Carrier Screening Programs for Cystic Fibrosis, Fragile X Syndrome, Hemoglobinopathies and Thalassemia, and Spinal Muscular Atrophy: A Health Technology Assessment.

Background: We conducted a health technology assessment to evaluate the safety, effectiveness, and cost-effectiveness of carrier screening programs for cystic fibrosis (CF), fragile X syndrome (FXS), hemoglobinopathies and thalassemia, and spinal muscular atrophy (SMA) in people who are considering a pregnancy or who are pregnant. We also evaluated the budget impact of publicly funding carrier screening programs, and patient preferences and values. Methods: We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias tool and the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS), and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted cost-effectiveness analyses comparing preconception or prenatal carrier screening programs to no screening. We considered four carrier screening strategies: 1) universal screening with standard panels; 2) universal screening with a hypothetical expanded panel; 3) risk-based screening with standard panels; and 4) risk-based screening with a hypothetical expanded panel. We also estimated the 5-year budget impact of publicly funding preconception or prenatal carrier screening programs for the given conditions in Ontario. To contextualize the potential value of carrier screening, we spoke with 22 people who had sought out carrier screening. Results: We included 107 studies in the clinical evidence review. Carrier screening for CF, hemoglobinopathies and thalassemia, FXS, and SMA likely results in the identification of couples with an increased chance of having an affected pregnancy (GRADE: Moderate). Screening likely impacts reproductive decision-making (GRADE: Moderate) and may result in lower anxiety among pregnant people, although the evidence is uncertain (GRADE: Very low).We included 21 studies in the economic evidence review, but none of the study findings were directly applicable to the Ontario context. Our cost-effectiveness analyses showed that in the short term, preconception or prenatal carrier screening programs identified more at-risk pregnancies (i.e., couples that tested positive) and provided more reproductive choice options compared with no screening, but were associated with higher costs. While all screening strategies had similar values for health outcomes, when comparing all strategies together, universal screening with standard panels was the most cost-effective strategy for both preconception and prenatal periods. The incremental cost-effectiveness ratios (ICERs) of universal screening with standard panels compared with no screening in the preconception period were $29,106 per additional at-risk pregnancy detected and $367,731 per affected birth averted; the corresponding ICERs in the prenatal period were about $29,759 per additional at-risk pregnancy detected and $431,807 per affected birth averted.We estimated that publicly funding a universal carrier screening program in the preconception period over the next 5 years would require between $208 million and $491 million. Publicly funding a risk-based screening program in the preconception period over the next 5 years would require between $1.3 million and $2.7 million. Publicly funding a universal carrier screening program in the prenatal period over the next 5 years would require between $128 million and $305 million. Publicly funding a risk-based screening program in the prenatal period over the next 5 years would require between $0.8 million and $1.7 million. Accounting for treatment costs of the screened health conditions resulted in a decrease in the budget impact of universally provided carrier screening programs or cost savings for risk-based programs.Participants value the perceived potential positive impact of carrier screening programs such as medical benefits from early detection and treatment, information for reproductive decision-making, and the social benefit of awareness and preparation. There was a strong preference expressed for thorough, timely, unbiased information to allow for informed reproductive decision-making. Conclusions: Carrier screening for CF, FXS, hemoglobinopathies and thalassemia, and SMA is effective at identifying at-risk couples, and test results may impact preconception and reproductive decision-making.The cost-effectiveness and budget impact of carrier screening programs are uncertain for Ontario. Over the short term, carrier screening programs are associated with higher costs, and also higher chances of detecting at-risk pregnancies compared with no screening. The 5-year budget impact of publicly funding universal carrier screening programs is larger than that of risk-based programs. However, accounting for treatment costs of the screened health conditions results in a decrease in the total additional costs for universal carrier screening programs or in cost savings for risk-based programs.The people we spoke with who had sought out carrier screening valued the potential medical benefits of early detection and treatment, particularly the support and preparation for having a child with a potential genetic condition.

Using DNA testing for the precise, definite, and low-cost diagnosis of sickle cell disease and other Haemoglobinopathies: findings from Tanzania.

