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Genetic screening, health care and the insurance industry. Should genetic information be made available to insurers?

The potential use of genetic tests in insurance has raised concerns about discrimination and individuals losing access to health care either because of refusals to test for treatable diseases, or because test-positives cannot afford premiums. Governments have so far largely sought to restrict the use of genetic information by insurance companies. To date the number of tests available with significant actuarial value is limited. However, this is likely to change, raising more clearly the question as to whether the social costs of adverse selection outweigh the social costs of individuals not accessing health care for fear of the consequences of test information being used in insurance markets. In this contribution we set out the policy context and model the potential trade-offs between the losses faced by insurers from adverse selection by insurees (which will increase premiums reducing consumer welfare) and the detrimental health effects that may result from persons refusing to undergo tests that could identify treatable health conditions. It argues that the optimal public policy on genetic testing should reflect overall societal benefit, taking account of these trade-offs. Based on our model, the factors that influence the outcome include: the size of and value attached to the health gains from treatment; deterrent effects of a disclosure requirement on testing for health reasons; incidence of the disease; propensity of test-positives to adverse select; policy value adverse selectors buy in a non-disclosure environment; and price elasticity of demand for insurance. Our illustrative model can be used as a benchmark for developing other scenarios or incorporating real data in order to address the impact of different policies on disclosure and requirement to test.

Genetic Privacy↗

Assessment of an interactive computer-based patient prenatal genetic screening and testing education tool.

The Enhancing Patient Prenatal Education study tested the feasibility and educational impact of an interactive program for patient prenatal genetic screening and testing education. Patients at two private practices and one public health clinic participated (N = 207). The program collected knowledge and measures of anxiety before and after use of the tool. Time in various prenatal visit activities was collected prior to and after the introduction of the education tool. Providers completed an assessment of their experiences with patients who had used the program. Results indicate that patient knowledge significantly increased from pre to post (p = .0001) with no increase in anxiety (p = .31). Time in clinic activities, including overall visit time, increased. A majority of providers indicated that the program disrupted clinic flow. This assessment suggests that the program increases patient knowledge and does not increase patient anxiety. However, challenges remain to using this program in a clinic setting.

Adolescent↗

On genetic screening of donors for artificial insemination.

Reliable information on the frequency of birth defects in children conceived by artificial insemination is lacking and should be collected. Genetic screening of donors for artificial insemination is recommended, and guidelines are proposed. These consider the kinds of disorder in the presumptive donor, or his relatives, that would preclude his use as a donor, and the steps to be taken with relatives, that would preclude his use as a donor, and the steps to be taken with respect to genetic counseling if a defective baby is born following the procedure.

Abortion, Spontaneous↗

Control of beta-thalassaemia by carrier screening, genetic counselling and prenatal diagnosis: the Sardinian experience.

Homozygous beta-thalassaemia in a number of at-risk populations (Greek and Turkish Cypriots, Greeks, Continental Italians and Sardinians) has been prevented at the population level by programmes based on carrier screening, genetic counselling and prenatal diagnosis. The Sardinian experience is based on a 20-year programme. Voluntary screening has been offered to prospective parents and, primarily, to women with an ongoing pregnancy. Education of the population at large, training of health personnel, and use of posters and informative booklets have been critical elements for the success of the programme. Genetic counselling has been carried out in a non-directive manner following well-established guidelines. The use of extended family screening magnified the efficacy of the screening programme, allowing the identification of the large majority of parents at risk by screening only 13% of the population at child-bearing age. Following counselling, the large majority of parents accepted prenatal diagnosis. Definition of the parents' mutation and prenatal diagnosis were carried out by a number of PCR-based procedures. The programme was effective, as indicated by the reduction of the birth rate of thalassaemia major from 1:250 live births to 1:4000.

Genetic Counseling↗

Novel genetic screen for genes involved in posterior body patterning in Drosophila.

Much of our current understanding of how cytoplasmic determinants are localized and activated stems from genetic analyses in Drosophila. Characterization of mutants defective in establishing the initial embryonic body pattern has revealed the importance of mRNA localization and translational control and identified several factors required for these processes. Nevertheless, many additional genes are likely to be involved. Here, we describe a novel genetic screen designed to identify genes that participate in posterior body patterning, an elaborate process involving the sequential use of two localized cytoplasmic determinants, the products of the oskar and nanos genes. From the screen, we recovered new alleles of genes known to be required for posterior body patterning, demonstrating the validity of the approach. In addition, we isolated numerous other mutants. Further characterization of one mutant, P58, revealed that it is a novel allele of bullwinkle. We find that in bullwinkle mutants, oskar mRNA localization is not maintained in the embryo and oskar protein accumulates ectopically and to abnormally high levels. These defects are distinct from previously described perturbations in oskar activity and provide new insights into the regulation of oskar.

