Monica Mazzucato

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

BackgroundAlthough rare diseases have become a major public health issue, there is a paucity of population-based data on rare diseases. The aim of this epidemiological study was to provide descriptive figures referring to a sizable group of unrelated rare diseases.MethodsData from the rare diseases registry established in the Veneto Region of north-east Italy (population 4,900,000), referring to the years from 2002 to 2012, were analyzed. The registry is based on a web-based system accessed by different users. Cases are enrolled by two different sources: clinicians working at Centers of expertise officially designated to diagnose and care patients with rare diseases and health professionals working in the local health districts. Deaths of patients are monitored by Death Registry.ResultsSo far, 19,547 patients with rare diseases have been registered, and 23% of them are pediatric cases. The overall raw prevalence of the rare diseases monitored in the population under study is 33.09 per 10,000 inhabitants (95% CI 32.56-33.62), whilst the overall incidence is 3.85 per 10,000 inhabitants (95% CI 3.67-4.03). The most commonly-recorded diagnoses belong to the following nosological groups: congenital malformations (Prevalence: 5.45/10,000), hematological diseases (4.83/10,000), ocular disorders (4.47/10,000), diseases of the nervous system (3.51/10,000), and metabolic disorders (2,95/10,000). Most of the deaths in the study population occur among pediatric patients with congenital malformations, and among adult cases with neurological diseases. Rare diseases of the central nervous system carry the highest fatality rate (71.36/1,000). Rare diseases explain 4.2% of general population Years of Life Lost (YLLs), comparing to 1.2% attributable to infectious diseases and 2.6% to diabetes mellitus.ConclusionsOur estimates of the burden of rare diseases at population level confirm that these conditions are a relevant public health issue. Our snapshot of their epidemiology is important for public health planning purposes, going to show that population-based registries are useful tools for generating health indicators relating to a considerable number of rare diseases, rather than to specific conditions.

Hospitalization of children with sickle cell disease in a region with increasing immigration rates

Sickle cell disease (SCD) has become a paradigm of immigration hematology in Europe. Accurate up-to date information is needed to determine SCD prevalence, define real burden of disease and develop appropriate clinical networks of care, especially in regions lacking screening programs. We used two independent sources of data (Regional Register of Rare Disorders and Regional Register of Hospital Discharge Records) to determine extent of SCD and pattern of hospitalization of pediatric patients in the Veneto Region of NorthEast Italy. A steady increase of case notifications and hospitalizations has been observed in the past five years. Ninety-five percent of patients are immigrants with HbS/HbS SCD. Specialized regional registers can be used to define disease extent and guide targeted interventions in regions still lacking comprehensive care screening programs.

The importance of helplines in National Plans

In the last years, the Internet has attracted a considerable attention as a means to provide health-related information. Rare diseases patients have been described as active internet users, accessing the web both for searching activities and for communication purposes [1]. Despite the great opportunities offered both by health 1.0 and health 2.0 applications, some concerns arise as well, particularly regarding the following aspects: the accuracy and reliability of the information provided, a reported increase in feelings of anxiety and protection of personal information. Furthermore, the use of the internet in the health domain is linked to inequalities issues. E-health literacy [2] has been reported to be lower in patients and caregivers experiencing a high disease burden, as the one caused by many rare conditions. The analysis of the activities of 11 help-lines, operating in 7 European countries and part of the European Network of Rare Diseases Help-lines, outlines that the phone still represents a valuable source of information provision and support [3]. Although communication through e-mail can be easier to follow and more comfortable for the user when discussing sensitive issues, the phone conversation provides an immediate feedback and has a higher potential on reducing distress. The combined use of different tools, according to users’ needs and preferences, can reduce potential inequalities in access to appropriate information and support. The existence of help-lines providing information on rare diseases has been identified as one of the core-indicators for the evaluation of National Plans/strategies. The added value of setting up such services relies on different aspects. First, access. Whilst nearly seven out of ten EU households have an Internet connection (68%), 98% have a phone access, either through a fixed line or a mobile [4]. Furthermore, the divide between European countries is narrower considering phone access with respect to internet access. Second, whilst most of the healthrelated web contents are available in English, help-lines deliver information and support in local languages, reaching a potential higher number of persons. Phone lines have the possibility to adapt immediately to the knowledge and education level of the users for a more efficient communication. Finally, the public health value of help-lines should be underlined. They can produce visible results in the short term with limited costs and represent excellent observation tools through which the Health Authorities can receive, both from patients and from professionals, an immediate feedback on the functioning of the rare diseases policies put in place.

