Matthew Darlison

Global epidemiology of haemoglobin disorders and derived service indicators

To demonstrate a method for using genetic epidemiological data to assess the needs for equitable and cost-effective services for the treatment and prevention of haemoglobin disorders. We obtained data on demographics and prevalence of gene variants responsible for haemoglobin disorders from online databases, reference resources, and published articles. A global epidemiological database for haemoglobin disorders by country was established, including five practical service indicators to express the needs for care (indicator 1) and prevention (indicators 2-5). Haemoglobin disorders present a significant health problem in 71% of 229 countries, and these 71% of countries include 89% of all births worldwide. Over 330,000 affected infants are born annually (83% sickle cell disorders, 17% thalassaemias). Haemoglobin disorders account for about 3.4% of deaths in children less than 5 years of age. Globally, around 7% of pregnant women carry b or a zero thalassaemia, or haemoglobin S, C, D Punjab or E, and over 1% of couples are at risk. Carriers and at-risk couples should be informed of their risk and the options for reducing it. Screening for haemoglobin disorders should form part of basic health services in most countries.

Survival in β-thalassaemia major in the UK: data from the UK Thalassaemia Register

About 50% of UK patients with beta-thalassaemia major die before the age of 35 years, mainly because conventional iron-chelation therapy is too burdensome for full adherence. Patients require an individually-tailored treatment plan incorporating new, more tolerable approaches.

Improved survival of thalassaemia major in the UK and relation to T2* cardiovascular magnetic resonance

BackgroundThe UK Thalassaemia Register records births, deaths and selected clinical data of patients with thalassaemia who are resident in the UK. A study of survival and causes of death was undertaken which aimed to include the possible impact of T2* cardiovascular magnetic resonance (CMR).MethodsThe Register was updated to the end of 2003, copies of death certificates were obtained, and causes of death in beta thalassaemia major were extracted. In addition, patients who had T2* CMR assessment of cardiac iron load and/or received the oral iron chelator deferiprone were identified from clinical records.ResultsThe main causes of death were anaemia (before 1980), infections, complications of bone marrow transplantation and cardiac disease due to iron overload. From 1980 to 1999 there were 12.7 deaths from all causes per 1,000 patient years. Forty per cent of patients born before 1980 had T2* cardiovascular magnetic resonance between 2000 and 2003, and 36% of these patients were prescribed deferiprone before end of 2003. In 2000–2003, the death rate from all causes fell significantly to 4.3 per 1,000 patient years (-62%, p < 0.05). This was mainly driven by the reduction in the rate of deaths from iron overload which fell from 7.9 to 2.3 deaths per 1,000 patient years (-71%, p < 0.05).ConclusionSince 1999, there has been a marked improvement in survival in thalassaemia major in the UK, which has been mainly driven by a reduction in deaths due to cardiac iron overload. The most likely causes for this include the introduction of T2* CMR to identify myocardial siderosis and appropriate intensification of iron chelation treatment, alongside other improvements in clinical care.

Epidemiology of haemoglobin disorders in Europe: an overview

Objective. As a result of global population movements, haemoglobin disorders (thalassaemias and sickle cell disorders) are increasingly common in the formerly non‐indigenous countries of Northern and Western Europe and in the indigenous countries of Southern Europe. This article presents an overview of the changing picture and a method for assessing service needs. Method. Data on country of birth or ethnic origin of residents are adjusted to obtain the estimated proportions of residents and births in non‐indigenous groups at risk for haemoglobin disorders in European countries. The results are combined with prevalence data in each country of origin to obtain country prevalence estimates. Service indicators (annual tests or other interventions required to ensure equitable delivery of treatment and prevention) are then derived by country. Results. Haemoglobin disorders now occur at comparable frequency throughout Northern, Western and Southern Europe. Annually, there are more affected conceptions in Northern and Western than in Southern Europe, and sickle cell disorders are more common than thalassaemias. There is growing need for health policy‐makers to support motivated professionals working to develop optimal patient care, carrier diagnosis, genetic counselling and access to prenatal diagnosis throughout the Region. Conclusion. There is a strong case for pan‐European collaboration on haemoglobin disorders to share policies, standards and the instruments required to support them. These include methods for needs assessment, service standards, education and information strategies and materials, and methods for evaluating service delivery.

