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Purpose: As part of the 100,000 Genomes Project, we set out to assess the potential viability and clinical impact of reporting genetic variants associated with drug-induced toxicity for patients with cancer recruited for whole-genome sequencing (WGS) as part of a genomic medicine service., Methods: Germline WGS from 76,805 participants was analyzed for pharmacogenetic (PGx) variants in four genes ( DPYD , NUDT15 , TPMT , UGT1A1 ) associated with toxicity induced by five drugs used in cancer treatment (capecitabine, fluorouracil, mercaptopurine, thioguanine, irinotecan). Linking genomic data with prescribing and hospital incidence records, a phenome-wide association study (PheWAS) was performed to identify whether phenotypes indicative of adverse drug reactions (ADRs) were enriched in drug-exposed individuals with the relevant PGx variants. In a subset of 7,081 patients with cancer, DPYD variants were reported back to clinicians and outcomes were collected., Results: We identified clinically relevant PGx variants across the four genes in 62.7% of participants in our cohort. Extending this to annual prescription numbers in England for the drugs affected by these PGx variants, approximately 14,540 patients per year could potentially benefit from a reduced dose or alternative drug to reduce the risk of ADRs. Validating PGx associations in a real-world data set, we found a significant association between PGx variants in DPYD and toxicity-related phenotypes in patients treated with capecitabine or fluorouracil. Reported DPYD variants were deemed informative for clinical decision making in a majority of cases., Conclusion: Reporting PGx variants from germline WGS relevant to patients with cancer alongside primary findings related to their cancer can be clinically informative, informing prescribing to reduce the risk of ADRs. Extending the range of actionable variants to those found in patients of non-European ancestry is important and will extend the potential clinical impact.

UK medical graduates will soon need to pass the medical licensing assessment, which assesses skills and knowledge in ethics using multiple choice questions (eg single best answer questions) and objective structured clinical examination. However, educational leaders have recognised that these methods lack the sophistication needed to accurately assess medical ethics. The reasons are two-fold. First, there may be a knowledge and practice gap in medical schools when it comes to preparing students for the assessment. To this end, this article shares peer advice about how best to use objective structured clinical examinations and single best answer questions for assessing medical ethics to help prepare students for the medical licensing assessment. Second, the design of the assessment is unlikely to adequately measure graduates' ethical values and behaviour in real world scenarios. Further work is needed to design assessments that are sophisticated enough to examine candidates' ethical reasoning and their actual behaviour.

The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities for precision cancer care within the UK National Healthcare System (NHS). Genomics England, alongside NHS England, analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis. The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes., (© 2024. The Author(s).)

Background: Fetal fraction (FF) measurement is considered important for reliable noninvasive prenatal testing (NIPT). Using minimal FF threshold as a quality parameter is under debate. We evaluated the variability in reported FFs of individual samples between providers and laboratories and within a single laboratory., Methods: Genomic quality assessment and European Molecular Genetics Quality Network provide joint proficiency testing for NIPT. We compared reported FFs across all laboratories and stratified according to test methodologies. A single sample was sequenced repeatedly and FF estimated by 2 bioinformatics methods: Veriseq2 and SeqFF. Finally, we compared FFs by Veriseq and SeqFF in 87 351 NIPT samples., Results: For each proficiency test sample we observed a large variability in reported FF, SDs and CVs ranging from 1.7 to 3.6 and 17.0 to 35.8, respectively. FF measurements reported by single nucleotide polymorphism-based methods had smaller SDs (0.5 to 2.4) compared to whole genome sequencing-based methods (1.8 to 2.9). In the internal quality assessment, SDs were similar between SeqFF (SD 1.0) and Veriseq v2 (SD 0.9), but mean FF by Veriseq v2 was higher compared to SeqFF (9.0 vs 6.4, P 0.001). In patient samples, reported FFs were on average 1.12-points higher in Veriseq than in SeqFF (P 0.001)., Conclusions: Current methods do not allow for a reliable and consistent FF estimation. Our data show estimated FF should be regarded as a laboratory-specific range, rather than a precise number. Applying strict universal minimum thresholds might result in unnecessary test failures and should be used with caution., (© American Association for Clinical Chemistry 2022.)