BACKGROUND: Sickle cell disease (SCD) is an important cause of under-five mortality. Tanzania is the 5th country in the world with the highest births prevalence of SCD individuals. Significant advances in the neonatal diagnosis of SCD using rapid point-of-care testing have been made. However genetic confirmation is still required for positive cases, in uncertain cases, in multiply transfused patients, to resolve compound heterozygosity (Hb S/ ß0 Thal or Hb S/ ß+ thal) not uncommon in the coastal regions of East Africa and increasingly also for pre-marital counselling and potentially for future curative approaches such as gene therapy. The currently available DNA tests are prohibitively expensive. Here, we describe an easy-to-use, affordable and accurate ß-globin sequencing approach that can be easily integrated within existing NBS for SCD and other haemoglobinopathies especially in Low- and Middle-income Countries. AIM: To evaluate an affordable DNA technology for the diagnosis of Sickle cell disease and other haemoglobinopathies in a resource-limited setting. METHODS: Laboratory-based validation study was conducted by Muhimbili University of Health and Allied Sciences and the University of Oxford involving sequencing of the entire ß -haemoglobin locus using the Oxford Nanopore MinION platform. A total number of 36 Dried blood spots and whole blood samples were subjected to conventional protein-based methods (isoelectric focusing, HPLC), and/or sequenced by the Sanger method as comparators. RESULTS: Sequencing results for SCD using the MinION were 100% concordant with those from the Sanger method. In addition, the long-read DNA sequencing method enabled the resolution of cases with unusual phenotypes which make up 1% of all children in Tanzania. The cost is £11/ sample for consumables, which is cheaper compared to other sequencing platforms. CONCLUSIONS: This is the first report of a comprehensive single DNA assay as a definitive diagnostic test for SCD and other haemoglobinopathies. The test is fast, precise, accurate and affordable.

Evaluation of role of HPLC (Merits & Pitfalls), in the diagnosis of various hemoglobinopathies & thalassemic syndromes.

BACKGROUND: : HPLC is one of the most important tools for accurate diagnosis of hemoglobinopathies and thalassemias. The advantage of the HPLC system is the excellent resolution, reproducibility &quantification of several normal and abnormal hemoglobin. RESULTS: BIO RAD Variant II analyzer was used. Sickle cell syndromes including double heterozygous states accounted for 56.13% of total cases. HbSS, HbS/ß0-th, HbS/ß+-th ß-thal trait comprises 29%, 6.5%, 5.1%& 10% of total cases respectively with mean MCV (fl) = 84, 68,71,64 respectively. The Mean HbA2 for ß-thal trait, HbE trait &HbE-ß thal showed 5.1 ± 1.1, 19 ± 9 & 24 ± 8 respectively. HbF is increased in 8.6% case (excluding SC syndromes & ß-thal disorders), of these 5.5% were infants & 12 cases of Aplastic Anemias. Peak P2 >7% (2.4% cases) was seen in uncontrolled diabetes mellitus which on quantification showed HbA1C = 8 ± 2.1 mmol/L. DISCUSSION: : HPLC in correlation with CBC parameters & family studies can aid in the diagnosis of majority of Hemoglobinopathies and thalassemic syndrome. The CBC & HPLC parameters of the present study are in good correlation with the research conducted by Tejinder Sing, RiouJ & Alla Joutovsky. Present study showed HPLC comprehensively characterizing HbS, A, A2, F, S, C, D from each other & was also applicable for the quantification of HbA1c for the monitoring of Diabetes Mellitus. CONCLUSION: : The merits of HPLC are small quantity of sample required, economical, less TAT, accurate categorization of HbS, HbA2 & F. But one has to be aware of the limitations and problems associated with this method due to variant hemoglobin within the same retention windows. The present findings show HPLC as an excellent & powerful diagnostic tool for the direct identification of hemoglobin variants with a high degree of precision in the quantification of normal and abnormal hemoglobin fractions.

The Changing Trends in Prenatal Diagnosis of Hemoglobinopathies in India: The Quest of a Single Center to Reduce the Burden of Disease over Three Decades.