The Epidemiology of Transition into Adulthood of Rare Diseases Patients: Results from a Population-Based Registry

Background: Despite the fact that a considerable number of patients diagnosed with childhood-onset rare diseases (RD) survive into adulthood, limited information is available on the epidemiology of this phenomenon, which has a considerable impact both on patients’ care and on the health services. This study describes the epidemiology of transition in a population of RD patients, using data from the Veneto Region Rare Diseases Registry (VRRDR), a web-based registry monitoring since 2002 a consistent number of RD in a defined area (4.9 million inhabitants). Methods: Longitudinal cohorts of patients born in the years 1988 to 1998 and enrolled in the VRRDR in their paediatric age were identified. Data referred to this group of patients, experiencing transition from paediatric to adult age during the years 2006–2016, are presented. Results: 2153 RD patients (44.1% females and 55.9% males) passed from childhood to adulthood in the study period, corresponding to a 3-fold increase from 2006 to 2016. The majority of these patients was affected by congenital anomalies (32.0%), by hematologic diseases (15.9%), eye disorders (12.1%) and neoplasms (7.9%). RD patients who experienced transition from paediatric age to adulthood represent the 9.2% of adult patients enrolled in the Registry at 31 December 2016. Conclusions: We described a subset of RD young adults experiencing transition into adulthood. The data reported can be considered as minimum values for estimating the size of this increasing population presenting specific transition needs. These figures are valuable for clinicians, patients and health planners. Public policy interventions are needed in order to promote dedicated care transition pathways in the broader framework of health policies devoted to RD.

Diagnosis of pervasive developmental disorders: when and how? An area-based study about health care providers

BackgroundPervasive developmental disorders (PDDs) can be very difficult to diagnose in children and to communicate such a diagnosis to their parents. Families of children with PDD learn of their child’s diagnosis long after the first symptoms are noted in the child’s behavior.MethodsAn area-based survey was conducted to assess all social and health care providers taking care of patients with PDDs in the Veneto Region (North-East Italy).ResultsOnly 28% of health care providers arrived at a definite diagnosis when the child was in his/her first year of age, 51% when the child was 2–3 years old and 21% from age of 4 years and up. On average, the latency between the time of the diagnosis and its communication to the family was 6.9 months. However, a number of families did not ever have a diagnosis communicated to them. Sometimes, 68% of the providers did not communicate a PDDs diagnosis to patient’s families, and 4% of them quite commonly.ConclusionThe well-known delay in making a diagnosis of PDDs has two distinct components: one relating to the difficulty of confirming a diagnosis of PDDs, the other, hitherto unrecognized, relating to the family being notified.

Children with Aniridia and Healthcare Systems: From Needs Assessment to a Comprehensive Program of Care and Assistance

Aniridia is a paradigm of the challenges posed to healthcare systems by childhood-onset rare diseases. The care of children with rare diseases presents peculiar aspects of complexity, due to the chronicity of these conditions and their disability spectrum, with different types of impairments and different severity levels, both within the same disease and the same patient across life. Recently, the provision of more comprehensive and effective care has been the aim of health policies specifically addressed to rare disease patients. The experience carried out in this field by the Veneto region (4.9 million inhabitants, north-east of Italy) is presented. An information system, accessed by all the different health professionals involved in patients’ care, has been developed. The system, adopted so far in other seven Italian Regions, allows patients’ recording, treatments’ prescription and provision and the formulation of care plans, according to the individual health care needs’ profile. The process of information sharing can effectively reduce the fragmentation of the care provided to these children and their families by a multiplicity of actors, medical and non-medical ones. Furthermore, it can ease the transition from paediatric to adult care, an emerging crucial issue in the care of children presenting special care needs, as children with aniridia.

Neonatal Expanded Screening For Inherited Metabolic Diseases: Planning By Simulation.