Background: Predictive biomarkers are essential for selecting the best therapeutic strategy in patients with cancer. The International Quality Network for Pathology, the European Cancer Patient Coalition and the European Federation of Pharmaceuticals Industries and Associations evaluated the access to and quality of biomarker testing across Europe., Methods: Data sources included surveys of 141 laboratory managers and 1.665 patients, and 58 in-depth interviews with laboratory managers, physicians and payers. Four access metrics (laboratory access, test availability, test reimbursement, test order rate) and three quality metrics (quality scheme participation, laboratory accreditation, test turnaround time) were applied to rank the results., Results: The access to precision medicines is higher in countries with public national reimbursement processes in place. Lack of diagnostic laboratory infrastructure, inefficient organization and/or insufficient public reimbursement narrow the access to single biomarker tests in many European countries. In countries with limited public reimbursement, pharma and patients' out of pocket were the primary funding sources for testing. Uptake of multi-biomarker next generation sequencing (NGS) is highly varied, ranging from 0% to >50%. Financial constraints, a lack of NGS testing capabilities and the failure to include NGS testing in the guidelines represent the main barriers to NGS implementation. The quality of biomarker testing is highest in Western and Northern Europe, with more than 90% of laboratories participating in quality assurance schemes., Conclusions: Our data clearly indicate the need for a call to action to ensure the clinical implementation of precision medicine in Europe., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Standardization of molecular diagnostics is fundamental for effective application of genetic analyses in personalized medicine. The amount of DNA extracted from a specimen can have a significant impact on diagnostic accuracy, especially in cases where the diagnostic variant has a low concentration such as cancer. Blood and tissue samples were supplied to genetic laboratories to assess the reproducibility of extraction methodologies; DNA was extracted using participants' routine procedures and returned to the external quality assessment provider. The amount of DNA was measured by two independent analytical techniques, fluorescence intensity of intercalating dye and digital PCR; DNA quality was evaluated by DNA integrity number scores. The amount of DNA extracted varied widely between and within participants and for different blood volumes, indicating that consistent diagnostic quality is challenging even within a single test center. The median digital PCR-measured amount of DNA was on average six times higher than the intercalating dye measurements obtained in this study, indicating the possibility that the latter quantitative method may significantly underestimate the amount of DNA, thus making it not fit for purpose. Standardization of genetic diagnostic tests will require a significant improvement in the reproducibility of DNA extraction; this could be achieved if suppliers and users of DNA extraction kits validate their extraction methodology using reliable quantitative measurements or reference materials., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Outcomes for neonatal intestinal failure (IF) have improved significantly over the past two decades, however, there is no consensus for decision making among UK paediatric subspecialists., Objectives: The aim was to describe clinician's attitudes to decision making in neonatal IF and examine variation between subspecialties., Methods: Neonatologists, paediatric surgeons and gastroenterologists were surveyed electronically. They were asked if they would recommend active or palliative care or allow the parents to decide in several scenarios; or if they considered treatment morally obligatory or impermissible., Results: Of 147 respondents, 81% of gastroenterologists would recommend active care (34.6% regardless of parental decision) for a term infant with total gut Hirschsprung's compared with 46% and 33% of surgeons and neonatologists. No gastroenterologist would recommend palliation while 23% of both neonatologists and surgeons would. Similarly, 77% of surgeons and 73% of neonatologists would recommend palliation for a 28-week infant with IF and bilateral parenchymal