Informed choice in genetic screening for thalassaemia during pregnancy: audit from a national confidential inquiry.

Abstract Objective: National audit of informed choice in antenatal screening for thalassaemia. Design: Audit from the UK Confidential Enquiry into Counselling for Genetic Disorders. Setting: Thalassaemia module of the UK Confidential Enquiry into Counselling for Genetic Disorders. Subjects: 138 of 156 couples who had had a pregnancy affected by a major β thalassaemia from 1990 to 1994. Main outcome measures: How and when genetic risk was identified for each couple, and whether and when prenatal diagnosis was offered. Results: Risk was detected by screening before or during the first pregnancy in 49% (68/138) of couples and by diagnosis of an affected child in 28% (38/138) of couples. Prenatal diagnosis was offered in 69% (274/400) of pregnancies, ranging from 94% (122/130) for British Cypriots to 54% (80/149) for British Pakistanis and from 90% in the south east of England to 39% in the West Midlands. Uptake of prenatal diagnosis was 80% (216/274), ranging from 98% (117/120) among British Cypriots in either the first or second trimester to 73% (35/48) among British Pakistanis in the first trimester and 39% (11/28) in the second trimester. A demonstrable service failure occurred in 28% (110/400) of pregnancies, including 110 of 126 where prenatal diagnosis was not offered and 48 of 93 that ended with an affected liveborn infant. Conclusion: Although antenatal screening and counselling for haemoglobin disorders are standard practices in the United Kingdom, they are delivered inadequately and inequitably. An explicit national policy is needed, aiming to make prenatal diagnosis in the first trimester available to all couples and including ongoing national audit.

The phenotype and genotype experiment object model (PaGE-OM): a robust data structure for information related to DNA variation

Torrents of genotype–phenotype data are being generated, all of which must be captured, processed, integrated, and exploited. To do this optimally requires the use of standard and interoperable “object models,” providing a description of how to partition the total spectrum of information being dealt with into elemental “objects” (such as “alleles,” “genotypes,” “phenotype values,” “methods”) with precisely stated logical interrelationships (such as “A objects are made up from one or more B objects”). We herein propose the Phenotype and Genotype Experiment Object Model (PaGE‐OM; www.pageom.org), which has been tested and implemented in conjunction with several major databases, and approved as a standard by the Object Management Group (OMG). PaGE‐OM is open‐source, ready for use by the wider community, and can be further developed as needs arise. It will help to improve information management, assist data integration, and simplify the task of informatics resource design and construction for genotype and phenotype data projects.Hum Mutat 30, 968–977, 2009.

Estimates of global and regional prevalence of neural tube defects for 2015: a systematic analysis.

Neural tube defects (NTDs) are associated with substantial mortality, morbidity, disability, and psychological and economic costs. Many are preventable with folic acid, and access to appropriate services for those affected can improve survival and quality of life. We used a compartmental model to estimate global and regional birth prevalence of NTDs (live births, stillbirths, and elective terminations of pregnancy) and subsequent under‐5 mortality. Data were identified through web‐based reviews of birth defect registry databases and systematic literature reviews. Meta‐analyses were undertaken where appropriate. For 2015, our model estimated 260,100 (uncertainty interval (UI): 213,800–322,000) NTD‐affected birth outcomes worldwide (prevalence 18.6 (15.3–23.0)/10,000 live births). Approximately 50% of cases were elective terminations of pregnancy for fetal anomalies (UI: 59,300 (47,900–74,500)) or stillbirths (57,800 (UI: 35,000–88,600)). Of NTD‐affected live births, 117,900 (∼75%) (UI: 105,500–186,600) resulted in under‐5 deaths. Our systematic review showed a paucity of high‐quality data in the regions of the world with the highest burden. Despite knowledge about prevention, NTDs remain highly prevalent worldwide. Lack of surveillance and incomplete ascertainment of affected pregnancies make NTDs invisible to policy makers. Improved surveillance of all adverse outcomes is needed to improve the robustness of total NTD prevalence estimation, evaluate effectiveness of prevention through folic acid fortification, and improve outcomes through care and rehabilitation.

