Triple Test Screening for Down Syndrome: Looking Back on a False-Positive Result and Having or Not Having a Triple Test in Subsequent Pregnancies

Objectives: It was the main aim of the present retrospective study carried out in Flanders to evaluate how women with a false-positive triple test result look back on their experience and decision making and how many of them make use of the triple test in subsequent pregnancies. Methods: All 508 women tested in the Centre for Human Genetics in Leuven in 1995 who had a positive triple test result followed by a normal amniocentesis outcome were invited to participate in a mailed questionnaire study with open and multiple choice questions in 1998. The response rate was 68%. Results: The answers to the multiple choice question assessing how they look back on their initial expectations regarding the exact meaning of the triple test revealed that less than one half reported that it concerned the identification of 'a higher risk of carrying a child with Down syndrome (DS)'. Reporting correct initial expectations was significantly associated with a higher education level. The same holds for indecisiveness regarding pregnancy termination should the amniocentesis have detected a fetus with DS. As expected, a large majority of the women reported a high level of distress or worry after the communication of the positive triple test result. Overall the findings show that retrospectively most women had the feeling that the decision to have amniocentesis was their own decision rather than a professional's. Of the subgroup with one or more subsequent pregnancies 70% had another triple test. Conclusions: The overall results of this study clearly reveal a need for a systematic approach aimed at better informing and counselling pregnant women about the implications and limitations of the triple test. Notwithstanding the reported high level of distress caused by a positive triple test result, a large majority of the women with subsequent pregnancies had another triple test; they represent a clearly higher percentage than in another recent study. Copyright 2001 S. Karger AG, Basel     

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.     

High distress in parents whose children undergo predictive testing for long QT syndrome

OBJECTIVES: To assess the psychological effect of predictive testing in parents of children at risk for long QT syndrome (LQTS) in a prospective study. METHODS: After their child was clinically screened by electrocardiography and blood was taken for DNA analysis, and shortly after delivery of the DNA test result, 36 parents completed measures of psychological distress. RESULTS: 24 parents were informed that at least one of their children is a mutation carrier. Up to 50% of the parents of carrier children showed clinically relevant high levels of distress. Parents who were familiar with the disease for a longer time, who had more experiences with the disease in their family and who received positive test results for all their children were most distressed. CONCLUSIONS: Predictive ECG testing together with DNA testing has a profound impact on parents whose minors undergo predictive testing for LQTS.     

Information-seeking behaviour and psycho-social interactions during the genetic testing process

OBJECTIVES: The first aim of this study was to investigate the information-seeking behaviour (ISB) of women attending cancer genetic consultations at which the possibility of BRCA testing is considered. We focused here specifically on ISB apart from the cancer genetic consultation, i.e. on what complementary sources of information about genetic testing were consulted and what factors were involved in this behaviour. The second aim was to study the role of the social network used by the patients to collect various opinions on which to base their decisions about being tested. METHODS: A prospective cohort study (2000-2002) was therefore carried out on all women attending a single cancer genetic clinic in France after a BRCA1/2 analysis had been proposed. Closed questionnaires were administered before and after the second cancer genetic consultation. The purpose of this consultation was to confirm the patient's decision to be tested. RESULTS: Results were analysed in 108 subjects (mean age 47 years, SD 11 years; 74% affected by breast/ovarian cancer). Prior to the 2nd consultation, 35.2% of the women had actively looked for information about BRCA1/2 testing, as compared to 25.0% afterwards. After multivariate adjustment by logistic regression, the pre-consultation ISB was found to be associated with greater satisfaction with the information about the psycho-social consequences of genetic testing [adjusted odds ratio (ORadj) 1.03, 95% confidence interval (CI) 1.01-1.06] (scale from 0 to 100) and about the certainty of being a gene carrier (ORadj 3.04, 95% CI 1.16-7.98). Those who actively looked for complementary information were also more often accompanied at the consultation by a family member (ORadj 4.82, 95% CI 1.85-12.56). The other variables tested (depression, coping, socio-demographic and medical characteristics) were not significant (p > 0.05). The role of the social network in the decision making process was perceived as being less helpful when the persons consulted tended to have neutral or unfavourable opinions about genetic testing. CONCLUSIONS: Few women actively sought complementary information about BRCA genetic testing in addition to the cancer genetic consultation. Those who did so differed from the others in terms of their social network and their satisfaction with the consultation. The cancer geneticist is the key actor in women's decision making about genetic testing.     