haemorrhages compared with 27% of gastroenterologists.Prognostic estimates also varied. A term baby with IF was estimated to have a survival of >80% at 5 years by 58% of gastroenterologists compared with 11.5% and 2.7% of surgeons and neonatologists. Only 11.5% of surgeons and 2.6% of neonatologist believed a 26-week preterm with IF would have a 5-year survival >60% compared with 59% of gastroenterologists., Conclusion: There is substantial variation in views about outcomes and management choices both within and between specialties; with gastroenterologists being consistently more positive. This is likely to lead to unjustified variation in counselling and parental choices., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Previous studies have described reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for the rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal/oropharyngeal swab and saliva samples. This multisite clinical evaluation describes the validation of an improved sample preparation method for extraction-free RT-LAMP and reports clinical performance of four RT-LAMP assay formats for SARS-CoV-2 detection. Direct RT-LAMP was performed on 559 swabs and 86,760 saliva samples and RNA RT-LAMP on extracted RNA from 12,619 swabs and 12,521 saliva samples from asymptomatic and symptomatic individuals across health care and community settings. For direct RT-LAMP, overall diagnostic sensitivity (DSe) was 70.35% (95% CI, 63.48%-76.60%) on swabs and 84.62% (95% CI, 79.50%-88.88%) on saliva, with diagnostic specificity of 100% (95% CI, 98.98%-100.00%) on swabs and 100% (95% CI, 99.72%-100.00%) on saliva, compared with quantitative RT-PCR (RT-qPCR); analyzing samples with RT-qPCR ORF1ab C T values of ≤25 and ≤33, DSe values were 100% (95% CI, 96.34%-100%) and 77.78% (95% CI, 70.99%-83.62%) for swabs, and 99.01% (95% CI, 94.61%-99.97%) and 87.61% (95% CI, 82.69%-91.54%) for saliva, respectively. For RNA RT-LAMP, overall DSe and diagnostic specificity were 96.06% (95% CI, 92.88%-98.12%) and 99.99% (95% CI, 99.95%-100%) for swabs, and 80.65% (95% CI, 73.54%-86.54%) and 99.99% (95% CI, 99.95%-100%) for saliva, respectively. These findings demonstrate that RT-LAMP is applicable to a variety of use cases, including frequent, interval-based direct RT-LAMP of saliva from asymptomatic individuals who may otherwise be missed using symptomatic testing alone., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Rapid, high throughput diagnostics are a valuable tool, allowing the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in populations so as to identify and isolate people with asymptomatic and symptomatic infections. Reagent shortages and restricted access to high throughput testing solutions have limited the effectiveness of conventional assays such as quantitative RT-PCR (RT-qPCR), particularly throughout the first months of the coronavirus disease 2019 pandemic. We investigated the use of LamPORE, where loop-mediated isothermal amplification (LAMP) is coupled to nanopore sequencing technology, for the detection of SARS-CoV-2 in symptomatic and asymptomatic populations., Methods: In an asymptomatic prospective cohort, for 3 weeks in September 2020, health-care workers across four sites (Birmingham, Southampton, Basingstoke and Manchester) self-swabbed with nasopharyngeal swabs weekly and supplied a saliva specimen daily. These samples were tested for SARS-CoV-2 RNA using the Oxford Nanopore LamPORE system and a reference RT-qPCR assay on extracted sample RNA. A second retrospective cohort of 848 patients with influenza-like illness from March 2020 to June 2020 were similarly tested from nasopharyngeal swabs., Results: In the asymptomatic cohort a total of 1200 participants supplied 23 427 samples (3966 swab, 19 461 saliva) over a 3-week period. The incidence of SARS-CoV-2 detection using LamPORE was 0.95%. Diagnostic sensitivity and specificity of LamPORE was >99.5% (decreasing to approximately 98% when clustered estimation was used) in both swab and saliva asymptomatic samples when compared with the reference RT-qPCR test. In the retrospective symptomatic cohort, the incidence was 13.4% and the sensitivity and specificity were 100%., Conclusions: LamPORE is a highly accurate methodology for the detection of SARS-CoV-2 in both symptomatic and asymptomatic population settings and can be used as an alternative to RT-qPCR., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