The ß-thalassemias and sickle cell disorders pose a considerable health burden in India. Of the more than 10,000 annual births of children with a severe hemoglobinopathy, only around 10.0% are managed optimally. Thus, genetic counseling and prenatal diagnosis (PND) is a valid option for a large and diverse country. Our center was one of the first to initiate PND and we present our experience over 30 years to evaluate the impact of awareness in changing the trends of PND of hemoglobinopathies. Both second and first-trimester diagnoses were undertaken by fetoscopy/cordocentesis and globin biosynthesis/high-performance liquid chromatography (HPLC) analysis of fetal blood and chorionic villus sampling (CVS) and DNA analysis. Over 30 years, 3478 couples (first trimester: 2475; second trimester: 1003) from all over India were offered PND. The number of couples coming in the first trimester increased significantly over each decade and couples coming prospectively increased from 2.5 to 18.4%. A cost-effective stepwise approach was used for molecular analysis. Eight hundred and one fetuses (23.0%) were affected and all except three couples opted for termination of these pregnancies. Genetic counseling and PND is the only way to reduce the burden of disease. With awareness, there was a shift from second trimester to first trimester PND over each decade, with an increasing number of couples coming during the first pregnancy. There are only 15 to 20 centers in India offering PND. We have compared our study with other reports on PND from different regions in India.

Comment on: Endocrinopathies complicating transfusion-dependent hemoglobinopathy. Need for better assessment of skeletal complications.

[No Abstract Available].

The Present and Future Global Burden of the Inherited Disorders of Hemoglobin.

The inherited disorders of hemoglobin represent the most common monogenic diseases. This article provides a brief description of the main inherited disorders of hemoglobin and their classification, and summarizes progress made in the last decade toward a better awareness and recognition of these disorders as a global health problem. Also presented are the main demographic, genetic, and environmental factors that influence the present and future health burden of these disorders. The strengths and limitations of existing estimates and current health policies in high-, low-, and middle-income countries are discussed.

Premarital screening for hemoglobinopathies: experience of a single center in Kurdistan, Iraq.

BACKGROUND: A program for the prevention of major hemoglobinopathies was initiated in 2008 in the Kurdistan region of Iraq. This study reports on the achievements and challenges of the program. METHODS: A total of 102,554 individuals (51,277 couples) visiting a premarital center between 2008 and 2012 were screened for carrier status of hemoglobinopathies, and at-risk couples were counseled. RESULTS: A total of 223 (4.3/1,000) couples were identified and counseled as high-risk couples. Available data on 198 high-risk couples indicated that 90.4% proceeded with their marriage plans, and 15% of these married couples decided to have prenatal diagnosis (PND) in subsequent pregnancies with the identification of 8 affected fetuses; all were terminated as chosen by the parents. Thirty affected births were recorded among the high-risk couples. The premarital program managed to reduce the affected birth rate of major hemoglobinopathies by 21.1%. Of the 136 affected babies born during the study period, 77.9% were born to couples married prior to the start of the program, while 22.1% were born to couples identified as having a high risk. The main reason for not taking the option of PND was unaffordable costs. CONCLUSIONS: Financial support would have increased opting for PND by high-risk couples. Further reduction in affected birth rates could be achieved by including parallel antenatal screening programs to cover those married before the initiation of the premarital program and improving the public health education and counseling programs.

The attitudes and intention to participate in hemoglobinopathy carrier screening in The Netherlands among individuals from Turkish, Moroccan, and Surinamese descent.

OBJECTIVE: To explore factors that influence intention to participate in hemoglobinopathy (HbP) carrier screening under Dutch subjects at risk, since HbP became more common in The Netherlands. METHOD: Structured interviews with 301 subjects from Turkish, Moroccan, or Surinamese ethnicity. RESULTS: Half of the participants were familiar with HbP, 27% with carrier screening. Only 55% correctly answered basic knowledge items. After balanced information, 83% percent of subjects express intention to participate in HbP carrier screening. Intention to participate was correlated with (1) anticipated negative feelings, (2) valuing a physician's advice, and (3) beliefs on significance of carrier screening. Risk perception was a significant determinant, while respondents were unaware of HbP as endemic in their country of birth. Respondents preferred screening before pregnancy and at cost < 50€. CONCLUSION: These findings show the importance of informing those at risk by tailored health education. We propose easy access at no costs for those willing to participate in HbP carrier screening.