Effects of individual and family functioning on interest in genetic testing

OBJECTIVE: The present study reports on the important issue of how family communication and support regarding breast cancer risk affects interest in genetic testing and mental health. METHODS: Participants (n = 221) were women aged 18-74 who had at least one relative of Ashkenazi Jewish descent, no personal history of breast or ovarian cancer, and lived within 60 miles of Seattle, Wash. RESULTS: Communication about breast cancer risk was reported with very low frequency across all types of relatives. Women talked with their mothers and sisters more often than their fathers, brothers, or children. The only significant predictor of interest in genetic testing was the individual level variable of seeking social support. CONCLUSION: Social support needs might be a part of the genetic testing process.     

A cytogenetic register of down syndrome in Lebanon

OBJECTIVES: To provide data on the cytogenetics and epidemiology of Down syndrome in our community. METHODS: All cases of Down syndrome diagnosed cytogenetically were entered over a period of 5 years together with data regarding age at referral, parental ages and parity. RESULTS: A total of 280 cases were entered. In postnatal cases, the mean maternal age was 32.19 years and 41.5% of mothers were over 35 years. Only 47.3% of Down syndrome children were diagnosed at less than 1 month of age. The male to female sex ratio of 1.66 is significantly more elevated than that reported in larger registers. CONCLUSIONS: Because of problems inherent to Lebanon, this register does not have a high level of ascertainment, however it appears that the emphasis in a potential prevention programme should be placed on education, information and family planning.     

Marfan syndrome in Europe

OBJECTIVES: Marfan syndrome (MFS) is a relatively frequent systemic connective tissue disorder with an important physical morbidity and mortality. The influences of MFS on physical problems, perception of severity, and impact on the quality of life and psychosocial well-being have been studied only limitedly. The aim of this study was to assess the association between the severity derived from the reported symptoms and subjectively experienced severity of MFS (expressed as a global judgment), with special emphasis regarding impact on relationships and pregnancies, psychosocial adjustment, and differences between the seven European countries. METHODS: A questionnaire designed specifically for this study and translated in each of the native languages was sent to 2,080 members of one of the patient support groups in Belgium, Denmark, France, Germany, The Netherlands, Switzerland, and the United Kingdom. 857 MFS patients of 13 years and older completed the questionnaire and were included in the data analysis. RESULTS: Physical impairments were scored by perception of severity of physical symptoms by the patients (physical severity perception score) and by their perception of the influence of MFS on their life (subjective severity score). Main discrepancy between physical severity perception and subjective severity score was the higher percentage of patients scoring in physical severity perception as severe (53.5%) compared to subjectively severe (26.5%). 61% of those who scored on the physical severity score as severely affected were designated as being mildly-moderately affected on subjective scoring. Both severity scores increased significantly with age. Two hundred-twenty women have carried 430 pregnancies (1.95 pregnancies/woman), with cardiovascular complications in 1.6%. Prenatal studies for MFS were rejected by 7.6% of MFS patients of 25 years and older, 33.6% were undecided, and 48.5% favored prenatal diagnosis for MFS if available. A positive general self-image was reported by 91.5% of patients. However, more than 90% stated that MFS had a negative influence on their sexual relationships, which they ascribed to negative perception of their body image. CONCLUSIONS: MFS has significant impact on daily life activities, but the majority of patients come to terms with their condition. Acceptance is mainly determined by subjective severity, and less by physical symptoms as reported by the patients themselves. It is important to stimulate a positive attitude towards MFS.     

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.     

Down syndrome and parity

OBJECTIVE: To investigate the effect of parity on Down syndrome (DS). METHODS: The study was conducted on data from Northeast Italy (NEI) (1981-1996) and Sicily (ISMAC) (1991-1996) Congenital Malformation Registries. In these areas, all DS births are recorded and confirmed by chromosomal analysis; the NEI Registry also registers pregnancy terminations (TOPs) after prenatal diagnosis of DS. In order to estimate the effect of parity independently of the mother's age and to reduce the truncation effect, different age classes and three classes of parity (1, 2-4, >4) were defined. RESULTS: The study sample consisted of 1,088 consecutive newborns and 169 consecutive fetuses affected by DS. In both NEI and ISMAC samples, we found a significantly increased risk of having a DS child for multiparas > or =35 years of age. In the NEI sample, the inclusion of TOP data did not seem to modify this finding. In the ISMAC sample, a significantly reduced risk for primiparas was found at all ages. CONCLUSIONS: Our data confirm a higher risk of having a DS child in women with parity >4. As this effect is evident only in women > or =35 years age, its practical impact is null because these women are usually offered prenatal diagnosis in any case. However, the mechanisms involved, if this association is true, are very intriguing and the observation should stimulate scientific studies allowing a better knowledge of the nondisjunction mechanism.     