If genome sequencing is performed in health care, in theory the opportunity arises to take a further look at the data: opportunistic genomic screening (OGS). The European Society of Human Genetics (ESHG) in 2013 recommended that genome analysis should be restricted to the original health problem at least for the time being. Other organizations have argued that 'actionable' genetic variants should or could be reported (including American College of Medical Genetics and Genomics, French Society of Predictive and Personalized Medicine, Genomics England). They argue that the opportunity should be used to routinely and systematically look for secondary findings-so-called opportunistic screening. From a normative perspective, the distinguishing characteristic of screening is not so much its context (whether public health or health care), but the lack of an indication for having this specific test or investigation in those to whom screening is offered. Screening entails a more precarious benefits-to-risks balance. The ESHG continues to recommend a cautious approach to opportunistic screening. Proportionality and autonomy must be guaranteed, and in collectively funded health-care systems the potential benefits must be balanced against health care expenditures. With regard to genome sequencing in pediatrics, ESHG argues that it is premature to look for later-onset conditions in children. Counseling should be offered and informed consent is and should be a central ethical norm. Depending on developing evidence on penetrance, actionability, and available resources, OGS pilots may be justified to generate data for a future, informed, comparative analysis of OGS and its main alternatives, such as cascade testing.

In personalized medicine, predictive biomarker testing is the basis for an appropriate choice of therapy for patients with cancer. An important tool for laboratories to ensure accurate results is participation in external quality assurance (EQA) programs. Several providers offer predictive EQA programs for different cancer types, test methods, and sample types. In 2013, a guideline was published on the requirements for organizing high-quality EQA programs in molecular pathology. Now, after six years, steps were taken to further harmonize these EQA programs as an initiative by IQNPath ABSL, an umbrella organization founded by various EQA providers. This revision is based on current knowledge, adds recommendations for programs developed for predictive biomarkers by in situ methodologies (immunohistochemistry and in situ hybridization), and emphasized transparency and an evidence-based approach. In addition, this updated version also has the aim to give an overview of current practices from various EQA providers.

Objective: In English paediatric practice, English law requires that parents and clinicians agree the 'best interests' of children and, if this is not possible, that the courts decide. Court intervention is rare and the concept of best interests is ambiguous. We report qualitative research exploring how the best interests standard operates in practice, particularly with decisions related to planned non-treatment. We discuss results in the light of accounts of best interests in the medical ethics literature., Design: We conducted 39 qualitative interviews, exploring decision making in the paediatric intensive care unit, with doctors, nurses, clinical ethics committee members and parents whose children had a range of health outcomes. Interviews were audio-recorded and analysed thematically., Results: Parents and clinicians indicated differences in their approaches to deciding the child's best interests. These were reconciled when parents responded positively to clinicians' efforts to help parents agree with the clinicians' view of the child's best interests. Notably, protracted disagreements about a child's best interests in non-treatment decisions were resolved when parents' views were affected by witnessing their child's physical deterioration. Negotiation was the norm and clinicians believed avoiding the courts was desirable., Conclusions: Sensitivity to the long-term interests of parents of children with life-limiting conditions is defensible but must be exercised proportionately. Current approaches emphasise negotiation but offer few alternatives when decisions are at an impasse. In such situations, the instrumental role played by a child's deterioration and avoidance of the courts risks giving insufficient weight to the child's interests. New approaches to decision making are needed., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Non-invasive prenatal testing (NIPT) is an emerging form of prenatal genetic testing that provides information about the genetic constitution of a foetus without the risk of pregnancy loss as a direct result of the test procedure. As with other prenatal tests, information from NIPT can help to make a decision about termination of pregnancy, plan contingencies for birth or prepare parents to raise a child with a genetic condition. NIPT can also be used by women and couples to test purely 'for information'. Here, no particular action is envisaged following the test; it is motivated entirely by an interest in the result. The fact that NIPT can be performed without posing a risk to the pregnancy could give rise to an increase in such requests. In this paper, we examine the ethical aspects of using NIPT 'purely for information', including the competing interests of the prospective parents and the future child, and the acceptability of testing for 'frivolous' reasons. Drawing on several clinical scenarios, we claim that arguments about testing children for genetic conditions are relevant to this debate. In addition, we raise ethical concerns over the potential for objectification of the child. We conclude that, in most cases, using NIPT to test for adult-onset conditions, carrier status or non-serious traits presenting in childhood would be unacceptable., (© 2014 John Wiley & Sons Ltd.)