Animals↗

Forward genetic screens to identify circadian rhythm mutants in mice.

This article describes the methods and techniques used to produce mutagenized mice to conduct high-throughput forward genetic screens for circadian rhythm mutants in the mouse. In particular, we outline methods to safely prepare and administer the chemical mutagen N-nitroso-N-ethylurea (ENU) to mice. We also discuss the importance of selecting mouse strain and outline breeding strategies, logistics, and throughput to produce these mutant mice. Finally, we discuss the breeding strategies that we use to confirm mutation heritability.

Animals↗

Are pregnant Australian women well informed about prenatal genetic screening? A systematic investigation using the Multidimensional Measure of Informed Choice.

BACKGROUND: Ethical practice requires that decisions to participate in medical care be well informed. Investigations into prenatal genetic screening for Down syndrome have assessed women's knowledge but have not examined whether being well informed about the potential consequences of screening, such as subsequent diagnostic testing, diagnosis and termination, is associated with psychological distress for women. AIMS: To assess informed choice to participate in second trimester maternal serum screening (2MSS) in pregnant women using a validated measure and to compare anxiety levels in women who were well informed versus poorly informed. METHODS: A prospective cohort study where pregnant women completed the Multidimensional Measure of Informed Choice and the Hospital Anxiety and Depression Scale immediately prior to the offer of 2MSS. Follow-up questionnaires assessing psychological symptomatology were completed at 20 and 30 weeks gestation. RESULTS: Only 37% of decisions were informed; those who participated in screening were more likely to have made an informed decision than those who did not (P = 0.01); 31% did not know that miscarriage was a possible consequence of diagnostic testing subsequent to an increased risk screening result and only 62% correctly identified that termination of pregnancy would be offered if Down syndrome were to be diagnosed. Short-term anxiety levels in those who were well informed were not significantly different from those who were poorly informed (P = 0.14). CONCLUSIONS: Health promotion strategies, which are readily applicable in clinical settings and address diverse learning needs and attitudes of pregnant women, are needed. The impact of antenatal screening on other dimensions of pregnancy psychology remains to be investigated.

Anxiety↗

Development of an enhanced GFP-based dual-color reporter to facilitate genetic screens for the recovery of mutations in mice.

Mutagenesis screens to isolate a variety of alleles leading to null and non-null phenotypes represent an important approach for the characterization of gene function. Genetic schemes that use visible markers permit the efficient recovery of chemically induced mutations. We have developed a universal reporter system to visibly mark chromosomes for genetic screens in the mouse. The dual-color reporter is based on a single vector that drives the ubiquitous coexpression of the enhanced GFP (EGFP) spectral variants yellow and cyan. We show that widespread expression of the dual-color reporter is readily detected in embryonic stem cells, mice, and throughout developmental stages. CRE-loxP- and FLPe-FRT-mediated deletion of each color cassette demonstrates the modular design of the marker system. Random integration followed by plasmid rescue and sequence-based mapping was used to introduce the marker to a defined genomic location. Thus, single-step placement will simplify the construction of a genomewide bank of marked chromosomes. The dual-color nature of the marker permits complete identification of genetic classes of progeny as embryos or mice in classic regionally directed screens. The design also allows for more efficient and novel schemes, such as marked suppressor screens, in the mouse. The result is a versatile reporter that can be used independently or in combination with the growing sets of deletion and inversion resources to enhance the design and application of a wide variety of genetic schemes for the functional dissection of the mammalian genome.

Animals↗

Genetic screen for modifiers of the rough eye phenotype resulting from overexpression of the Notch antagonist hairless in Drosophila.