'A morass of considerations': exploring attitudes towards ethnicity-based haemoglobinopathy-carrier screening in primary care.

BACKGROUND: The Netherlands does not have a national haemoglobinopathy (HbP)-carrier screening programme aimed at facilitating informed reproductive choice. HbP-carrier testing for those at risk is at best offered on the basis of anaemia. Registration of ethnicity has proved controversial and may complicate the introduction of a screening programme if based on ethnicity. However, other factors may also play a role. OBJECTIVE: To explore perceived barriers and attitudes among GPs and midwives regarding the registration of ethnicity and ethnicity-based HbP-carrier screening. METHODS: Six focus groups in Dutch primary care, with a total of 37 GPs (n = 9) and midwives (n = 28) were conducted, transcribed and content analysed using Atlas-ti. RESULTS: Both GPs and midwives struggled with correctly identifying ethnicities at risk for HbP. Ethical concerns regarding privacy seemed to originate from World War II experiences, when ethnic and religious registration facilitated deportation of Jewish citizens, coupled with the political climate at the time focus groups were held. Some respondents thought the ethnicity question might undermine the relationship with their clients. Software programmes prevented GPs from registering ethnicity of patients at risk. Financial implications for patients were also a concern. Despite this, respondents seemed positive about screening and were familiar with identifying ethnicity and used this for individual patient care. CONCLUSIONS: Although health professionals are generally positive about screening, ethical, financial and practical issues surrounding ethnicity-based HbP-carrier screening need to be clarified before introducing such a programme. Primary care professionals can be targeted through professional organizations but they need national policy support.

Cost effective improvement in the protocol for detection of haemoglobin variants -a step forward in quality assurance.

BACKGROUND: We report the results of a cost effective improvement in the protocol for detection of haemoglobin variants which incorporates the findings of peripheral blood film along with the results of HPLC. FINDINGS: A total of n = 10,844 samples were received from January 2011 till August 2011. Diagnosis of haemoglobinopathy was made in n = 1123 samples while other abnormalities included iron deficiency anaemia, megaloblastic anaemia, malarial parasite, autoimmune haemolytic anaemia and G6PD deficiency (n = 2473). CONCLUSION: We diagnosed 23% of abnormalities other than haemoglobinopathy by reviewing peripheral smear of samples received for detection of haemoglobin variants. This resulted in providing proper diagnosis to the referring physician without increment in cost.

Practical diagnosis of red cell disorders in southern Spain.

BACKGROUND: Hereditary red cell disorders are associated with a protective effect against malaria, which results in an increased prevalence in malaria-endemic areas. Migratory flows from these areas are resulting in a marked increase in such abnormalities in Southern Spain. METHODS: All hemoglobin disorders diagnosed between 1997 and 2010 have been recorded. Since 2008, we have performed systematic screening for hemoglobinopathies on African patients. A high-pressure liquid chromatography system was used as screening method for structural hemoglobinopathies and for separation of hemoglobin (Hb) F and A(2). RESULTS: We detected 666 cases in patients of foreign origin and 308 in native Spanish patients. Thalassemias (thal) are the most frequent disorders amongst the local population: ß-thal minor, 57.1% (176/308); α-thal, 18.2% (56/308), and δß-thal, 7.8% (24/308). In ethnic minorities, there is a huge variety of hemoglobinopathies: heterozygous Hb S, 45% (300/666); heterozygous Hb C, 15% (100/666); ß-thal minor, 13.7% (91/666); α-thal, 10.2% (68/666); Hb SS in 14 patients, and Hb CC in 9 patients. Of the native patients, 14 were found to have Hb AS and 9 Hb AC. CONCLUSION: Given the modern migratory flows, greater knowledge of these disorders is needed by all medical staff, and new practical and cost/time-effective diagnostic approaches have to be devised.