Inherited metabolic diseases are rare but may cause severe damages if not cared for in time. A neonatal screening program, including a first quick test to all newborns and a second accurate test for patients with positive results, is being planned in Veneto region, northeast Italy. A simulation model describing all operations has been built and implemented with the scope of giving suitable dimension to operating centres, in order to care for all revealed pathology within the maximum time before they may become dangerous for the involved patients. The model is pretty general and its application may be extended to changed situation of the same region or to other regions. INTRODUCTION The screening is the application of a test to all subjects of a population with the scope of identifying a disease at the moment when it is asymptomatic. A screening test has not the significance of a diagnostic test: it identifies a person who appears to be sound but probably suffers from a disease among people who do not; people with either positive or suspicious result shall be sent to the doctor for diagnosis and necessary therapy. The idea of an early disease diagnosis and treatment is simple; conversely the path, which brings on one side to care people for a previously undiagnosed disease and on the other side not to damage those who do not need any treatment, is not simple. Then in (Wilson and Junger 1968) leading criteria were fixed to identify pathologies for which a screening program is appropriate; such criteria were repeatedly updated and are synthetized in (Andermann et al. 2008) as follows: the screening program shall meet a recognized need; screening objectives shall be defined from the beginning; target population shall be defined; scientific evidence of screening program effectiveness is necessary; the plan shall integrate education, evaluation, clinical services and management plans; a quality control, which minimizes potential screening risks, is necessary; the plan shall assure well informed choices, confidentiality and autonomy respect; the plan shall promote screening access and equity to the whole population; evaluation plans shall be prepared from the beginning; screening total benefits shall outweigh damages. The scope of neonatal screening lays in identifying newborns with severe pathologies in order to promote appropriate interventions to avoid or to improve adverse outcomes (Wilcken and Wiley 2008). Biochemical mass test on newborns began in 1960 with the adoption of a screening for phenylketonuria, a rare congenital metabolism error which, if not treated, leads to a severe mental retardation. Gutrie in 1960 developed a methodology to measure phenylalanine concentration in blood; this test required a few blood drops taken from the heel and soaked into a blotting paper now known as Gutrie card (Marsden and Levy 2010); moreover it has the characteristic of being quickly effected on a large sample number. Such a test first became compulsory in Massachusetts in 1963, but soon in many states neonatal screening test plans took place. Note that the same sample may be used for many tests, so that other pathologies were introduced in the neonatal screen plans. In the 90’s the development of tandem mass spectrometry brought a great change to neonatal screening, as this method permits identification of a large number of metabolites from the same sample of a few blood drops on the blotting paper, so that the screening for 30-40 metabolic pathologies is possible. Pilot plans developed in Australia and New England studied tandem mass screening effectiveness and revealed a higher identification capacity if compared with clinical diagnoses (Zytkovicz et al. 2001, Wilcken et al. 2003); moreover results showed the advantage of better prognosis of identified and precociously treated patients. Neonatal screening programs with tandem mass technology were developed in Australia, Canada, Qatar and in the majority of U.S.A.. In Europe 24 states Proceedings 25th European Conference on Modelling and Simulation ©ECMS Tadeusz Burczynski, Joanna Kolodziej Aleksander Byrski, Marco Carvalho (Editors) ISBN: 978-0-9564944-2-9 / ISBN: 978-0-9564944-3-6 (CD) activated such plans, either applied to the whole country or limited to some regions (Bodamer et al. 2007). The set of screened metabolic diseases is different among the various states. Even if many papers were written about simulation in health care, no paper was found about simulation of neonatal screening except (Da Fre 2011). PROJECT FOR AN EXPANDED NEONATAL SCREENING IN VENETO REGION A project to execute an expanded neonatal screening in Veneto region (northeast Italy), 4,900,000 inhabitants, has been recently initiated. Such a project plans to create a network which includes two already operating centres, placed in Verona (West Veneto) and in Padova (East Veneto); the catchment area includes 42 birth centres, of which 15 in the provinces of Verona and Vicenza, which will refer to Verona, with about 19,000 newborns per year, and 27 in the provinces of Padova, Rovigo, Treviso, Venezia and Belluno, which will refer to Padova, with about 27,000 newborns per year. Probably the catchment area will expand to two neighbour regions in the future. Pahologies to be screened for are listed below; for each pathology there is written the official name, the usual abbreviation and the priority; high priority pathologies are characterized