Hairless was identified as antagonist in the Notch signaling pathway based on genetic interactions. Molecularly, Hairless inhibits Notch target gene activation by directly binding to the Notch signal transducer Su(H). Additional functional domains apart from the Su(H) binding domain, however, suggest additional roles for the Hairless protein. To further our understanding of Hairless functions, we have performed a genetic screen for modifiers of a rough eye phenotype caused by overexpression of Hairless during eye development. A number of enhancers were identified that comprise mutations in components of Notch- and EGFR-signaling pathways, some unknown genes and the gene rugose. Mutant alleles of rugose display manifold genetic interactions with mutants in Notch and EGFR signaling pathway components. Accordingly, the rugose eye phenotype is rescued by Hairless and enhanced by Delta. Molecularly, interactions might occur at the protein level because rugose appears not to be a direct transcriptional target of Notch.

A Kinase Anchor Proteins↗

[Preimplantation genetic screening for numerical chromosomal abnormalities in embryos from women of 35 years of age and older; first results in The Netherlands].

OBJECTIVE: To assess the results of preimplantation genetic screening (PGS) for numerical chromosomal abnormalities in embryos from women of 35 years of age and older. DESIGN: Prospective, descriptive. METHOD: Women who were at least 35 years received standard IVF/ICSI treatment including ovarian hyperstimulation, after which matured oocytes were recovered and inseminated. Three days after insemination, one cell was biopsied from each of the available embryos. In these cells, the copy number of 5 (first 21 patients) or 8 chromosomes was determined using fluorescence in situ hybridisation (FISH). Only embryos with a normal or unknown FISH result were implanted in the uterus. Data were collected in an electronic database. RESULTS: PGS was done for 28 IVF- and 22 ICSI-treatments; the average age of the 50 women at the beginning of treatment was 38.5 years. There were 360 embryos generated; of the 288 biopsied embryos 156 (54%) contained an abnormal number of chromosomes. In 45 women, 1 or 2 embryos were transferred. This resulted in 8 ongoing pregnancies (8/50; 16%) and the birth of 9 children, all of whom were found to be healthy on a paediatric examination at 3 to 10 months of age. In 4 cases there was no embryo transfer because all the embryos were chromosomally abnormal. CONCLUSION: In the first 50 patients in The Netherlands, PGS resulted in an ongoing pregnancy rate of 16% per woman. All children showed normal growth and development.

Adult↗

Diagnostic approach, genetic screening and prognostic factors of medullary thyroid carcinoma.

Medullary thyroid carcinoma is the least frequent thyroid neoplasm; it originates in thyroid parafollicular cells (calcitonin secreting C cells). In 80% of cases it is sporadic, in the remaining 20% it is familial, associated or not to other endocrinopathies as pheochromocytoma and hyperparathyroidism (MEN 2A, MEN 2B, and isolated familial medullary thyroid carcinoma). Preclinical diagnosis in relatives of affected subjects (preferably at pediatric age) is essential for successful therapy and is performed with genetic and biochemical screening tests. The genetic screening is based on DNA analysis (RET proto-oncogene mutations) of the patient, and if positive of all first degree relatives, to separate sporadic (somatic mutations) from familial (germline mutations) forms. The biochemical screening is based on calcitonin determination and its increase after pentagastrin stimulation, (a peculiar characteristic of medullary thyroid carcinoma, the first biochemical disorder in a subject at risk) and is mainly used in genetically silent familial medullary thyroid carcinoma. The principal negative prognostic factors of medullar thyroid carcinoma and the debate concerning the use of calcitonin determination in the diagnosis of the "cold" thyroid nodule have been analyzed.

Algorithms↗

Future impact of genetic screening in occupational and environmental medicine.

New genetic technologies open up the possibility of predictive screening, both for individual genetic risk factors for susceptibility to workplace hazards and for late onset (both single gene and multifactorial) hereditary disease. Although the initiative for testing may lie with employers and employees there are many potential stakeholders--from family members and workplace colleagues to insurers and society in general. The role of the occupational health professional will not only involve the contextual interpretation of genetic test results but also the myriad of associated ethical and moral questions. This paper considers a range of ethical issues with which the occupational health professional may be confronted as genetic technology advances.

Environmental Medicine↗

A mosaic genetic screen for genes necessary for Drosophila mushroom body neuronal morphogenesis.