Ethical implications and practical considerations of ethnically targeted screening for genetic disorders: the case of hemoglobinopathy screening.

The prevalence of hemoglobinopathies differs among populations due to genetic differences and due to the protective effects of the heterozygote (carrier) state against malaria. Because of the difference in genetic distribution, public health programs have weighed the ethical versus practical implications of ethnically targeted versus universal newborn, and where applicable, prenatal screening. We examine newborn and prenatal screening for hemoglobinopathies in relation to the use of 'race' and ethnicity to assess risk for genetic conditions. First, categories of race/ethnicity are social constructs, therefore, observed or self-identified broad racial/ethnic categories are correlated but not necessarily reliable indicators of geographic ancestry or genetic risk. Second, targeting based on ethnicity poses serious issues of logistics and equity for public health programs and clinical services. In the past, newborn screening for hemoglobinopathies in the United States and United Kingdom was often selective, targeted to women of certain ethnic groups or areas with large concentrations of ethnic minority groups. Presently, newborn screening for hemoglobinopathies is universal in both countries and programs emphasize that individuals of all ethnic backgrounds are at risk for carrying a hemoglobin genetic variant. Reported race/ethnicity is still used as a criterion for offering prenatal carrier testing in the United States, where it is not a public health responsibility. In the United Kingdom, prenatal screening under the National Health Service is universal in high-prevalence areas and in low-prevalence areas is targeted based on reported ancestry. The continued use of targeted prenatal screening in both countries reflects the different purposes and modes of laboratory testing in newborn and prenatal screening. The ethical imperative to identify as many affected infants with life-threatening conditions as possible in newborn screening programs is not applicable to prenatal carrier testing. Because newborn screening dried blood spot specimens are tested for multiple disorders, targeted screening poses serious logistical challenges which is not the case in prenatal screening.

Internet-based approach to population screening for common hemoglobinopathies in United Arab Emirates.

This article reports on efforts to overcome common hurdles that were faced during population-based screening for common hemoglobinopathies in the United Arab Emirates. An Internet-based approach was designed and implemented to increase the acceptance of the screening program. The process involved: an awareness campaign, a simple bilingual (Arabic/English) online consent form and registration process, the use of a barcode for sample labeling, an equipment upgrade, electronic communication of a successful registration process, test results, and a counseling process. Before the implementation of the Internet-based system, great concern was noted among the clients in terms of the availability of accurate and timely test results, the need for pretest and post-test counseling, and the way that their personal health information was handled. Lapses in information exchange between the clients who participated in the screening program for the carrier state of inherited disorders and the screening laboratory posed significant challenges. The emphasis on confidentiality and the ease of access to services was instrumental in increasing the level of acceptance of these services in our community. Based on an analysis of > 10,000 samples, we conclude that Internet-based reporting holds much promise for improving the quality of care that clients receive.

Australian guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle cell disease and other congenital anaemias.

Iron overload is the most important cause of mortality in patients with thalassaemia major. Iron chelation is therefore a critical issue in the management of these patients and others with transfusion-dependent haemoglobinopathies and congenital anaemias. In recent years, significant developments have been made in the assessment of iron overload, including the use of magnetic resonance imaging for measuring liver and cardiac iron. Advances in the modalities available for iron chelation, with the advent of oral iron chelators including deferiprone and deferasirox in addition to parenteral desferrioxamine, have expanded treatment options. A group of Australian haematologists has convened to formulate guidelines for managing iron overload on the basis of available evidence, and to describe best consensus practice as undertaken in major Australian Haemoglobinopathy units. The results of their discussions are described in this article, with the aim of providing guidance in the management of iron overload in these patients.

Thalassemia and hemoglobinopathies in Southeast Asian newborns: diagnostic assessment using capillary electrophoresis system.

