The diffusion of new genetic tests for predicting disease.

This paper examines the pathways by which new genetic tests will become available to the public. In view of the scarcity of genetic specialists, the pathway is likely to involve primary care physicians. Other pathways entail state-mandated testing, community-based programs, or testing by laboratories without much involvement of primary care physicians. When testing does become available the "destination" will be either family-centered testing or population-oriented screening. The deterrent to screening will not be the inability to detect disease-causing mutations but the costs and attitudes of providers and the public. When tests are provided primarily to provide information about risks to future children, some people will oppose screening on religious or moral grounds. When there are no inexpensive treatments, some will fear that insurance companies and employers will use tests to deny them health care coverage. Some may not want to know their risks for disorders about which little can be done. For common, multifactorial disorders, genetic tests will have low predictive value. Because of these problems, the decision to be tested, regardless of the destination, requires that "testees" be fully informed and consent to testing. When acceptance rates are low, screening is less likely to be cost-effective; family-centered testing becomes the default destination.     

Genetic counseling for beta-thalassemia trait following health screening in a health maintenance organization: comparison of programmed and conventional counseling.

Providing adequate counseling of patients identified in genetic screening programs is a major responsibility and expense. Adults in a health maintenance organization, unselected for interest, were screened for beta-thalassemia trait as part of preventive health care. Counseling was provided by either a trained physician (conventional counseling) or by a videotape containing the same information followed by an opportunity to question a trained physician (programmed counseling). Immediately before and after counseling, knowledge of thalassemia, knowledge of genetics, and mood change were assessed by questionnaire. Comparable mood changes and similar learning about thalassemia and genetics occurred with both counseling methods. Thus, as judged by immediate effects on knowledge and mood, videotaped instruction can greatly reduce professional time required for genetic counseling and facilitate the incorporation of genetic screening into primary health care.     

Mental health policies on reporting child sexual abuse and physician‐patient sexual relationships

The reporting of child sexual abuse (CSA) and physician-patient sexual relationships (PPSR) are currently the focus of professional, legal and media attention in several countries. This paper briefly reviews mental health policies on these issues and reports on a WPA survey of them. While the WPA Madrid Declaration permits breaching confidentiality for mandatory reporting of CSA and clearly prohibits PPSR, it is not known how or to what extent these policies are implemented in WPA Member Societies’ countries. It is also not known whether policies or laws exist on these topics nationally or to what extent psychiatrists and the public are aware of them. Representatives of WPA Member Societies were e-mailed a survey about issues pertaining to CSA and PPSR. Fifty-one percent of 109 countries replied. All reporting countries had laws or policies regarding the reporting of CSA, but this was often voluntary (63%) and without protection for reporting psychiatrists either by law (29%) or by Member Societies (27%). A substantial number of psychiatric leaders did not know the law (27%) or their Society’s policy (11%) on these matters. With respect to PPSR, some reporting countries lacked laws or policies about PPSR with current (17%) or past (56%) patients. Fewer than half of responding representatives believed that their Society’s members or the public were well informed about the laws and policies pertaining to CSA or PPSR. There is clearly a wide range of laws, policies and practices about CSA and PPSR in WPA Member Societies’ countries. There is a need in some countries for laws or supplemental policies to facilitate the protection of vulnerable child and adult patients through clear, mandatory reporting policies for CSA and PPSR. Mechanisms to protect and support reporting psychiatrists should also be developed where they do not already exist. There is also a need in some countries to develop strategies to improve the education of psychiatrists, trainees, and the public on these issues.     

Twenty-year outcome analysis of genetic screening programs for Tay-Sachs and beta-thalassemia disease carriers in high schools.