An overview of concepts and approaches used in estimating the burden of congenital disorders globally

Congenital disorders are an important cause of pregnancy loss, premature death and life-long disability. A range of interventions can greatly reduce their burden, but the absence of local epidemiological data on their prevalence and the impact of interventions impede policy and service development in many countries. In an attempt to overcome these deficiencies, we have developed a tool—The Modell Global Database of Congenital Disorders (MGDb) that combines general biological principles and available observational data with demographic data, to generate estimates of the birth prevalence and effects of interventions on mortality and disability due to congenital disorders. MGDb aims to support policy development by generating country, regional and global epidemiological estimates. Here we provide an overview of the concepts and methodological approach used to develop MGDb.

Chromosomal disorders: estimating baseline birth prevalence and pregnancy outcomes worldwide.

Chromosomal disorders, of which Down syndrome is the most common, can cause multi-domain disability. In addition, compared to the general population, there is a higher frequency of death before the age of five. In many settings, large gaps in data availability have hampered policy-making, programme priorities and resource allocation for these important conditions. We have developed methods, which overcome this lack of data and allow estimation of the burden of affected pregnancies and their outcomes in different settings worldwide. For example, the methods include a simple equation relating the percentage of mothers 35 and over to Down syndrome birth prevalence. The results obtained provide a starting point for consideration of services that can be implemented for the care and prevention of these disorders.

Sickle-cell disorders: limits of descriptive epidemiology

The global mapping of sickle haemoglobin (HbS) allele frequencies in neonates at a fi ne-grained 5×5 km resolution, undertaken by Frédéric Piel and colleagues in The Lancet, uses a new approach extended from work on malaria (with which haemoglobin variation is closely associated), and thus adds a powerful new instrument to the haemoglobin research community’s arma mentarium. The contribution is multifaceted: updating the literature review to 2010; applying a rigorous method including use of the global rural urban mapping project (GRUMP); and publication of results in a prestigious journal, which highlights the position of sickle-cell disorders as a global health concern. Although the coverage is currently limited to HbS, its extension, in time, to other alleles that interact with HbS to cause sickle-cell disorders (principally haemoglobin C and β-thalassaemias) will greatly enrich the outputs. At this stage, however, the current outputs of the 5×5 km approach must be classed as an input to a further tier of systems—those systems designed to support strategic epidemiology. The concept of strategic epidemiology—epidemiology geared not only to describing the prevalence and geographical spread of an entity of interest, but to informing the delivery of health services to mitigate its burden—is intuitively understood by those tasked with making strategic decisions about services (care and prevention). However, the fi eld lacks the consensus on detailed information specifi cations—of inputs, outputs, and the terms in which they are to be expressed—that would ensure strict comparability of epidemiological numbers and rates derived (a) for the same disorder by diff erent means, and (b) for diff erent disorders. A consequence of this void is that less rigorous interpretations of data could go unnoticed, and misunderstandings could ensue. Available input data are evolving continually, and no consensus exists on a standard demographic starting point for strategic epidemiological prediction. Piel and colleagues estimated that 312 302 infants (IQR 294 307–329 729) were born with sickle cell anaemia in 2010, compared with our 2008 estimate of 222 785, which used the best UN demographic data then available (for 2003). The 2010 edition of UN World Population Prospects now removes such time lags. Piel and colleagues used birth estimates from the World Population Prospects for 2010–15: with the same input our model estimates 307 630 infants were born with sickle cell anaemia in 2010. The increase above our earlier estimate is largely due to increasing annual births in Africa. However, the similarity of the estimates for 2010–15 by Piel and colleagues conceals substantial regional diff erences—for example, we estimate more births in Africa and fewer in India. 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