BACKGROUND: We have investigated the Capillarys 2 Hemoglobin testing system to assist in presumptive diagnosis of thalassemia and hemoglobinopathies commonly found in Southeast Asia. METHODS: Study was conducted on 226 newborns. Hematological parameters were recorded and Hb profiles were examined on the Capillarys 2 Hemoglobin analyzer (SEBIA). DNA analyses were used to establish the final diagnoses. RESULTS: Among 226 newborns examined, 122 had thalassemias with 17 different genotypes. The capillary electrophoresis system could provide useful data for presumptive diagnoses of cases, especially those with Hb E and α-thalassemia. Hb E was found to be 2.6-6.2% in heterozygote whereas Hb Bart's were clearly observed in cases with compound heterozygous or homozygous α(+)-thalassemia and heterozygous α(0)-thalassemia. Hb H disease and other forms of α-thalassemia could be differentiated based on the presence of Hb Bart's and its percentage. CONCLUSION: The capillary electrophoresis system is applicable to newborn screening for common forms of thalassemia in Southeast Asia.

Neonatal screening for hemoglobinopathies: results of a public health system in South Brazil.

AIM: The aim of this study was to estimate the prevalence of hemoglobinopathies in South Brazil. METHODS: Samples of dried blood spots collected by heel prick in neonates were evaluated by isoeletric focusing and/or high-performance liquid chromatography techniques. All variants were characterized at the molecular level. RESULTS: A total of 437,787 samples were evaluated. Among these, 6391 showed an abnormal hemoglobin pattern. These included 48 cases (0.01%) of sickle cell disorders (33 hemoglobin SS [Hb SS], 7 Hb SC, 7 Hb S/beta thalassemia, 1 Hb SD), 1 neonate who was homozygous for beta thalassemia, 6272 (1.4%) newborns who were heterozygous for Hb S, C, or D, and 71 (0.02%) neonates who were carriers for rare hemoglobin variants. Most of these rare variants were identified for the first time in Brazil. CONCLUSIONS: Comparing these results with those obtained in other Brazilian regions, we observe a highly heterogeneous distribution. This knowledge is useful in healthcare planning and allocation of resources, as well as identifying at-risk couples, which will assist with disease prevention.

Frequency of haemoglobinopathies at premarital health screening in Dohuk, Iraq: implications for a regional prevention programme.

beta-thalassaemia major and sickle-cell disease are important health problems in Iraq. To provide information for a prevention programme, the frequency of haemoglobin disorders was mapped in Dohuk governorate. A total of 591 couples (1182 individuals) attending health centres for premarital health screening were tested; 44 (3.7%) were found to be carriers of ,-thalassaemia, 14 (1.2%) of the sickle-cell gene and 1 (0.1%) of deltabeta3-thalassaemia. A total of 3 couples (i.e. 5/1000) were at risk of having a child with beta-thalassaemia major, and the estimated number of affected children with a major haemoglobinopathy was 39 per year. The findings stress the importance of a regional prevention programme for haemoglobinopathies based on premarital screening, counselling and prenatal diagnosis.

Premarital screening programmes for haemoglobinopathies, HIV and hepatitis viruses: review and factors affecting their success.

This literature review is a comprehensive summary of premarital (prenuptial) screening programmes for the most prevalent hereditary haemoglobinopathies, namely thalassaemia and sickle cell disease, and the important infections HIV (human immunodeficiency virus) and hepatitis viruses B and C (HBV and HCV). It describes the background to premarital screening programmes and their value in countries where these diseases are endemic. The use of premarital screening worldwide is critically evaluated, including recent experiences in Saudi Arabia, followed by discussion of the outcomes of such programmes. Despite its many benefits, premarital testing is not acceptable in some communities for various legal and religious reasons, and other educational and cultural factors may prevent some married couples following the advice given by counsellors. The success of these programmes therefore depends on adequate religious support, government policy, education and counselling. In contrast to premarital screening for haemoglobinopathies, premarital screening for HIV and the hepatitis viruses is still highly controversial, both in terms of ethics and cost-effectiveness. In wealthy countries, premarital hepatitis and HIV testing could become mandatory if at-risk, high-prevalence populations are clearly identified and all ethical issues are adequately addressed.