Deliverable 14: Report of the epidemiological results concerning RA in scientific papers Executive summary Project number: 2008 12 10 Project Acronym: ENERCA 3 Title: European Reference Network of Expert Centres in Rare Anaemias Deliverable: D14 Delivery Date: May 2012 Short description: Deliverable D14 includes a revision of the epidemiological data available in scientific papers on Rare Anaemias • Responsible partner: ERASME and CLINIC • Partners involved: LCHA, CDN, UNIVR, TIF, UMCU, UULM • Made available to: Internal and ENERCA website 1 D14 ‐ Report of the epidemiological results concerning RA Introduction • Clinical epidemiology, originally confined to the global problems of infectious diseases, became, in the last 50 years, the fundament of today’s evidence based medicine. No medical stakeholder is able to oversee the abundance of data describing prevalence, incidence, clinical patterns and health risks from all regions in the world. The majority of studies are concerned with common diseases, but there is still a paucity of data for rare diseases, which came in the scope of medical stakeholders in the last decade. ENERCA is concerned with the special problems of rare anaemias, and aims to obtain valid epidemiological evidence of their prevalence, life expectancy and effects of therapy. • In rare anaemias, as in other rare and very rare disorders, supranational networks only can provide valid data. ENERCA has concentrated on data from the member states (MS) of the European Union (EU) (nevertheless including patients from Switzerland and other Non‐EU European countries) and also on a subset on Rare Anemias. However, the methodological experience gained by ENERCA can (and has been) be used for other rare blood diseases. In the context of this section of the White Book, methodological experience denotes primarily the advances and procedures of networking, but also the problems to bundle results of different general and medical cultures in the different countries. For example, it is often overlooked that social‐economic conditions and medical practices are different in the different MS, resulting in different recognition of the epidemiological data studied. Methods and definitions • Frequency is a general term to compare differences between the occurrence of a given disease, in the case of rare anaemias between populations defined by geographic regions or populations of different origin (formerly called races) in a given region. The latter became of paramount importance with the ongoing immigration of people the mediterranian basin to North‐ and Middle Europe and from Asia and Africa to all MS, as mentioned above. Frequency is useful in any first attempt and useful to decide on the methodology to estimate more exact parameters. No one would challenge the fact, that thalassemia is much more frequent in the Mediterranean or in immigrants to the North European countries. However, mathematically defined parameters are needed for research and health care planning. Prevalence or more exact prevalence proportion is the main indicator used for any epidemiological studies in congenital diseases, representing the vast majority of conditions considered in disease category. PNH is an exception, with incidence being of major significance alike for the situation of D14 ‐ Report of the epidemiological results concerning RA cancers. Prevalence is the probability that an individual is recognized as a case at time, with the total population considered as denominator. However, for very rare anaemias included in ENERCA, usually period prevalence is measured, using a defined number of observation years rather than an index day as used for the so called point prevalence in common diseases. Another useful measure is the number of affected children of all live births in a given observation period; in this case, the period of definition of live birth (e. g. days after birth) should be indicated, to avoid bias due to early mortality. An effective instrument to measure true prevalence proportions isare obtained with pre‐ and post‐natal screening programs, as described for SCD. • Ideally, all cases of a given disease or disease category in a population at time should represent the “true” prevalence. However, in the case of rare anaemias, the detection rate (number of detected / number of existing cases) is often less than 1. As shown by the work of ENERCA, there are strong indicators that the detection rates in the MS vary considerably dependent on socio‐economic conditions, and the same is true for the proportion of misclassifications. These data are of importance for ENERCAs attempts to equalize the diagnosis of rare anemias in the European countries. Sources of data • Registries are among the main sources for epidemiological data in rare anemias. They are a structured collation of cases of one of the disease categories considered by ENERCA III, in the rule in a digital data bank. Harmonisation of the basic structures and basic data fields were attempted in some disease categories. Originally, a joint ENERCA epidemiological registry including all disease categories was discussed. Differences of national regulations for data protection as well as limitations of time and resources prevented to realize this target. However the work done by several ENERCA working parties, and intensive discussions in the Executive Committee meetings and symposia yielded very useful experiences on the suited strategies, methodological problems, pitfalls and risk of biases in supranational projects of epidemiology of rare disease, a shown paradigmatically for the rare anemias. • An inherent, unsolved problem of all registries is sustainability. Time trends, so important considering the influence of scientific as well as population changes due to both demographic evolution and migration can only be ascertained if sustainability can be guaranteed by recourses of much longer duration of sponsorship than available to day. • Clinical trials, even though primarily directed to progress of therapeutic measures and often dependent on industrial interests are another source of D14 ‐ Report of the epidemiological results concerning RA epidemiological data. Only few such trials are performed in the group of very rare anemias and are not supported by ENERCA. However, data from such trials are available for some of the disease categories considered by ENERCA. Further reading • Gulbis,B., Eleftheriou,A., Angastiniotis,M., Ball,S., Surralles,J., Castella,M., Heimpel,H., Hill,A., & Vives‐Corrons,J.L. (2010) Epidemiology of rare anaemias in Europe. Rare Diseases Epidemiology. (ed. by S. Groft & M. Posada), pp. 375‐395. Springer. • Posada,M. & et al (2010) Rare diseases Epidemiology epidemiology research. In: Rare Diseases Epidemiology. (ed. by S. Groft & M. Posada), pp. 17‐39. Springer. Epidemiology of Rare Anaemia categories • According to their frequency, the rare anaemias can be classified into two main groups 1. Hemoglobinopathies (Sickle cell disease and Thalassemia syndromes). It was a priory known that these disorders are endemic in the MS surrounding the Mediterranean, due to the holoendemic malaria still present up to the 20th century. Prevalence in the MS of middle and Northern Europe MS, are largely the result of history of migration and the influence of the Turkish dominance of the Balkan and today’s Hungary and Austria. Considering the new migration starting after Word War 2, and the ongoing immigration from South to North and from East to West, data from the middle and North European MS are of particular interest for health care planning in the EU. 2. Very rare anaemias (VRAs) such as enzyme disorders of the red blood cell, red blood cell membrane disorders, Congenital Dyserythropoetic Anemias (CDA), Diamond–Blackfan anaemia (DBA) and Fanconi Anaemia, Primary iron metabolism disorders, including Hereditary Sideroblastic Anaemia (HSA) and other VRAs , Congenital defects of vitamins B12 and folic acid and Paroxysmal Nocturnal Haemoglobinuria (PNH). Here, only few data on regional distribution were available, ENERCA has added data supporting the hypothesis that in contrast to the diseases mentioned above, prevalence is not dependent on environmental factors but rather D14 ‐ Report of the epidemiological results concerning RA on rate of new mutations, consanguinity and detection rates at least in disorders of autosomal recessive heredity. Sickle cell disorders: Sickle cell disease in Europe is predominantly a disorder seen in immigrant communities. The gene in its carrier state form arose originally as it offered some degree of protection against malaria hence it is most commonly seen in people originating from malarial areas, most usually people of African origin. The gene however is seen in many other communities, it is present in many groups of Middle Eastern origin; some Indian groups also have a high prevalence. Intermarriage is spreading the gene into communities with historically low prevalence. The communities involved are largely immigrants within Europe although there is low background prevalence in the Caucasian community and some indigenous Southern European people also carry the gene. Many of those affected by Sickle cell disease are relatively recent arrivals in Europe; they have tended to concentrate initially in large urban centres with already established communities whilst looking to establish them. This results in a very uneven distribution of Sickle cell disease throughout Europe, the disorder being a major health issue in some large urban centres whilst