A comparison of the effectiveness of extracorporeal shock wave and ultrasound therapy in the management of heel pain

The aim of this study was to compare the effectiveness of extracorporeal shock wave therapy (ESWT) and ultrasound therapy (US) for managing heel pain. Thirty-seven subjects received either: ESWT (once a week), US (three times a week), or CONTROL (no treatment) for 3 consecutive weeks and were followed-up for 3 more weeks. A visual analogue scale (VAS), the maximum tolerable duration for prolonged walking or standing, and the Mayo clinical scoring system (MCSS) were evaluated. Mixed models treating baseline measures as covariates were adopted for statistical analysis. By week 3, intensity of heel pain on palpation was reduced by 37% (VAS score from 7.5 to 4.6) in the ESWT group, 24% (from 5.3 to 4.2) in the US group, and increased by 3% (5.6–5.7) in the control group; this difference was significant after adjusting for baseline VAS scores (p = 0.022). The improvements in the maximum tolerable duration of prolonged walking or standing was only significant in the ESWT group (157% increase, p = 0.043) but not the other two groups. Both active treatment groups maintained the treatment effect at the three-week follow-up. We conclude that ESWT is potentially more effective in reducing heel pain than ultrasound therapy but additional evidence is needed due to the various limitations of the study.      

The reactions of general practitioners, nurses and midwives in Flanders concerning breast cancer risks in a high-risk situation

OBJECTIVE: To investigate the reactions of general practitioners (GPs), nurses and midwives concerning the cancer risks in a high-risk family. METHODS: Questionnaires were sent to 356 GPs, 881 nurses and 119 midwives. RESULTS: The response rate was 60% for GPs, 58% for midwives and 33% for nurses. The breast cancer risk of an unaffected patient from a high-risk family as well as the risk of her daughter were mostly (>80%) correctly evaluated as increased. The percentage answering 'increased risk' dropped to 40% for the daughters of the patient's brother. Half of the GPs and nurses/midwives explicitly mentioned that a predictive DNA test was available. Less than one third would recommend such a test for a young child. Reluctance was also observed regarding prophylactic mastectomy. CONCLUSION: These results should be taken into account in genetic education initiatives for GPs, nurses and midwives.     

Risk factors for neonatal mortality in low-income population subgroups in Karachi, Pakistan

This paper assesses the risk factors for neonatal mortality (0-28 days of life) for full-term singleton live births. The study sample comprised 1,011 ever-married women who were residents of four multi-ethnic, multi-religious low-income areas of Karachi, Pakistan during 1995. The analysis sample was restricted to 4,488 live births to 912 women. Results showed that 4.8% (n = 217) of all births ended in death in the neonatal period, and 76% (n = 164) of these neonatal deaths occurred in the first week of life. While neonatal mortality rates had declined appreciably over time, a large proportion of neonatal deaths were clustered in a small group of women. The univariate analysis showed a statistically significant association between a number of maternal-level parameters (e.g., mother's age at birth, level of formal education, employment status, religious affiliation, and consanguinity) and child-level parameters (e.g., birth order, birth interval, survival status of the preceding child, sex of the neonate, year of death). At the multivariate level, consanguinity, birth order and year of death were found to be statistically significant risk factors for neonatal mortality analyses despite adjustment for death clustering. The study highlights the importance of inbreeding as a determinant of early offspring death, and points to the need for better understanding of why deaths are clustered in certain families. Given the widespread practice of close cousin marriages in Pakistan across all socio-economic groups, there is a need to validate the findings in less economically disadvantaged population subgroups within the country.     

