Preconceptional screening of couples for carriers of cystic fibrosis: a prospective evaluation of effects, costs and savings for different mutation detection methods

OBJECTIVE: The aim of this study was to perform a prospective evaluation of the effects, costs and savings of a preconceptional screening programme of couples for carriers of cystic fibrosis (CF). METHODS: A decision model for both single-entry two-step (SETS) and double-entry two-step (DETS) couple screening was constructed. Two mutation detection methods were considered: allele-specific oligonucleotide (ASO) hybridisation screening of 32 mutations, with a sensitivity of 90%, and denaturing gradient gel electrophoresis (DGGE), with a sensitivity of 98%. In our model, the following combinations were used: (1) ASO for both steps; (2) DGGE for both steps, and (3) ASO for the first step and DGGE for the second step. The model is demonstrated using figures from the Netherlands, where there is a carrier frequency of 1:30. We estimated the value of different choices and probabilities in a decision tree and determined the costs of screening for CF and the costs of the illness itself. RESULTS: We found that with most of the combinations of mutation detection methods, SETS couple screening could offer positive net savings in the Netherlands. The ASO/DGGE combination resulted in the highest net savings. DETS couple screening for all combinations, including testing with DGGE in both steps, did not show a positive cost-savings balance at all, not even with an uptake rate of 100%. The maximum number of carrier couples identified when screening 100,000 couples with the ASO/DGGE combination was 98 (SETS). This could result in about 25 fewer children born with CF each year in the Netherlands, under the following assumptions: (1) each couple has two children and 10% of couples are unable to have children; (2) of detected carrier couples, 15% decide not to have children and 85% make use of prenatal diagnosis; (3) of those fetuses diagnosed with CF, 80% are aborted, and (4) prenatal diagnosis carries a 0.75% risk of iatrogenic abortion. CONCLUSIONS: The results of this evaluation show that there are no financial objections to the preconceptional screening of couples in the Netherlands when the above-mentioned assumptions apply; thus, further evaluation can concentrate on the balance of the non-economic consequences of screening for participants and for society.     

Economic evaluation of prenatal population screening for fragile X syndrome

OBJECTIVES: This paper models costs and benefits of a population screening programme for pregnant women to detect fragile X syndrome. Given the high lifetime costs of fragile X and the high sensitivity and specificity of testing, such a programme may seem attractive. METHODS: Economic evaluation. RESULTS: Our base case results indicate that such a programme seems close to cost neutral, so may indeed seem attractive for this reason. However, sensitivity analysis shows that assumptions regarding lifetime costs are crucial to results; our results suggest if lifetime costs are under AUD 2.5 million, costs of screening will exceed future costs avoided. CONCLUSIONS: Economic modelling of screening programmes reveals valuable information which might have an influence on the debate on the social value of a population screening programme for fragile X in pregnant women.     

How should preconceptional cystic fibrosis carrier screening be provided? Opinions of potential providers and the target population

BACKGROUND: Since the identification of the cystic fibrosis (CF) gene, large-scale CF carrier screening has become possible. One possible target group is couples planning a pregnancy (preconceptional screening), providing a maximum number of reproductive options and a minimum of time constraints. OBJECTIVES: To identify obstacles in the implementation of a preconceptional CF carrier screening programme, to find out how potential providers and the target population think the screening should be implemented, and to determine whether potential providers think they are able to provide the screening programme. METHODS: A survey was conducted among 200 general practitioners (GPs), 134 Municipal Health Service (MHS) workers and 303 recently married couples. RESULTS: 52% (102/197) of the eligible GPs participated, 84% (113/134) of the MHS workers and 70% (380/544) of the individuals planning a pregnancy. In general, potential providers and the target population had a positive attitude towards CF screening. Preferred methods of informing the target population were: in leaflets, during a GP consultation for those people seeking advice before pregnancy, and sending a personal invitation to all people of reproductive age. Potential providers believed that they would be able to provide the screening programme. Important perceived obstacles were the absence of a preconceptional care setting, high workload, and lack of financial resources. CONCLUSION: Different intervention strategies will be necessary to overcome the obstacles in the implementation. The positive attitude towards CF carrier screening in combination with the willingness of the potential providers to participate in the screening programme will make it easier to overcome the obstacles.     

