Rare Diseases Epidemiology is a novel action field still largely unexplored. However, Rare Diseases is a topic of growing interest at world level. The aims of this chapter are to revise useful epidemiological tools and define areas where epidemiology can help improve the rare disease knowledge, and facilitate policy decisions taking into account the real burden of rare diseases in society. This chapter also seeks to describe: the problems of coding and classification of diseases, measuring disease frequency, the study designs and association studies, the causality, the evolution from descriptive to epigenetic epidemiology and the natural history of disease. One of the major challenges facing analytical epidemiology and clinical epidemiological research into rare diseases is that genes can be involved in both aetiology and prognosis. Despite the many similarities between genetic association studies and classic observational epidemiological studies, the former pose several specific limitations, including an unprecedented volume of new data and the likelihood of very small individual effects, as well other limitations. Selecting the appropriate pathway from among all those available, i.e. the one that best relates genes from the various known regions and disease mechanisms, is crucial for the success of this type of studies.

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The aim of this study was to assess the trend of motor neuron disease mortality in Spain from 1990 to 2005, and to ascertain the existence of geographical differences in mortality rates. MND deaths are registered by the National Statistics Institute of Spain – International Classification of Diseases (ICD) codes ICD9 335.2 (1990-1998) and ICD10 G12.2 (1999-2005). Annual sex- and age-specific rates, as well as rates adjusted for the standard European population were obtained. Provincial standardized mortality ratios (SMRs) were calculated for the study period. Respective provincial SMRs were smoothed with data from adjacent provinces using a Poisson model. Results showed that MND mortality increased in Spain from 1990 to 2005. Geographical differences between provinces were evident throughout the study period. In general, risk of death due to MND was higher in regions lying to the north of Spain. In conclusion, the temporal and geographical variability observed might be explained by genetic factors, differences in environmental exposures and the possible influence of the type of medical care and treatment received. Mortality depends also on health service quality and diagnostic validity. All these factors may play a very important role in analysis of MND mortality in Spain, and the contribution of each of these will have to be examined in depth by ad hoc studies.

Topical clonazepam, which previous analyses of clinical evidence have shown to be the drug of choice for BMS, also proved to be the most cost-effective of the drugs analysed for this condition.

This study aimed to analyse population-based mortality attributed to rare congenital anomalies (CAs) and assess the associated time trends and geographical differences in Spain. Data on CA-related deaths were sourced from annual mortality databases kept by the National Statistics Institute of Spain (1999–2013). Based on the ICD-10, only CAs corresponding to rare diseases definition were included in this study. Annual age-adjusted mortality rates were calculated and time trends were evaluated by joinpoint regression analysis. Geographical differences were assessed using standardised mortality ratios and cluster detection. A total of 13,660 rare-CA-related deaths (53.4% males) were identified in the study period. Annual age-adjusted mortality rates decreased by an average of −5.2% (−5.5% males, −4.8% females, p < 0.001). Geographical analysis showed a higher risk of rare-CA-related mortality in regions largely located in the south of the country. Despite their limitations, mortality statistics are essential and useful tools for enhancing knowledge of rare disease epidemiology and, by extension, for designing and targeting public health actions. Monitoring rare-CA-related mortality in Spain has shown a 15-year decline and geographical differences in the risk of death, all of which might well be taken into account by the health authorities in order to ensure equality and equity, and to adopt appropriate preventive measures.

Background: The focus on the quality of the procedures for data collection, storing, and analysis in the definition and implementation of a rare disease registry (RDR) is the basis for developing a valid and long-term sustainable tool. The aim of this study was to provide useful information for characterizing a quality profile for RDRs using an analytical approach applied to RDRs participating in the European Platform for Rare Disease Registries 2011-2014 (EPIRARE) survey. Methods: An indicator of quality was defined by choosing a small set of quality-related variables derived from the survey. The random forest method was used to identify the variables best defining a quality profile for RDRs. Fisher's exact test was employed to assess the association with the indicator of quality, and the Cochran-Armitage test was used to check the presence of a linear trend along different levels of quality. Results: The set of variables found to characterize high-quality RDRs focused on ethical and legal issues, governance, communication of activities and results, established procedures to regulate access to data and security, and established plans to ensure long-term sustainability. Conclusions: The quality of RDRs is usually associated with a good oversight and governance mechanism and with durable funding. The results suggest that RDRs would benefit from support in management, information technology, epidemiology, and statistics.

Background: Huntington's disease (HD) is a progressive neurodegenerative condition characterized by chorea, dystonia, behavioral disturbances and cognitive decline. The aim of this study is to assess temporal and spatial changes on mortality attributable to HD over 30 years in Spain. Methods: HD data were extracted from the nationwide mortality registry for the period 1984-2013. Annual and 5-year gender- and age-specific rates adjusted for the standard European population were calculated. Geographic analysis was performed by districts from 1999 through 2013, and then estimated standardized mortality ratios (SMRs) and smoothed SMRs. Results: There were 1,556 HD-related deaths across the study period. An increasing trend in age-adjusted HD mortality was in evidence, specifically from 1994 through 1998. On a year-by-year basis, age-adjusted mortality rates increased from 0.076 per 100,000 population in 1984 to 0.157 in 2013. Geographical differences among districts were evident in specific areas and in the southwest of Spain with a significantly higher HD mortality risk. Conclusion: HD mortality rising trends in Spain might be attributable to improvements in diagnosis leading to a rise in prevalence. Geographical variability in HD mortality could be related to regional differences in disease prevalence, health-care disparities, or other factors which call for in-depth assessment in future studies.

The aim of this study is to analyze population-based mortality attributed to cystic fibrosis (CF) over 36 years in Spain. CF deaths were obtained from the National Statistics Institute, using codes 277.0 from the International Classification of Diseases (ICD) ninth revision (ICD9-CM) and E84 from the tenth revision (ICD10) to determine the underlying cause of death. We calculated age-specific and age-adjusted mortality rates, and time trends were assessed using joinpoint regression. The geographic analysis by district was performed by standardized mortality ratios (SMRs) and smoothed-SMRs. A total of 1002 deaths due to CF were identified (50.5% women). Age-adjusted mortality rates fell by −0.95% per year between 1981 and 2016. The average age of death from CF increased due to the annual fall in the mortality of under-25s (−3.77% males, −2.37% females) and an increase in over-75s (3.49%). We identified districts with higher than expected death risks in the south (Andalusia), the Mediterranean coast (Murcia, Valencia, Catalonia), the West (Extremadura), and the Canary Islands. In conclusion, in this study we monitored the population-based mortality attributed to CF over a long period and found geographic differences in the risk of dying from this disease. These findings complement the information provided in other studies and registries and will be useful for health planning.