Molecular testing is becoming an important part of the diagnosis of any patient with cancer. The challenge to laboratories is to meet this need, using reliable methods and processes to ensure that patients receive a timely and accurate report on which their treatment will be based. The aim of this paper is to provide minimum requirements for the management of molecular pathology laboratories. This general guidance should be augmented by the specific guidance available for different tumour types and tests. Preanalytical considerations are important, and careful consideration of the way in which specimens are obtained and reach the laboratory is necessary. Sample receipt and handling follow standard operating procedures, but some alterations may be necessary if molecular testing is to be performed, for instance to control tissue fixation. DNA and RNA extraction can be standardised and should be checked for quality and quantity of output on a regular basis. The choice of analytical method(s) depends on clinical requirements, desired turnaround time, and expertise available. Internal quality control, regular internal audit of the whole testing process, laboratory accreditation, and continual participation in external quality assessment schemes are prerequisites for delivery of a reliable service. A molecular pathology report should accurately convey the information the clinician needs to treat the patient with sufficient information to allow for correct interpretation of the result. Molecular pathology is developing rapidly, and further detailed evidence-based recommendations are required for many of the topics covered here., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and potentially serious condition with a limited evidence base for treatment. Specialist treatment for paediatric CFS/ME uses interventions recommended by National Institute for Health and Clinical Excellence (NICE) including cognitive behavioural therapy, graded exercise therapy and activity management. The Lightning Process (LP) is a trademarked intervention derived from osteopathy, life-coaching and neuro-linguistic programming, delivered over three consecutive days as group sessions. Although over 250 children with CFS/ME attend LP courses each year, there are no reported studies on the effectiveness or cost-effectiveness., Methods: This pragmatic randomised controlled trial is set within a specialist paediatric CFS/ME service in the south west of England. Children and young people with CFS/ME (n = 80 to 112), aged 12 to 18 years old will be randomised to specialist medical care (SMC) or SMC plus the LP. The primary outcome will be physical function (SF-36 physical function short form) and fatigue (Chalder Fatigue Scale)., Discussion: This study will tell us whether adding the LP to SMC is effective and cost-effective compared to SMC alone. This study will also provide detailed information on the implementation of the LP and SMC., Trial Registration: Current Controlled Trials ISRCTN81456207 (31 July 2012).

Background: Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is relatively common in children with limited evidence for treatment. The Phil Parker Lightning Process (LP) is a trademarked intervention, which >250 children use annually. There are no reported studies investigating the effectiveness or possible side effects of LP., Methods: The trial population was drawn from the Bath and Bristol NHS specialist paediatric CFS or ME service. The study was designed as a pilot randomized trial with children (aged 12 to 18 years) comparing specialist medical care with specialist medical care plus the Lightning Process. Integrated qualitative methodology was used to explore the feasibility and acceptability of the recruitment, randomization and interventions., Results: A total of 56 children were recruited from 156 eligible children (1 October 2010 to 16 June 2012). Recruitment, randomization and both interventions were feasible and acceptable. Participants suggested changes to improve feasibility and acceptability and we incorporated the following in the trial protocol: stopped collecting 6-week outcomes; introduced a second reminder letter; used phone calls to collect primary outcomes from nonresponders; informed participants about different approaches of each intervention and changed our recommendation for the primary outcome for the full study from school attendance to disability (SF-36 physical function subscale) and fatigue (Chalder Fatigue Scale)., Conclusions: Conducting randomized controlled trials (RCTs) to investigate an alternative treatment such as LP is feasible and acceptable for children with CFS or ME. Feasibility studies that incorporate qualitative methodology enable changes to be made to trial protocols to improve acceptability to participants. This is likely to improve recruitment rate and trial retention., Trial Registration: Feasibility study first randomization: 29 September 2010. Trial registration: Current Controlled Trials ISRCTN81456207 (31 July 2012). Full trial first randomization: 19 September 2012.