Community-based program for the diagnosis and prevention of genetic disorders in Cuba. Twenty years of experience

The author's experience of 20 years as director of the medical genetic services program in Cuba is presented. The setting of the infrastructure for equipment and the training of personnel for the medical genetic program began in 1981 in the city of Havana, and was progressively extended to cover the whole country in 1988. Between 1982 and 2002, 2.8 million pregnant women were tested for sickle cell carrier status, 96,000 carriers and 4,786 couples at risk were detected and offered genetic counseling and prenatal diagnosis. In the same period, the combination of maternal serum alpha-fetoprotein screening and fetal ultrasound led to the prenatal diagnosis of anomalies in several thousand fetuses. The accessibility to legal abortion, and the autonomous decisions by the majority of couples to terminate abnormal pregnancies reduced the prevalence of neural tube defects and sickle cell disease at birth by 90 and 65%, respectively, by 2002. In the span of approximately 20 years, 22,690 pregnant women at risk received prenatal chromosomal diagnosis. Newborn screening for phenylketonuria and congenital hypothyroidism was established. Genetic counseling was offered to every detected person or family at risk for genetic conditions. The network of medical genetic services established in the country received a very positive acceptance by the population. A very successful connection with the primary health care level was established.     

Attitudes toward genetic counseling in the United Arab Emirates

AIMS: To assess the level of understanding of genetic advice given in the Genetic Clinic and attitudes toward consanguineous marriages, and prenatal, abortion and preconception diagnoses. METHODS: One hundred couples underwent structured interviews, and various social and educational data, reason for referral and diagnosis and advice given were recorded. Three months later, the couples were asked open-ended questions about the perceived causation of the disease, recurrence risk, plans for births, and prenatal, abortion and preconception diagnoses. RESULTS: Half of the couples acknowledged a genetic basis for their child's condition but only 10 remembered the risk given to them. There was a high correlation between educational level and remembering the risk, and the number of healthy children and future plans for further children. Almost half preferred consanguineous marriages and only 10% agreed with prenatal diagnosis and abortion, while 75% agreed with carrier screening and preconception diagnosis in affected families. CONCLUSION: Effective genetic counseling in this community requires an informed educated population and introduction of carrier screening and preconception diagnosis in affected families.     

Genetic services and research in the state of Minas Gerais, Brazil

The state of Minas Gerais in Brazil has a surface of 586,528 km(2), and 18 million inhabitants. Infant mortality rate is 20/1,000, and congenital anomalies are its second cause. There are 11 medical schools where basic genetics, but not clinical genetics, is taught. Genetic services in the state include: newborn screening for hypothyroidism, phenylketonuria, sickle cell disease and cystic fibrosis; clinical-genetic diagnostic evaluation and counseling; prenatal diagnosis, fetal medicine and paternity testing. Medical genetic services and research are underdeveloped because of limitations such as lack of health policies in genetics, small number of trained specialists, little knowledge about genetics among health professionals and low reimbursement rates.     

Detection of Congenital Anomalies by Fetal Ultrasonographic Examination across Europe

Objectives: Birth defects are a major health burden. Primary prevention is at present emerging, i.e. folate supplementation. When it is not possible, as is still the case for most birth defects, research is needed to determine how an optimal provision of prenatal diagnosis and use of services can be achieved. Ultrasound scans in the midtrimester of pregnancy are now a routine part of antenatal care in most European countries. The objective of this study was to evaluate the prenatal diagnosis of congenital anomalies by fetal ultrasonographic examination across Europe. Methods: Data from 20 registries of congenital malformations in 12 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to 3 fetal scans offered, including 2 for biometric purposes and 1 for search of congenital anomalies, the anomaly scan. Results: There were 8,126 cases with congenital anomalies with an overall prenatal detection rate of 44.3%. Termination of pregnancy was performed in 1,657 cases (21.8%). There was significant variation in the prenatal detection rate between regions with the lowest detection rate in registries of countries without routine fetal screening (Denmark and The Netherlands) and the highest detection rate in registries of countries with at least 1 anomaly scan (France, Germany, Italy, Spain, UK). However, there were large variations among the registries with a high detection rate. There were significant differences in the prenatal detection rate and proportion of induced abortions between isolated anomalies and associated anomalies (chromosomal aberrations, recognized syndromes, and multiple without chromosomal aberrations or recognized syndromes). Conclusions: Prenatal detection rate of congenital anomalies by fetal scan varies significantly between registries of European countries even with the same screening policy. Prenatal detection of congenital anomalies is significantly higher when associated malformations are present. The rate of induced abortions varies between registries of countries even with the same detection rate of congenital anomalies. The variation described may be due to cultural and policy differences. Copyright 2002 S. Karger AG, Basel     

