Ancestry, race and ethnicity: the role and relevance of language in clinical genetics practice.

BACKGROUND: The terms ancestry, race and ethnicity are used variably within the medical literature and within society and clinical care. Biological lineage can provide an important context for the interpretation of genomic data, but the language used, and practices around when to ascertain this, vary. METHODS: Using a fictional case scenario we explore the relevance of questions around ancestry, race and ethnicity in clinical genetic practice. RESULTS: In the UK, data on 'ethnicity' are routinely collected by those using genomic medicine, as well as within the wider UK National Health Service, although the reasons for this are not always clear to practitioners and patients. Sometimes it is requested as a proxy for biological lineage to aid variant interpretation, refine estimations of carrier frequency and guide decisions around the need for pharmacogenetic testing. CONCLUSION: There are many challenges around the use and utility of these terms. Currently, genomic databases are populated primarily with data from people of European descent, and this can lead to health disparities and poorer service for minoritised or underserved populations. Sensitivity and consideration are needed when communicating with patients around these areas. We explore the role and relevance of language around biological lineage in clinical genetics practice.

Secondary (additional) findings from the 100,000 Genomes Project: Disease manifestation, health care outcomes, and costs of disclosure.

PURPOSE: The UK 100,000 Genomes Project offered participants screening for additional findings (AFs) in genes associated with familial hypercholesterolemia (FH) or hereditary cancer syndromes including breast/ovarian cancer (HBOC), Lynch, familial adenomatous polyposis, MYH-associated polyposis, multiple endocrine neoplasia (MEN), and von Hippel-Lindau. Here, we report disclosure processes, manifestation of AF-related disease, outcomes, and costs. METHODS: An observational study in an area representing one-fifth of England. RESULTS: Data were collected from 89 adult AF recipients. At disclosure, among 57 recipients of a cancer-predisposition-associated AF and 32 recipients of an FH-associated AF, 35% and 88%, respectively, had personal and/or family history evidence of AF-related disease. During post-disclosure investigations, 4 cancer-AF recipients had evidence of disease, including 1 medullary thyroid cancer. Six women with an HBOC AF, 3 women with a Lynch syndrome AF, and 2 individuals with a MEN AF elected for risk-reducing surgery. New hyperlipidemia diagnoses were made in 6 FH-AF recipients and treatment (re-)initiated for 7 with prior hyperlipidemia. Generating and disclosing AFs in this region cost £1.4m; £8680 per clinically significant AF. CONCLUSION: Generation and disclosure of AFs identifies individuals with and without personal or familial evidence of disease and prompts appropriate clinical interventions. Results can inform policy toward secondary findings.

Ethical preparedness in genomic medicine: how NHS clinical scientists navigate ethical issues.

Much has been published about the ethical issues encountered by clinicians in genetics/genomics, but those experienced by clinical laboratory scientists are less well described. Clinical laboratory scientists now frequently face navigating ethical problems in their work, but how they should be best supported to do this is underexplored. This lack of attention is also reflected in the ethics tools available to clinical laboratory scientists such as guidance and deliberative ethics forums, developed primarily to manage issues arising within the clinic.We explore what ethical issues are being experienced by clinical scientists, how they think such issues could be best analysed and managed, and whether their practice might be enhanced by more situated approaches to ethics deliberation and practice such as ethical preparedness. From thematic analysis of cases presented by clinical scientists at a specially convened meeting of the UK Genethics Forum, we derived three main ethical themes: (1) the redistribution of labour and responsibilities resulting from the practice of genomic medicine; (2) the interpretation and certainty of results and (3) the proposal that better standardisation and consistency of ethical approaches (for example, more guidelines and policy) could resolve some of the challenges arising.We argue that although standardisation is important for promoting shared understandings of good (including ethical) practice, supplementary approaches to enhance and sustain ethical preparedness will be important to help clinical scientists and others in the recently expanded genetic/genomic medicine environment foster quality ethical thinking.

Utility of polygenic risk scores in UK cancer screening: a modelling analysis.

BACKGROUND: It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer). METHODS: For this modelling analysis, we used age-stratified cancer incidences for the UK population from the National Cancer Registration Dataset (2016-18) and published estimates of the area under the receiver operating characteristic curve for current, future, and optimised PRS for each of the eight cancer types. For each of five PRS-defined high-risk quantiles (ie, the top 50%, 20%, 10%, 5%, and 1%) and according to each of the three PRS tools (ie, current, future, and optimised) for the eight cancers, we calculated the relative proportion of cancers arising, the odds ratios of a cancer arising compared with the UK population average, and the lifetime cancer risk. We examined maximal attainable rates of cancer detection by age stratum from combining PRS-based stratification with cancer screening tools and modelled the maximal impact on cancer-specific survival of hypothetical new UK programmes of PRS-stratified screening. FINDINGS: The PRS-defined high-risk quintile (20%) of the population was estimated to capture 37% of breast cancer cases, 46% of prostate cancer cases, 34% of colorectal cancer cases, 29% of pancreatic cancer cases, 26% of ovarian cancer cases, 22% of renal cancer cases, 26% of lung cancer cases, and 47% of testicular cancer cases. Extending UK screening programmes to a PRS-defined high-risk quintile including people aged 40-49 years for breast cancer, 50-59 years for colorectal cancer, and 60-69 years for prostate cancer has the potential to avert, respectively, a maximum of 102, 188, and 158 deaths annually. Unstratified screening of the full population aged 48-49 years for breast cancer, 58-59 years for colorectal cancer, and 68-69 years for prostate cancer would use equivalent resources and avert, respectively, an estimated maximum of 80, 155, and 95 deaths annually. These maximal modelled numbers will be substantially attenuated by incomplete population uptake of PRS profiling and cancer screening, interval cancers, non-European ancestry, and other factors. INTERPRETATION: Under favourable assumptions, our modelling suggests modest potential efficiency gain in cancer case detection and deaths averted for hypothetical new PRS-stratified screening programmes for breast, prostate, and colorectal cancer. Restriction of screening to high-risk quantiles means many or most incident cancers will arise in those assigned as being low-risk. To quantify real-world clinical impact, costs, and harms, UK-specific cluster-randomised trials are required. FUNDING: The Wellcome Trust.