Preimplantation genetic diagnosis (PGD) was first performed over 20 years ago and has become an accepted part of genetic testing and assisted reproduction worldwide. The techniques and protocols necessary to carry out genetic testing at the single-cell level can be difficult to master and have been developed independently by the laboratories worldwide offering preimplantation testing. These factors indicated the need for an external quality assessment (EQA) scheme for monogenic disease PGD. Toward this end, the European Society for Human Reproduction and Embryology came together with United Kingdom National External Quality Assessment Services for Molecular Genetics, to create a pilot EQA scheme followed by practical EQA schemes for all interested parties. Here, we detail the development of the pilot scheme as well as development and findings from the practical (clinical) schemes that have followed. Results were generally acceptable and there was marked improvement in results and laboratory scores for those labs that participated in multiple schemes. Data from the first three schemes indicate that the EQA scheme is working as planned and has helped laboratories improve their techniques and result reporting. The EQA scheme for monogenic PGD will continue to be developed to offer assessment for other monogenic disorders.

Non-invasive prenatal testing for single gene disorders is now clearly on the horizon. This new technology offers obvious clinical benefits such as safe testing early in pregnancy. Before widespread implementation, it is important to consider the possible ethical implications. Four hypothetical scenarios are presented that highlight how ethical ideals of respect for autonomy, privacy and fairness may come into play when offering non-invasive prenatal testing for single gene disorders. The first scenario illustrates the moral case for using these tests for 'information only', identifying a potential conflict between larger numbers of women seeking the benefits of the test and the wider social impact of funding tests that do not offer immediate clinical benefit. The second scenario shows how the simplicity and safety of non-invasive prenatal testing could lead to more autonomous decision-making and, conversely, how this could also lead to increased pressure on women to take up testing. In the third scenario we show how, unless strong safeguards are put in place, offering non-invasive prenatal testing could be subject to routinisation with informed consent undermined and that woman who are newly diagnosed as carriers may be particularly vulnerable. The final scenario introduces the possibility of a conflict of the moral rights of a woman and her partner through testing for single gene disorders. This analysis informs our understanding of the potential impacts of non-invasive prenatal testing for single gene disorders on clinical practice and has implications for future policy and guidelines for prenatal care.

Pharmacists who refuse to provide certain services or treatment for reasons of conscience have been criticized for failing to fulfil their professional obligations. Currently, individual pharmacists in Great Britain can withhold services or treatment for moral or religious reasons, provided they refer the patient to an alternative source. The most high-profile cases have concerned the refusal to supply emergency hormonal contraception, which will serve as an example in this article. I propose that the pharmacy profession's policy on conscientious objections should be altered slightly. Building on the work of Brock and Wicclair, I argue that conscientious refusals should be acceptable provided that the patient is informed of the service, the patient is redirected to an alternative source, the refusal does not cause an unreasonable burden to the patient, and the reasons for the refusal are based on the core values of the profession. Finally, I argue that a principled categorical refusal by an individual pharmacist is not morally permissible. I claim that, contrary to current practice, a pharmacist cannot legitimately claim universal exemption from providing a standard service, even if that service is available elsewhere., (© 2011 Blackwell Publishing Ltd.)