Community genetics and dignity in diversity in the Quebec Network of Genetic Medicine

The Quebec Network of Genetic Medicine (QNGM), implemented in 1971, has been an integrated program of community genetics serving the population (approximately 7.5 million) of Quebec province in Canada. QNGM reported to the Minister of Social Affairs and operated under an umbrella of universal health insurance in the province. The Network's programs have been run by members of the four university medical schools of the province under the direction of a central committee. A global annual budget was awarded to QNGM from its inception. Among its many programs, QNGM supported: (1) two newborn screening programs (using blood and urine samples) for early diagnosis, treatment and research in phenylketonuria, hereditary tyrosinemia, congenital hypothyroidism, and in a large number of other hereditary metabolic diseases; (2) follow-up of confirmatory diagnostic tests at regional centers, followed by supervision of ambulatory treatment modalities; (3) carrier screening and reproductive counseling for Tay-Sachs and beta-thalassemia diseases; (4) a spectrum of feasibility (research) studies (e.g., screening for biotinidase deficiency, neuroblastoma, hemoglobinopathies, and cystic fibrosis) to inform policy decisions. QNGM performed economic analyses of its major programs and followed prevailing ethical guidelines. Its global budget and integrated structure terminated in 1994, although some of its programs continue independently.     

The Hungarian periconceptional service as a model for community genetics

OBJECTIVES: This review describes the methods and results of the Hungarian periconceptional service consisting of counselling, examinations and medical interventions. (The term periconceptional is used instead of preconceptional because the early postconceptional period is also involved to this service.) METHODS: The service was based on three steps: check-up examination of reproductive health (i.e., preconceptional screenings), a 3-month preparation for conception, dispensed and/or supervised by qualified nurses, and a better protection in early pregnancy for the most sensitive early development of the embryo for voluntary and eligible couples. RESULTS: Experiences from the coordinating centre of the Hungarian periconceptional service are summarized between February 1, 1984, and January 31, 1999, thus 15 years. Participants with positive family histories, case histories and subjects with genito-urinary infections had a more effective flow towards secondary care. Infertile couples were diagnosed and treated sooner. The periconceptional service is effective for the introduction of periconceptional folic acid-containing multivitamin supplementation and for the reduction of smoking and alcohol consumption in females in the preconceptional period. The rate of major congenital abnormalities (20.6 per 1,000) was significantly lower than expected. CONCLUSIONS: The periconceptional service is feasible and has many benefits. Thus, proper preparation for conception is the earliest and probably the most important effort to prevent genetic diseases.     