Assessment of two 'low-tech' genetic health care procedures performed by prenatal care providers in Washington state: implications for future policy development activities

Equity in health care demands that patients be treated fairly, impartially and with justice. Health care professionals and others have long been aware of the concept of equity, and the many inequities that exist in our health care system. As part of our analysis of postpartum data collected between 1993 and 1996 by the Washington Pregnancy Risk Assessment Monitoring System (PRAMS) from self-administered patient surveys, we explored equity as it pertains to two 'low-tech' prenatal genetic health care procedures: (1) whether or not prenatal care providers asked their patients about a family history of birth defects/genetic disorders, and (2) whether or not prenatal care providers talked to their patients about prenatal testing for birth defects/genetic disorders. Overall, about 80% of pregnant women reported that they had been asked about their family history of birth defects/genetic disorders, and about 85% said that their prenatal care provider(s) had talked to them about prenatal testing. Maternal characteristics associated with a lower likelihood of receiving these two low-tech genetic health care procedures appeared to be young maternal age, and low education and income levels, regardless of where women with these attributes received their prenatal care (e.g. community, migrant, health department or military health care clinics, private physicians, or health maintenance organizations).     

Fractional Discrete-Time Signal Processing: Scale Conversion and Linear Prediction

A generalization of the linear prediction for fractional steps isreviewed, widening well-known concepts and results. This prediction isused to derive a causal interpolation algorithm. A reconstructionalgorithm for the situation where averages are observed is alsopresented. Scale conversion of discrete-time signals is studied takingas base the fractional discrete-time system theory. Some simulationresults to illustrate the behaviour of the algorithms will be presented.A new algorithm for performing the zoom transform is also described.     

BRCA1/2 mutation carriers: living with susceptibility

OBJECTIVES: To examine whether being a BRCA1/2 mutation carrier affects a wide array of aspects of life, and if so, how. METHODS: Participants were grouped according to their carrier status (carrier and noncarrier status), health status (affected or unaffected by cancer), and their enrollment at the counseling service (probands and other family members). One hundred and sixty-five women completed a self-administered questionnaire following their genetic consultation session. RESULTS: Probands/nonprobands and carriers/noncarriers did not differ with regard to demographic characteristics, health behaviors including medical checkups, the distress they experience or their resources (sense of coherence, social integration, religiosity). Individuals affected by cancer did differ on some of these aspects from participants without cancer. CONCLUSIONS: From the results of this study, being a carrier could not be considered a psychosocial risk factor, nor does it seem to have an effect on carriers' resources and lifestyle.     

Public experiences, knowledge and expectations about medical genetics and the use of genetic information

OBJECTIVE: The objectives of this study were (1) to explore public experiences, genetic knowledge, expectations of future medical genetic developments, and the attitudes towards the use of genetic information, and (2) to determine whether there are subject characteristics associated with these variables. METHODS: Participants (n = 1,308, age > or = 25 years) of a Dutch consumer panel were sent a questionnaire, specifically designed for this study. RESULTS: Response was 63% (817/1,308). A minority of respondents reported to know someone with a hereditary disease (34%) or to have used a genetic test (8%). Overall, 57% perceived a lack of genetic knowledge. In multivariate analyses, high self-rated knowledge, younger age, having heard of genetic testing, high educational level, female gender, having children living at home, being a health professional, and familiarity with genetic testing were positively associated with genetic knowledge. Future expectations of the consequences of developments in medical genetics varied between the subjects. The great majority expected great benefits for medical practice such as an increasing use of genetic aspects of disease for diagnosis or prevention. One fifth, mainly older people, anticipated a negative impact of genetic developments on society. The results also show that most people are reserved to share their genetic information with others, especially with regard to the wider public domain (e.g. industry and insurers) and employers. Remarkably, respondents were more willing to share their genetic information with scientific researchers (68%) than with their relatives (54%). CONCLUSION: This study suggests that although one fifth anticipates negative consequences of genetic developments, the great majority has high expectations about the increasing use of genetics in prevention, diagnosis and treatment of diseases. In developing educational programmes about genetic innovations in medicine, policymakers will have to take into account pre-existing lay knowledge, views and expectations of different groups of citizens towards these developments.     

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.     

Ultrasound calibration with ladder phantom at multiple depths for breast biopsy navigation system

Ultrasound guided breast biopsy navigation system with a graphical user interface and a passive robotic needle holder is developed to increase the performance and reliability of the radiologist. Ultrasound calibration and tool tip calibration are required before using the system. A ladder phantom is developed to be used for ultrasound calibration in real time system with only one ultrasound image required. The passive robotic needle holder structure results in an identity matrix for the makes the rotation matrix; therefore, only translation and scaling are required in the system. This method can be applied to multiple ultrasound depths, which has a relationship at each depth and a relationship to the ultrasound image on the display. The results show high accuracy (<1 mm.) and rapid calibration (5–10 minutes) which is suitable for a real time system like a breast biopsy navigation system based on tests with a breast phantom.