria, and routinely audited by the Regional Health Authority. Although patient registration is linked to the issue of an exemption, the quality of the clinical data collected is higher than in an administrative database [15]. Furthermore, the level of diagnostic detail adopted by the Veneto Regional registry is also higher than in the list contained in the Italian law in order to identify patients’ diagnoses as specifically as possible because the information system on which the registry is based was designed to enable clinicians at the Centers of expertise to prescribe drugs and devices on-line, draw up health care plans, and monitor patients’ major clinical events. Linking the registration process with the care dimension guarantees a good-quality data collection and its maintenance over time.

An additional limitation of this study warrants specific consideration. The list of rare diseases monitored by the registry described here is not as exhaustive as the Orphanet one, for instance [55]. This limitation will be partially overcome in future when the Italian Government is expected to add another 109 single diseases or groups of diseases to its original list. For the time being, specific groups of diseases, such as infectious diseases, respiratory disorders, renal diseases, rheumatological diseases and rare tumors, are particularly under-represented. Some diseases (or groups of diseases), including cystic fibrosis and rare tumors, are monitored in Italy and many other European countries by dedicated registries that often have a long history of data collection. Leaving rare cancers aside, the list of rare diseases in the various groups monitored by the registry described in the present work cover the 58% of all those on the Orphanet list so, to obtain a global estimate of the burden of rare diseases, we considered prevalence data from multiple sources and referring to groups particularly under-represented in the Italian law (i.e. diseases of the respiratory system, infectious diseases, renal diseases and rheumatological diseases). The list of rare diseases for which prevalence estimates are available and updated regularly by Orphanet was therefore used to estimate the overall prevalence of rare diseases not currently monitored by our registry [50]. The prevalence of the vast majority of the unmonitored entities is unknown or extremely low because these conditions are so rare that they have been described in just a few individuals or families worldwide (Figure 3), and this means that increasing the number of diseases being monitored would not necessarily coincide with a parallel increase in the number of cases being registered. After comparing our own list with the Orphanet list, the overall estimated prevalence of all the diseases not currently monitored by our registry is 3.3/1,000 population, which rises to a maximum of 19.5/1,000, if we include rare tumors. However, a salami-slicing effect can be seen for these conditions, that raises the number of entities qualifying as rare diseases, starting from common phenotypic conditions [56]. It can also be argued that incidence is more appropriate than prevalence as an indicator for estimating the burden of cancer at population level [57]. This is because prevalent cancer cases form a very heterogeneous group that – by definition –includes all individuals who have ever been diagnosed with cancer at any time in their life [58], so this group can include people still receiving therapy as well as disease-free survivors, whereas the prevalent cases of other rare diseases are usually individuals living with long-standing chronic conditions.

Despite the above-mentioned limitations, we consider the data presented here of some value because they stem from a good-quality, fully-computerized population-based registry. The monitoring system described here not only provides epidemiological figures for a sizable group of rare diseases that are useful for estimating the magnitude of the problem at population level, it also enables us to establish the relative contribution of different nosological entities to the global burden of rare diseases.

Among others, four elements are fundamental to the successful implementation of this type of registry: the use of a shared web-based system; the feasibility of a modular development of the infrastructure supporting the registry; the "multi-data use" principle; and the registry’s development within the framework of broader health policies addressed to patients with rare diseases.

First, the use of a web-based system simplifies the data collection process and offers economies of scale. The use of a shared infrastructure can promote data collection on ultra-rare diseases, or conditions for which no treatment is currently available, both situations in which a dedicated registry would be difficult to establish and maintain [59]. As demonstrated by the French experience too, involving health professionals from different backgrounds sharing the same information system promotes a multidisciplinary approach to patient care, which is always a challenge, but especially when dealing with complex rare conditions [60, 61].

The second element (the modular approach used to develop the information system) ensured a high level of participation in the data collection process, enabling an increasing number of health professionals working in different care network settings to become involved, and facilitating the adoption of the same information system by other Italian regions.

The third element concerns the “multi-data use” principle according to which the data output has to be useful to people who input the data [62]. From the patients’ standpoint, the system ensures a rapid information flow, minimizing the time it takes to obtain benefits, and simplifying the paperwork involved [63]. On the other hand, it enables users to produce on-line statistics based on the data entered and to run searches on all the contents, making the registry a powerful research tool.

Finally, a key issue concerns the registry’s governance. The legally mandatory involvement of governmental bodies (the Regional Health Authorities in the decentralized Italian National Health System scenario) in the setup and maintenance of rare disease monitoring systems guarantees the long-term sustainability of the registration process because it is the first step in the provision of patient care. In addition, as the debate on orphan drug post-marketing surveillance has underscored, the availability of data from independent registries has become very important for the purpose of orienting clinical practice and transparently supporting the decision-making process [64]. In our view, public governance of such registries should be interpreted as evidence of the attention that should be paid to rare disease patients by the community as a whole.