Campaign to control genetic blood diseases in Bahrain

Genetic blood diseases are frequent in Bahrain as in all Middle Eastern countries. Previous neonatal screening in 1984-1985 showed that the birth prevalence of sickle cell disease (SCD) was 2.1%, of sickle cell trait 11% and of glucose-6-phosphate dehydrogenase (G6PD) deficiency 25%. The Ministry of Health recognized the importance of controlling these diseases. In 1984, the first genetic clinic was established, which started the educational campaigns. Information booklets were prepared and distributed widely in schools and clubs in an attempt to increase awareness about these diseases among students and the public. In 1991, the Bahrain Hereditary Anemia Society was formed. In 1992, the Minister of Health formed a national committee for the prevention of genetic diseases in Bahrain. Screening of all pregnant women began, followed by newborn testing if the mother was found to be a carrier. In 1993, a premarital counseling (PMC) service was organized and in 1998, a student-screening project began. At this stage, we want to update the national birth prevalence figure by screening Bahraini newborns for these genetic diseases. This will help to design prevention programs and to measure the effect of health education on the previous birth prevalence figure. SUBJECTS AND METHODS: A newborn screening study was conducted to determine the effects of this long-term campaign (16-18 years). Cord blood samples from 2,000 Bahraini newborns were tested for hemoglobinopathies and G6PD deficiency using HPLC. RESULTS: 18 newborns were found to have SCD. The new birth prevalence figure for SCD in Bahrain is 0.9%, which indicates a 60% decline in the birth prevalence rate. CONCLUSION: With the continuation of education, awareness campaigns, screening of carriers and PMC, we expect the number of affected children born to be reduced tremendously over the next few years.     

Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency

OBJECTIVES: To compare the overall birth prevalence of diagnosed glycogen storage disease type II (GSD II) with the predicted frequency based on mutation screening, in order to determine whether GSD II is an underdiagnosed condition, and to analyze which medical disciplines recognize GSD II. METHODS: Retrospective data on all enzymatic diagnoses of GSD II were collected from diagnostic labs throughout the Netherlands, covering the period from January 1, 1972 to December 31, 1996. Age-specific diagnostic incidence rates were calculated for the entire study period. By adding together the diagnostic incidences for all age groups, we calculated the birth prevalence of diagnosed GSD II and compared these figures with the predicted frequency based on mutation screening in a random sample from the general population. The medical specialization of the referring clinicians was also recorded. RESULTS: GSD II was diagnosed in 154 individuals, including 11 prenatal diagnoses. The birth prevalences of the various phenotypes were 1/101,000 (infantile form), 1/720,000 (juvenile form) and 1/53,000 (adult form). The birth prevalence of the adult and infantile phenotype together was 1/35,000. Eighty-two percent of the patients were diagnosed in university hospitals. Of the patients with infantile GSD II, 71% were diagnosed by a pediatrician, whereas most patients with adult GSD II were diagnosed by a neurologist (80%). CONCLUSIONS: There is no evidence for the underdiagnosis of GSD II in the Netherlands, as the calculated birth prevalences of the disease are consistent with previous predictions based on mutation screening in a random sample of newborns. The worldwide birth prevalence of the disease may well be higher than 1 in 100,000. GSD II is mainly diagnosed in university hospitals.     

Screening for alpha-thalassemia-1 heterozygotes in expecting couples by the combination of a simple erythrocyte osmotic fragility test and a PCR-based method

OBJECTIVE: To develop a simple method for the prospective identification of couples at risk of homozygous alpha-thalassemia-1 (Hb Bart's hydrops fetalis) in pregnancy. METHODS: Antenatal care (ANC) women and their husbands were analyzed using a simple erythrocyte osmotic fragility (EOF) test and a PCR-based method for the detection of the mutation leading to alpha-thalassemia-1 of the Southeast Asian type (SEA). RESULTS: Heterozygosity for the alpha-thalassemia-1 (SEA) deletion was found to correlate with an EOF value <60%. For a prospective screening, ANC women and their husbands are analyzed with the EOF test and only those having a value <60% were further checked by PCR. Of 2,769 cases analyzed during a 6-month period, 24 couples in which both partners are heterozygotes could be identified for genetic counseling and prenatal diagnosis. The application of the EOF test decreased the workload for PCR by approximately 80%. CONCLUSION: Prospective screening for alpha-thalassemia-1 (SEA) heterozygotes in northern Thailand is becoming easier to realize by the combination of EOF test and PCR.     