Recent scientific advances mean the widespread introduction of non-invasive prenatal diagnosis (NIPD) for chromosomal aneuploidies may be close at hand, raising the question of how NIPD should be introduced as part of antenatal care pathways for pregnant women. In this paper, the authors examine the ethical implications of three hypothetical models for using NIPD for aneuploidy in state-funded healthcare systems and assess which model is ethically preferable. In comparing the models, the authors consider their respective timings; how each model would fit with current screening and diagnostic tests offered to pregnant women; the implications of offering NIPD at different stages of pregnancy; and the potential for each model to support reproductive autonomy and informed decision-making. The authors conclude by favouring a model that would be offered at 11-13 weeks gestation, alongside existing combined screening, provided that this is accompanied by measures to maximise informed decision-making, for example, provision of adequate pretest and post-test counselling.

Empirical evidence suggests that some health professionals believe consent procedures for the emerging technology of non-invasive prenatal diagnosis (NIPD) should become less rigorous than those currently used for invasive prenatal testing. In this paper, we consider the importance of informed consent and informed choice procedures for protecting autonomy in those prenatal tests which will give rise to a definitive result. We consider whether there is anything special about NIPD that could sanction a change to consent procedures for prenatal diagnosis or otherwise render informed decision-making less important. We accept the claim that the absence of risk of miscarriage to some extent lessens the gravity of the decision to test compared with invasive methods of testing. However, we also claim that the definitive nature of the information received, and the fact that the information can lead to decisions of great significance, makes NIPD an important choice. This choice should only be made by means of a rigorous and appropriately supported decision-making process (assuming that this is what the pregnant woman wants). We conclude that, on balance, consent procedures for NIPD should mirror those for invasive testing, albeit without the need to emphasise procedure-related risk.

Objective: Informed choice is a fundamental concept within prenatal care. The present study assessed the extent to which the introduction of non-invasive prenatal diagnosis (NIPD) of Down's syndrome may undermine the process of making informed choices to undergo prenatal testing or screening for Down's syndrome by altering the quality and quantity of pre-test counselling., Methods: 231 obstetricians and midwives were randomly allocated one of three vignettes, each describing a different type of test: (a) invasive prenatal diagnosis (IPD), (b) non-invasive prenatal diagnosis (NIPD) or (c) Down's syndrome screening (DSS). Participants were then asked to complete a questionnaire assessing (1) the information considered important to communicate to women, (2) whether test offer and uptake should take place on different days, and (3) whether signed consent forms should be obtained prior to testing., Results: Across the three test types, five out of the seven presented topics were considered equally important to communicate, including the information that testing is the woman's choice. Compared with participants receiving the IPD vignette, those receiving the NIPD and DSS vignettes were less likely to report that counselling and testing should occur on different days (IPD 94.7% versus 74.1% and 73.9% for NIPD and DSS respectively, p=.001) and that written consent was a necessity (IPD 96.1% versus 68.3% and 75.4% for NIPD and DSS respectively, p<.001)., Conclusion: This study provides the first empirical evidence to demonstrate that practitioners may view the consent process for NIPD differently to IPD. There is potential for the introduction of NIPD to undermine women making informed choices in the context of prenatal diagnostic testing for conditions like DS., Practice Implications: Given the importance of informed choice in reproductive decision-making, implementation of any programme based on NIPD should be designed to facilitate this.

Purpose: To ascertain the extent to which the value obstetricians and gynaecologists attach to informed choice in the context of prenatal testing varies across countries., Method: The values attached to informed choice and the perceived importance of test decisions reflecting the views of others considered significant to pregnant women were assessed and compared across obstetricians and gynaecologists in six countries: UK (n = 176), Netherlands (n = 331), Italy (n = 254), Greece (n = 116), China (n = 116) and India (n = 123)., Results: While respondents from the United Kingdom and the Netherlands almost unanimously believed prenatal testing should reflect a parental choice (94%), substantial minorities in Greece, India, and China and to a lesser extent Italy, believed testing should either reflect a family choice or no choice (11-41%). Respondents who attached a low value to the views of others attached greater value to parental choice. Multinomial logistic regression analysis confirmed the independent predictive value of a country and perceived importance of test decision reflecting the views of significant others., Conclusion: While many obstetricians and gynaecologists favour prenatal testing reflecting a parental choice, the extent to which their values may affect the likelihood that informed choice is realised, may vary across countries. The impact of these findings on patient autonomy is raised.