Programs for education, screening, and counseling of senior-high-school students, in populations at high risk for Tay-Sachs and beta-thalassemia diseases, have existed for >20 years in Montreal. Four process and outcome variables are reported here: (i) voluntary participation rates in the high-school cohort; (ii) uptake rates for the screening test; (iii) origin of carrier couples seeking the prenatal diagnosis option in the programs; and (iv) change in incidence of the two diseases. Between 1972 and 1992, we screened 14,844 Ashkenazi-Jewish students, identified 521 HexA-deficient carriers (frequency 1:28), reached 89% of the demographic cohort in the educational component of the program, and achieved 67% voluntary participation in the subsequent screening phase. The corresponding data for the beta-thalassemia program are 25,274 students (mainly of Mediterranean origin) representing 67% of the cohort with 61% voluntary participation in the screening phase (693 carriers; frequency 1:36). From demographic data, we deduce that virtually all the carriers identified in the high-school screening program remembered their status, had their partner tested if they did not already know they were a carrier couple, and took up the options for reproductive counseling/prenatal diagnosis. In Montreal, the current origin of all couples using prenatal diagnosis for Tay-Sachs and beta-thalassemia diseases is the corresponding genetic screening/testing program, whereas, at the beginning of the programs, it was always because there was a history of an affected person in the family. Incidence of the two diseases has fallen by 90%-95% over 20 years; the rare new cases are born (with two exceptions) outside the target communities or to nonscreened couples.     

Fostering caring relationships: Suggestions to rethink liberal perspectives on the ethics of newborn screening

Newborn screening (NBS) involves the collection of blood from the heel of a newborn baby and testing it for a list of rare and inheritable disorders. New biochemical screening technologies led to expansions of NBS programs in the first decade of the 21st century. It is expected that they will in time be replaced by genetic sequencing technologies. These developments have raised a lot of ethical debate. We reviewed the ethical literature on NBS, analyzed the issues and values that emerged, and paid particular interest to the type of impacts authors think NBS should have on the lives of children and their families. Our review shows that most authors keep their ethical reflection confined to policy decisions, about for instance (a) the purpose of the program, and (b) its voluntary or mandatory nature. While some authors show appreciation of how NBS information empowers parents to care for their (diseased) children, most authors consider these aspects to be ‘private’ and leave their evaluation up to parents themselves. While this division of moral labor fits with the liberal conviction to leave individuals free to decide how they want to live their private lives, it also silences the ethical debate about these issues. Given the present and future capacity of NBS to offer an abundance of health‐related information, we argue that there is good reason to develop a more substantive perspective to whether and how NBS can contribute to parents’ good care for children.     

Lack of interest by nonpregnant couples in population-based cystic fibrosis carrier screening.

We used signs and letters to offer free cystic fibrosis (CF) carrier screening to nonpregnant adults in stable relationships who visited numerous clinical and nonclinical sites in Nashville. A total of 179 individuals (<<1% of those eligible) elected to be tested. To understand this observation, we used questionnaires to assess individuals' attitudes about genetic testing in general and about CF carrier screening in particular (n=873). Participants expressed conflicting views about carrier screening. More than 90% of people thought that genetic testing should at least be available. Most respondents said that the views of their partners and physicians were important in their decision making, and most believed that these others favored genetic testing. Yet, more than two-thirds indicated that such factors as insurability, being "at risk," what they would need to learn, abortion, and religious beliefs were important in their decision making, opinions that mitigated against genetic testing. In particular, one-third feared that carriers would lose their health insurance, one-quarter said that they would have been more interested had they been able to provide DNA by buccal swab rather than by finger stick, and less than one-sixth believed that genetic testing was meddling in God's plan. In the face of both the low level of use of free CF carrier screening by nonpregnant couples when it was not offered in person by health-care professionals and the wide variety of concerns demonstrated, we believe that clinicians should not routinely offer carrier screening to nonpregnant individuals who do not have a family history of CF.     

Issues in newborn screening

Newborn screening aims at the earliest possible recognition of disorders so that intervention with effective treatment can prevent the most serious consequences of the disorder. However, of several thousand known genetic disorders, therapy is presently available for only a small proportion of them. Newborn screening was first applied to phenylketonuria (PKU). Presently, newborn screening programs have been implemented in 26 countries for different diseases. However, potential problems in newborn screening programs that make implementation of newborn screening programs difficult include quality assessment, concerns about professional and technical competence, and ethical considerations. It has been shown that in the process from sampling the newborn to reporting of the screening results most errors are made in the pre- and post-analytical phases. It appears that much more could be done for the fetus if genetic screening and diagnostics could be accomplished early in pregnancy rather than after birth.     

Screening and genetic counseling for beta-thalassemia trait in a population unselected for interest: effects on knowledge and mood.