by +++, which specifies that such pathologies require beginning the appropriate therapy within the first week of life, middle priority pathologies by ++, as they require to begin the therapy within the second week of life, low priority by +, as they do not require any therapy within the first two weeks of life: Phenylketonuria (PKU) ++ Tyrosinemia, Type I (TYR I) +++ Citrullinemia (CIT) +++ Argininosuccinic Aciduria (ASA) +++ Arginase Deficiency (ARG) +++ Maple Syrup Urine Disease (MSUD) +++ Propionic Acidemia (PA) +++ Methylmalonyl-CoA Mutase (MMA) +++ Methylmalonic acidemia with homocystinuria type C/D (Cbl C/D) +++ Isovaleric acidemia (IVA) +++ Glutaric aciduria 1 (GA I) ++ Very long chain acyl-CoA dehydrogenase deficiency (VLCAD) +++ Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) +++ Medium chain acyl-CoA dehydrogenase deficiency (MCAD) ++ Short chain Acyl-CoA dehydrogenase deficiency (SCAD) +++ Glutaric aciduria 2 (GA II) ++ Carnitine palmitoyl transferase 1 deficiency (CPT I) ++ Carnitine palmitoyl transferase II deficiency (CPT II) +++ Carnitine-acylcarnitine translocase deficiency (CACT) +++ Carnitine uptake deficiency (CUD) ++ Glycogen Storage Disease Type II (Pompe Disease) (GSD II) ++ Fabry Disease (FD) + Mucopolysaccharidosis I, II, VI (MPS I, II, VI) + Actions related to neonatal screening for metabolic diseases are reported in Figure 1. Within two-three days from birth a sample is taken from every newborn; the sample is quickly dispatched to the first level centre of reference, where it is measured as soon as the machine is idle; if the first measuring gives a borderline result, then a second measuring is performed; if the result is uncertain a new sample is taken immediately, if it is related to a premature newborn a new sample is taken after fifteen days; if the result is clear and positive, the newborn is sent to the second level centre in Padova, to make a further test, in order to get an accurate diagnosis and to set up a therapy plan; the second level test is executed as soon as a free slot is found. Note that first level centres are planned to operate for six days a week.and the only second level centre for five days a week. THE PROBLEM The main concern of Region Health authorities is to find the right dimension for the two first level centres, placed in Verona and Padova, in terms of capacity, i.e., number of measured samples per day, and for the second level centre, placed in Padova, in terms of number of tests executed per week. It is obvious the capacity shall be decided in order not to impose dangerous delays in the processing of samples and positive patients, but not to require excessive expense by creating overdimensioned centres. Keep in mind that the study shall be open to reconsider centres dimensioning in the case either the population of the catchment area changes, or the catchment area expands. Given the variability of birth process and the flexibility we require to the model, we chose simulation as the most suitable technique to solve the problem; such a methodology permits us to know in advance the effects of our suggestions without implementing any new method in clinical practice; moreover many different alternatives can be tested witout any actual experiment. DATA ANALYSIS Data concerning birth process were obtained from the local birth records reporting births of year 2009. An accurate study revealed that the birth rate depends both on the month of the year and on the day of the week: the expected amount of births per day is given by a regression model expressed by the formula: μij = α + βi + δj where i=1,...,12 and j=1,...,7 Figure 1: Flow Chart of Actions Related to Screening according to the following parameters: α 105,48 β10 2,45 β 1 0,00 β 11 -6,13 β 2 -1,57 β 12 -3,59

The Role of a Registry in Familial Adenomatous Polyposis

The revolution in information technology has transformed the processes of collection, transmission, analysis, and storage of data, leading to the improvement of many large-scale systematic data-collection systems of health-related events. Familial adenomatous polyposis (FAP) represents a paradigmatic example of how the establishment of a data-collection system, starting from family tracing and evolving to more complex registration processes, increases knowledge on different aspects of the disease and ultimately can influence patients’ clinical management and professionals’ attitudes. Many years have passed since the establishment of the first polyposis registry at St Mark’s Hospital in London. An historical overview of FAP registries is presented, discussing potentials and limitations of population-based registries versus clinical registries. In the context of recently developed health policies on rare diseases, the experience of a registry monitoring FAP as well as other rare conditions, population-based, and at the same time with features of a clinical one, is presented. The value of FAP registries relies on their ability to provide a snapshot of aspects of disease as well as of its management, producing evidence and translating this into clinical practice. Our belief is that such registries, really patientcentered, should be developed as an integral part of the healthcare network, becoming connecting informative tools between vertical networks, namely centers of expertise, horizontal care networks, and other institutions and persons involved in the care of FAP patients.