Comparison of hybrid and standard discontinuous Galerkin methods in a mesh-optimisation setting

This paper assesses the benefits of hybridization on the accuracy and efficiency of high-order discontinuous Galerkin (DG) discretizations. Two hybridized methods are considered in addition to DG: hybridized DG (HDG) and embedded DG (EDG). These methods offer memory and computational time savings by introducing trace degrees of freedom on faces that become the only globally-coupled unknowns. To mitigate the effects of solution singularities on accuracy, the methods are compared in an adaptive setting on meshes optimised for the accurate prediction of chosen scalar outputs. Compressible flow results for the Euler and Reynolds-averaged Navier-Stokes equations demonstrate that the hybridized methods offer cost savings relative to DG in memory and computational time. In addition, for the cases tested, EDG yields the lowest error levels for a given number of degrees of freedom. These benefits disappear on uniformly-refined meshes, indicating the importance of using order-optimised meshes when comparing the discretizations.     

Is cystic fibrosis carrier screening cost effective?

Between 2001 and 2005, 6,166 females underwent cystic fibrosis (CF) carrier screening at our institution. Only 36% were Caucasian. We identified 143 carrier females and subsequently tested 85 of their partners. The observed carrier frequency was not significantly different than expected for any racial or ethnic group tested. We identified 6 positive couples (5 Caucasian, 1 Arab American) and 1 affected fetus. In just under 4 years, our institution spent approximately $334,000 on CF population screening. Comparing this to the lifetime medical cost for a CF patient, CF population-based carrier screening is cost effective at our institution, despite the high number of non-Caucasians being screened.     

Informed consent and subject motivation to participate in a large, population-based genomics study: the Marshfield Clinic Personalized Medicine Research Project

BACKGROUND: The objective of this study was to measure subject perspective and reaction to participation in the Personalized Medicine Research Project (PMRP) and to identify factors predicting understanding of the study elements. METHOD: Self-administered questionnaires were mailed to 1,593 subjects (10% sample). The questionnaire had three sections: section A consisted of 21 factual questions; section B consisted of 14 questions to assess the level of understanding about the PMRP concepts, and section C asked about the purpose of the PMRP. RESULTS: The mean age of the 924 survey respondents was 52 years (SD = 16.9), with a range of 18-95 years. The majority of participants were female (n = 561, 61%). The percent of total correct responses for section A was significantly higher for females compared with males (males: 58.4% and females: 60.4%, t test = -2.18, p = 0.03) and age was significantly inversely related to percent of correct responses (beta coefficient = -0.122, p < 0.001). More than one third of the participants indicated that the USD 20 greatly influenced their decision to participate in the project. In a multiple logistic regression model, people living outside of Marshfield were significantly more likely to indicate that the USD 20 greatly influenced their decision to participate (odds ratio = 1.40, 95% confidence limit = 1.06, 1.86) and age was inversely related to the monetary influence on decision to participate (odds ratio = 0.98, 95% confidence limit = 0.97, 0.98). CONCLUSION: Future community consultation efforts should highlight areas of lower understanding. In addition, research coordinators may need to take more time informing males and older individuals about project details so that they are making truly informed decisions about study participation.     

Preventing congenital anomalies in developing countries

The birth prevalence of congenital anomalies in developing countries is similar to that observed in developed countries. However, the health impact of birth defects is higher because of a lack of adequate services for the care of affected infants and a higher rate of exposures to infections and malnutrition. A number of successful measures for the prevention of congenital anomalies are being taken in a number of developing nations. Primary prevention programs are based on public education about preconceptional and prenatal risks. Prevention based on reproduction options includes teratogen information services and prenatal screening for fetal anomalies. In addition, programs for the detection of congenital malformations at birth, followed by early treatment, are contributing to secondary prevention. Prevention of congenital anomalies in the developing world requires: (a) good epidemiological data on the prevalence and types of birth defects and genetic disorders; (b) educating health professionals in the goals and methods of preventing birth defects at low cost but with high impact, and (c) expansion of family planning and improvement of antenatal care combined with educational campaigns to avoid the risks for birth defects. The basis for public health preventive measures should be the primary health care level. In a sizable proportion of developing countries, the stage is already set for these measures to be implemented. Required are education, political will, and proper organization and allocation of resources.     