To evaluate the effects of genetic screening and counseling in a population unselected for interest, adults in a health maintenance organization (HMO) were screened for beta-thalassemia trait as part of health care or multiphasic screening. Counseling was provided by either a trained physician or a videotape containing the same information, followed by an opportunity to question a trained physician. Knowledge of thalassemia, knowledge of genetics, and mood were assessed by standardized questionnaires and by interview immediately before and after counseling. Compared to controls, trait subjects demonstrated significant learning about thalassemia (P less than .001) and about genetics (P less than .001) and recorded significant mood changes, namely, surprise (startle) (P less than .05), increased alertness (decreased deactivation) (P less than .05), and decreased skepticism (P less than .01). Screening and genetic counseling for beta-thalassemia trait conducted as part of multiphasic screening of the population of a HMO, essentially and unselected population, can result in significant overall learning with acceptable effects on mood.     

The aims of expanded universal carrier screening: Autonomy,prevention, and responsible parenthood

Expanded universal carrier screening (EUCS) entails a population‐wide screening offer for multiple disease‐causing mutations simultaneously. Although there is much debate about the conditions under which EUCS can responsibly be introduced, there seems to be little discussion about its aim: providing carrier couples with options for autonomous reproductive choice. While this links in with current accounts of the aim of foetal anomaly screening, it is different from how the aim of ancestry‐based carrier screening has traditionally been understood: reducing the disease burden in the population. The reasons why the aim of EUCS is presented in terms of ‘autonomy’ rather than ‘prevention’ have not been spelled out in the literature. This paper seeks to fill this gap by considering the morally relevant similarities and dissimilarities between foetal anomaly screening, ancestry‐based carrier screening and EUCS. When carrier screening is performed in the prenatal period, enhancing autonomy appears the most appropriate aim of EUCS, as the alternative of ‘prevention through selective abortion’ would urge women to terminate wanted pregnancies. However, when screening is conducted in the preconception period, carrier couples can avoid the birth of affected children by other means than selective abortion, for instance preimplantation genetic diagnosis. To the extent that this increased control over passing on a genetic disorder raises questions of parental responsibility, it seems necessary that the account of the aims of EUCS is wider than only in terms of enhancing reproductive autonomy.     

Knowledge and attitudes toward Tay-Sachs disease among a college student population.

To assess the feasibility of screening the single Jewish population for Tay-Sachs disease (TSD), a questionnaire examining the knowledge of and attitudes toward TSD and genetic screening was sent to 348 Yale University Jewish undergraduates. Of those students responding (63 percent), 78 percent were able to answer general genetic questions correctly while only 1.9 percent could answer specific Tay-Sachs questions correctly. A majority of the students (93.9 percent) indicated some concern about being a carrier for TSD, believed that carrier status would affect future social and reproductive behavior, and expressed an interest in having TS carrier status determined while still single (77.4 percent). Strong correlations were found between knowledge and attitudes, but no significant differences appeared between male and female respondents. In addition to leading to improvements in Tay-Sachs screening programs, the observations have led to suggestions that may be generalized to other genetic screening programs.     

Carrier screening for Gaucher disease in couples of mixed ethnicity

With the advent of mutational analysis for Gaucher disease, carrier screening has been incorporated into many Jewish genetic disease screening programs. Frequencies and mutations for Gaucher disease in non-Jewish populations are less well established and the detection rate of carriers are lower. Testing is problematic for resolving residual risk in a couple of mixed ethnicity. We report the testing choices made by 20 consecutive couples of mixed ethnicity where the Ashkenazi Jewish partner was identified to be a Gaucher disease gene carrier. Carrier studies of the non-Jewish partner were elected as follows: DNA studies alone, 5 (25%); enzymatic assay, 2 (10%); both, 6 (30%); no carrier studies, 7 (35%). Of the 7 couples not electing carrier studies, one was not in a pregnancy and 6 elected prenatal diagnosis in lieu of parental testing by enzymatic analysis of amniocytes. One couple elected parental carrier studies as well as prenatal diagnosis. All couples electing prenatal Gaucher determination had amniocentesis for other indications as well (4, advanced maternal age; 4, parental anxiety). We conclude that Gaucher screening is feasible for couples of mixed ethnicity if appropriate counseling and testing are offered.     

DNA elution and amplification by polymerase chain reaction from dried blood spots.

A quick, sensitive and easily automatizable method for PCR amplification of genomic DNA eluted from dried blood spots is described. DNA is eluted from a 3-mm spot routinely used for neonatal screening of inherited diseases either by boiling or by sonication. A preliminary and brief spot-autoclaving step is mandatory to ensure optimal and reproducible PCR amplifications. Only 1% of the eluted DNA is required for PCR analysis allowing the execution of multiple genetic tests on the same blood spot. The method has been successfully applied to the detection of a known phenylketonuria-causing mutation and will facilitate the analysis of the genetic repository provided by Guthrie's cards stored in neonatal screening laboratories.     