Molecular genetic techniques have entered many areas of clinical practice. Public expectations from this technology are understandably high. To maintain confidence in this technology, laboratories must implement the highest standards of quality assurance (QA). External quality assessment (EQA) is recognized as an essential component of QA. The United Kingdom National External Quality Assessment Service (UKNEQAS) for Molecular Genetics, first set up in 1991, is currently the longest provider of EQA to molecular genetic testing laboratories in the UK, The Netherlands, and Ireland. Errors in the scheme are sporadic events. However, evidence from this and other EQA schemes suggests that a residual error rate persists, which should be taken into account in clinical practice. This EQA scheme has evolved from the respective scientific bodies of the constituent countries and retains a strong emphasis on collective peer review. It is essential that the steps taken to ensure quality in this rapidly expanding field are clear and transparent to participants and public alike. We describe the procedures developed and the governance imposed to monitor and improve analytical and reporting standards in participant laboratories and we compare our experiences with those of equivalent EQA services in the United States.

In order to investigate the effect of the Oct-2 POU family transcription factor on the regulation of genes encoding synaptic proteins, we have used cell lines in which the level of Oct-2 has been greatly reduced using an antisense approach. The reduced Oct-2 level results in enhanced expression of SNAP-25 and synapsin I, indicating that the genes encoding these proteins are normally repressed by Oct-2 in neuronal cells. In contrast, no alteration was observed in the levels of the synaptic proteins, synaptophysin and synaptotagmin. Although the neuronal forms of Oct-2 can repress the synapsin I promoter in co-transfection experiments, indicating that they have a direct effect on the expression of this gene, they have no effect on the activity of the SNAP-25 promoter, indicating that the effect of Oct-2 on this gene is likely to be indirect. These effects are discussed in terms of the differential effect of Oct-2 and the related POU family transcription factor Brn-3a, on the promoters of genes encoding different synaptic proteins.

The Oct-2 transcription factor has been shown previously to repress both the cellular tyrosine hydroxylase and the herpes simplex virus immediate-early genes in neuronal cells. Here we identify the gene encoding the neuronal nitric-oxide synthase (nNOS) as the first example of a gene activated in neuronal cells by Oct-2. The levels of the nNOS mRNA and protein are greatly reduced in neuronal cell lines in which Oct-2 levels have been reduced by an antisense method, although these cells have enhanced levels of tyrosine hydroxylase. Moreover, the nNOS gene regulatory region is activated by Oct-2 expression vectors upon cotransfection into both neuronal and non-neuronal cells, and this response is dependent upon a 20-amino acid region within the COOH-terminal activation domain of Oct-2. Of the two closely linked promoters that drive nNOS gene expression, only the downstream 5.1 promoter is activated by Oct-2, whereas the 5.2 promoter is unaffected. These effects are discussed in terms of the potential role of Oct-2 in regulating nNOS expression in the nervous system.

The POU family transcription factor Oct-2 was originally identified in B lymphocytes but has been shown to be expressed in neuronal cells, although it is absent in most other cell types. Cotransfection of Oct-2 expression vectors into nonneuronal cells with a tyrosine hydroxylase promoter/reporter plasmid suggests that Oct-2 can repress this promoter in this artificial situation. Here we report that reduction of endogenous Oct-2 levels in a neuronal cell line by an antisense approach results in an increase in endogenous tyrosine hydroxylase levels. In contrast, the level of the neuronal marker protein PGP9.5 remains unchanged in the antisense lines whereas that of the neuronal nitric oxide synthase decreases. Hence, the tyrosine hydroxylase gene is a natural target for repression by Oct-2 in neuronal cells. The significance of this effect is discussed in terms of the processes that regulate tyrosine hydroxylase gene expression and the role of Oct-2 in neuronal cells.