Cancer genetics service provision: a comparison of seven European centres

OBJECTIVE: To conduct a survey in seven European cancer genetics centres to compare service provision, organisation and practices for familial breast and colon cancer consultations and testing. Information was obtained on aspects of services both nationally and locally. METHODS: A detailed survey questionnaire was adapted collaboratively to obtain the required information. Initial survey data were collected within each centre and interim results were discussed at two European Workshops. Where differences in practice existed, details were clarified to ensure accuracy and adequacy of information. Participating centres were Haifa (Israel), Hannover (Germany), Leiden (The Netherlands), Leuven (Belgium), Manchester (UK), Marseille (France) and Milan (Italy), representing countries with populations ranging from 6.5 to 80 million. RESULTS: The European countries diverged in regard to the number of cancer genetics centres nationally (from 8 in Belgium to 37 in France), and the average population served by each centre (from 0.59 million in Israel to 3.32 million in Italy). All centres offered free care at the point of access, but referral to specialist care varied according to national health care provision. At a centre level, staff roles varied due to differences in training and health care provision. The annual number of counsellees seen in each participating centre ranged from 200 to over 1,700. Access to breast surveillance or bowel screening varied between countries, again reflecting differences in medical care pathways. These countries converged in regard to the wide availability of professional bodies and published guidelines promoting aspects of service provision. Similarities between centres included provision of a multidisciplinary team, with access to psychological support, albeit with varying degrees of integration. All services were dominated (70-90%) by referrals from families with an increased risk of breast cancer despite wide variation in referral patterns. Collection of pedigree data and risk assessment strategies were broadly similar, and centres used comparable genetic testing protocols. Average consultation times ranged between 45 and 90 min. All centres had access to a laboratory offering DNA testing for breast and bowel cancer-predisposing genes, although testing rates varied, reflecting the stage of service development and the type of population. Israel offered the highest number of genetic tests for breast cancer susceptibility because of the existence of specific founder mutations, in part explaining why the cancer genetics service in Haifa differed most from the other six. CONCLUSION: Despite considerable differences in service organisation, there were broad similarities in the provision of cancer genetic services in the centres surveyed.     

A Commentary on the NIH Consensus Development Statement 'Genetic Testing for Cystic Fibrosis'

A NIH Consensus Development Statement recommends implementation of a cystic fibrosis carrier screening in the general pregnant and pre-pregnant population. This suggestion is discussed in the light of missing or insufficient data about the reasons for high uptake rates in pilot projects, psychological and social risks, and optimal educational and counselling settings. It is concluded that the recommendation is not defendable and, at best, premature.     

Economic evaluation of the familial cancer programme in Western Australia: predictive genetic testing for familial adenomatous polyposis and hereditary non-polyposis colorectal carcinoma

AIM: To evaluate costs and outcomes of genetic testing for familial colorectal cancer through services provided by Genetic Services of Western Australia (GSWA). METHODS: Costs and outcomes of predictive DNA-based testing for inherited colorectal cancers (CRC) were assessed, specifically for familial adenomatous polyposis (FAP) and hereditary non-polyposis CRC (HNPCC) using a decision-analysis model. Costs were assigned according to standards of care in Western Australia (WA). Cancer risks and the efficacy of surveillance on long-term outcomes were derived from the published literature. RESULTS: The cost-effectiveness of genetic testing was compared in first-degree relatives of known mutation carriers who have a 50% risk of carrying the mutated gene (intervention group) to individuals with the same risk but who do not undergo a genetic test (control subjects). Compared with control subjects undergoing the same high-level surveillance and surgery, the FAP and HNPCC intervention groups provided total savings of 13,390 US dollars and 14,783-15,460 per person (males-females), respectively. HPNCC mutation carriers also gained 1 CRC-free year. Compared to control subjects having only population surveillance, individuals in the FAP intervention group delayed the onset of CRC by 40 years for a net cost of 9,042 US dollars. Individuals in the HNPCC intervention group delayed the onset of CRC by 8 years at a net cost of 12,141 US dollars for males and 12,596 US dollars for females. CONCLUSIONS: Genetic testing for familial CRC in WA allows targeted surveillance for mutation carriers, which ensures the efficient use of resources and reduces cancer-related morbidity, if clinical recommendations for intervention are adopted.