Somatic chromosomal abnormalities in infertile men and women

Infertility--the inability to achieve conception or sustain a pregnancy through to live birth--is very common and affects about 15% of couples. While chromosomal or genetic abnormalities associated with azoospermia, severe oligozoospermia or primary ovarian failure were of no importance for reproduction prior to the era of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), advances in assisted reproductive techniques (ART) now enable many infertile couples to have children. These developments have raised the question of the genetic consequences of ICSI: concerns of the potential harm of the invasive procedure and concerns about the genetic risk. The infertile male and female definitely have an increased risk to carry a chromosomal abnormality. Detection of such an abnormality is of fundamental importance for the diagnosis of infertility, the following treatment, the evaluation of the risk for the future child and the appropriate management of the pregnancy to be obtained. Therefore, cytogenetic screening of both partners is mandatory prior to any type of ART. The present review is based on several surveys on male and female infertility and analyzes the types and frequencies of the different reported chromosome abnormalities according to the type of impairment of spermatogenesis and the type of treatment planned or performed. With regard to assisted reproductive techniques (especially ICSI) the main types of chromosomal abnormalities are discussed and their potential risks for ICSI. If available, reported cases of performed ICSI and its outcome are presented. The detection of an abnormal karyotype should lead to comprehensive genetic counselling, which should include all well-known information about the individual type of anomaly, its clinical relevance, its possible inheritance, the genetic risk of unbalanced offspring, and the possibilities of prenatal diagnosis. Only this proceeding allows at-risk couples to make an informed decision regarding whether or not to proceed with ART. These decisions can be made only when both partners have clearly understood the genetic risks and possible consequences when ART is used.     

Population-based genetic screening.

A preventive genetic programme aimed to control beta-thalassemia in the Sardinian population is based on a combination of increased awareness of the population, carrier screening, genetic counselling and prenatal diagnosis. As a result, the registry of thalassemia major demonstrated a profound decline in the incidence of this disease from 1 per 250 to 1 per 1200 live births, with 90% of cases effectively prevented.     

CMA says no to mandatory hepatitis B vaccination,screening for MDs

Should vaccination of physicians against hepatitis B, as well as subsequent screening for the virus, be mandatory? The CMA says no: the voluntary route is the way to go. But Health Canada disagrees. Its new guidelines call for mandatory vaccination and subsequent screening of exposure-prone physicians for the virus.     

Role of the physician in screening for carriers of Tay-Sachs disease.

A screening test for carriers of Tay-Sachs disease has been available in Toronto for more than 6 years. In that time more than 11 000 Jewish residents have been tested. Most had requested testing after hearing about the screening program from friends or the media; few had been advised by their physicians to be tested. To sample the attitudes of physicians in Toronto towards carrier screening, we studied questionnaire responses of 42 physicians whose practices were composed largely of Jewish patients. Only 31% regularly advised their young adult Jewish patients to have a carrier screening test but 76% said they had patients who asked if they should be tested. Of the 14 (33%) who had had one or more patients with Tay-Sachs disease 6 did not advise carrier testing. There was a positive correlation between specialty training and support for the screening program. Methods for increasing physician advocacy of these programs are discussed.     

Cancer risk models and preselection for screening

Objective: The invitation to population screening is based on age criteria in many countries. Screening is not offered to younger or older participants, because the benefits in these age groups do not outweigh the harms. One could argue that it is not so much age that determines the benefits but the risk of developing preclinical and treatable cancer. Cancer risk varies with age but is also affected by other factors. Methods: We performed a systematic review for risk models for the three types of cancer for which population screening programs exist: breast, cervical and colon cancer. We used an evaluation scheme that distinguishes three phases of model development: model derivation, validation and impact analysis. Data were collected in August 2010. Results: We identified two colorectal, four breast and three cervix cancer risk models. One colorectal, four breast and none of the cervix cancer models have been externally validated. We could not identify evaluations of the impact on population screening effectiveness. Conclusion: We conclude that risk models for the pre-selection of screening have been developed. These models could improve the pre-selection for screening, help in making personal decisions about participation, and reduce adverse effects of population screening. The validity of this hypothesis, as well as practicalities and issues of equity and reliability, have to be tested in further studies.     