Neurons undergo extensive morphogenesis during development. To systematically identify genes important for different aspects of neuronal morphogenesis, we performed a genetic screen using the MARCM system in the mushroom body (MB) neurons of the Drosophila brain. Mutations on the right arm of chromosome 2 (which contains approximately 20% of the Drosophila genome) were made homozygous in a small subset of uniquely labeled MB neurons. Independently mutagenized chromosomes (4600) were screened, yielding defects in neuroblast proliferation, cell size, membrane trafficking, and axon and dendrite morphogenesis. We report mutations that affect these different aspects of morphogenesis and phenotypically characterize a subset. We found that roadblock, which encodes a dynein light chain, exhibits reduced cell number in neuroblast clones, reduced dendritic complexity and defective axonal transport. These phenotypes are nearly identical to mutations in dynein heavy chain Dhc64 and in Lis1, the Drosophila homolog of human lissencephaly 1, reinforcing the role of the dynein complex in cell proliferation, dendritic morphogenesis and axonal transport. Phenotypic analysis of short stop/kakapo, which encodes a large cytoskeletal linker protein, reveals a novel function in regulating microtubule polarity in neurons. MB neurons mutant for flamingo, which encodes a seven transmembrane cadherin, extend processes beyond their wild-type dendritic territories. Overexpression of Flamingo results in axon retraction. Our results suggest that most genes involved in neuronal morphogenesis play multiple roles in different aspects of neural development, rather than performing a dedicated function limited to a specific process.

Animals↗

Genetic screening for hearing loss.

The recent discovery that mutations in GJB2, the gene that encodes connexin 26 (Cx26), are responsible for up to half the cases of autosomal recessive non-syndromic hearing loss and a significant proportion of sporadic hearing loss has had immense implications for medical evaluation and genetic screening. It is now possible to couple mutational analysis of GJB2 with universal screening and provide an unequivocal diagnosis of inherited hearing loss in up to 50% of babies with severe to profound non-syndromic hearing loss. Currently, other genetic tests should be performed on the basis of specific clinical features. Current potential candidates for screening include SLC26A4, in the presence of specific temporal bone anomalies, and WFS1, in the presence of a low-frequency hearing loss.

Connexin 26↗

Genetic screening of newborns.

Screening of newborn infants for genetic disease began over 35 years ago as a public health measure to prevent mental retardation in phenylketonuria (PKU). It was so successful that tests for several other genetic disorders were added. We review the current status of this screening, including discussions of the genetic disorders often covered and the results of newborn screening for them. We emphasize recent advances. These include expansion of coverage for genetic disorders with the new methodology of tandem mass spectrometry (MS-MS) and the introduction of molecular (DNA) testing to increase the specificity of testing for several disorders, thereby reducing false-positive rates. These and other advances have also produced issues of criteria for screening, missed cases, and appropriate use of stored newborn specimens.

Age Factors↗

Genetic screening technology: ethical issues in access to tests by employers and health insurance committees.

Whereas the introduction of new technologies previously has raised the ethical question of who ought to have access to a new procedure or device, genetic testing technology raises the new ethical question of to whom access to a new technology ought to be limited. In this article we discuss the implications of employers and private health insurance companies having access to genetic testing technology. Although there may be legitimate business interests in allowing employers and insurers to conduct genetic screening, there are other valid societal interests in regulating or limiting the use of this technology by third parties. Public policy developed in the area of new genetic technology must reflect such interests.

Employment↗

[Genetic screening of patients with familial hypercholesterolemia and insurability for life insurance policies and disability cover policies].

In the Netherlands, people with familial hypercholesterolaemia (FH) have been actively screened since 1994 by means of DNA analysis. Recently, the Stichting Opsporing Erfelijke Hypercholesterolemie (Foundation for the Detection of Familial Hypercholesterolaemia) initiated a large scale-screening programme aimed at finding all 40,000 people. The Dutch ministry of Health, Welfare and Sport is providing the financial support. Genetic screening has social implications and raises questions on insurability. The Dutch Medical Examination Act prohibits insurers from posing questions about untreatable, serious inheritable conditions for insured sums under a certain value: for life-insurance policies < [symbol: see text] 150,000 and for disability-cover policies < [symbol: see text] 30,000 in the 1st year and < [symbol: see text] 20,000 in the 2nd year and following years. The Health Council of the Netherlands has defined FH as a serious disease, but one which responds well to treatment. Therefore insurers can request information for the purpose of an accurate risk classification. Insurance contracts can be accepted at normal rates if the target value of LDL-cholesterol < 4 mmol/l and additional risk factors such as smoking and an abnormal BMI are absent; the risk is determined by the phenotype and clinical factors and not by the genotype.

DNA Mutational Analysis↗