Gène CFTR et infertilité masculine en 2001 Conseil génétique, diagnostic prénatal, diagnostic pré-implantatoire

As the vas deferens is also absent in the majority of CF (cystic fibrosis) males, it has been proposed that CBAVD (Congenital Bilateral Absence of Vas Deferens) males may present an incomplete or mild form of CF. Many studies using more extensive mutation analysis have confirmed the role of CFTR gene defects: 80% of CBAVD patients carry one or two mutations. Each patient with a diagnosis of CBAVD should also be examined for pulmonary and pancreatic signs, and sweat tests should be performed. In couples with CBAVD linked to CFTR mutations, the risk of having children with CF or infertility is increased if the female is also a carrier. The woman should be screened for the most frequent CFTR mutations according to her ethnic background. After screening for 80% of the mutations responsible for CF, the residual risk of being a carrier with negative screening is: Z=h(1?a)/(1?ah)=1/120 considering a carrier frequency of 1/25 in the general population. In the case of positive screening, antenatal diagnosis by chorionic villus sampling may be proposed. However, in some situations it is difficult to predict the phenotypic consequences for the child, particularly when a severe transmutation of a variable allele is identified. As these couples require medically-assisted reproduction techniques, pre-implantation genetic diagnosis appears to be more appropriate than antenatal diagnosis. Only embryos that inherit the non-mutated maternal CFTR allele are replaced in the uterus. Examination of childre born to couples with CBAVD is mandatory: immunoreactive trypsinogen assay at 3 days of age, sweat test at 3 months and clinical examination, especially looking for signs of CF. Identification of CFTR mutations in a CBAVD patient has important consequences for his family. Each sibling has a 50% risk of being a carrier and a 25% risk of inheriting the same genotype. The genetic counsellor must inform these siblings about the possible risk of having CF children if they carry CFTR mutations and if their partner is also a carrier.     

Combining several screening tests: optimality of the risk score

The development of biomarkers for cancer screening is an active area of research. While several biomarkers exist, none is sufficiently sensitive and specific on its own for population screening. It is likely that successful screening programs will require combinations of multiple markers. We consider how to combine multiple disease markers for optimal performance of a screening program. We show that the risk score, defined as the probability of disease given data on multiple markers, is the optimal function in the sense that the receiver operating characteristic (ROC) curve is maximized at every point. Arguments draw on the Neyman-Pearson lemma. This contrasts with the corresponding optimality result of classic decision theory, which is set in a Bayesian framework and is based on minimizing an expected loss function associated with decision errors. Ours is an optimality result defined from a strictly frequentist point of view and does not rely on the notion of associating costs with misclassifications. The implication for data analysis is that binary regression methods can be used to yield appropriate relative weightings of different biomarkers, at least in large samples. We propose some modifications to standard binary regression methods for application to the disease screening problem. A flexible biologically motivated simulation model for cancer biomarkers is presented and we evaluate our methods by application to it. An application to real data concerning two ovarian cancer biomarkers is also presented. Our results are equally relevant to the more general medical diagnostic testing problem, where results of multiple tests or predictors are combined to yield a composite diagnostic test. Moreover, our methods justify the development of clinical prediction scores based on binary regression.     

HIV-infection in Estonia

Only a few cases of clinical AIDS have been diagnosed in the Baltic countries that previously were part of the Soviet Union. This suggests that the spread of HIV-infection has been much slower than in several other countries belonging to the previous Eastern Europe. To get a more precise picture of the situation, we have analyzed the data from seroepidemiological screening programs that have been conducted in Estonia since June 1987. Large population groups were tested according to a decree by the former soviet All-Union center on AIDS. On several occasions the tests were mandatory and probably had a coverage close to 100%. After more than a million serum samples were tested, 29 HIV-infected persons, 3 women and 26 men have been identified. One of them was HIV-2 positive. Most of them live in Tallinn, the capital city of Estonia. All cases probably have a sexually transmitted infection. In one the infection has proceeded to clinical AIDS. Analysis of the gene sequences of several strains suggests that the strains are closely related and that the number of sources of infection is quite small. The study suggests that the spread of HIV in Estonia is still quite limited. A contributing factor may be the restricted possibilities for travel to the Western countries during the Soviet era.