A digital pathway for genetic testing in UK NHS patients with cancer: BRCA-DIRECT randomised study internal pilot.

BACKGROUND: Germline genetic testing affords multiple opportunities for women with breast cancer, however, current UK NHS models for delivery of germline genetic testing are clinician-intensive and only a minority of breast cancer cases access testing. METHODS: We designed a rapid, digital pathway, supported by a genetics specialist hotline, for delivery of germline testing of BRCA1/BRCA2/PALB2 (BRCA-testing), integrated into routine UK NHS breast cancer care. We piloted the pathway, as part of the larger BRCA-DIRECT study, in 130 unselected patients with breast cancer and gathered preliminary data from a randomised comparison of delivery of pretest information digitally (fully digital pathway) or via telephone consultation with a genetics professional (partially digital pathway). RESULTS: Uptake of genetic testing was 98.4%, with good satisfaction reported for both the fully and partially digital pathways. Similar outcomes were observed in both arms regarding patient knowledge score and anxiety, with <5% of patients contacting the genetics specialist hotline. All progression criteria established for continuation of the study were met. CONCLUSION: Pilot data indicate preliminary demonstration of feasibility and acceptability of a fully digital pathway for BRCA-testing and support proceeding to a full powered study for evaluation of non-inferiority of the fully digital pathway, detailed quantitative assessment of outcomes and operational economic analyses. TRIAL REGISTRATION NUMBER: ISRCTN87845055.

Ethical preparedness and developments in genomic healthcare.

Considerations of the notion of preparedness have come to the fore in the recent pandemic, highlighting a need to be better prepared to deal with sudden, unexpected and unwanted events. However, the concept of preparedness is also important in relation to planned for and desired interventions resulting from healthcare innovations. We describe ethical preparedness as a necessary component for the successful delivery of novel healthcare innovations, and use recent advances in genomic healthcare as an example. We suggest that practitioners and organisations charged with delivering innovative and ambitious healthcare programmes can only succeed if they are able to exhibit the attribute of ethical preparedness.

Beyond regulatory approaches to ethics: making space for ethical preparedness in healthcare research.

Centralised, compliance-focused approaches to research ethics have been normalised in practice. In this paper, we argue that the dominance of such systems has been driven by neoliberal approaches to governance, where the focus on controlling and individualising risk has led to an overemphasis of decontextualised ethical principles and the conflation of ethical requirements with the documentation of 'informed consent'. Using a UK-based case study, involving a point-of-care-genetic test as an illustration, we argue that rather than ensuring ethical practice such compliance-focused approaches may obstruct valuable research. We call for an approach that encourages researchers and research communities-including regulators, ethics committees, funders and publishers of academic research-to acquire skills to make morally appropriate decisions, and not base decision-making solely on compliance with prescriptive regulations. We call this 'ethical preparedness' and outline how a research ethics system might make space for this approach.

Discussion of off-target and tentative genomic findings may sometimes be necessary to allow evaluation of their clinical significance.

We discuss a case where clinical genomic investigation of muscle weakness unexpectedly found a genetic variant that might (or might not) predispose to kidney cancer. We argue that despite its off-target and uncertain nature, this variant should be discussed with the man who had the test, not because it is medical information, but because this discussion would allow the further clinical evaluation that might lead it to becoming so. We argue that while prominent ethical debates around genomics often take 'results' as a starting point and ask questions as to whether to look for and how to react to them, the construction of genomic results is fraught with ethical complexity, although often couched as a primarily technical problem. We highlight the need for greater focus on, and appreciation of, the ethical work undertaken daily by scientists and clinicians working in genomic medicine and discuss how public conversations around genomics need to adapt to prepare future patients for potentially uncertain and unexpected outcomes from clinical genomic tests.

In the family: access to, and communication of, familial information in clinical practice.

How an individual's genetic information is governed by confidentiality, and how the interests of others-such as close relatives-in knowing such information might be respected, has been the topic of much debate ever since genetic testing has become more prevalent. In this paper, two authors who often appear to have different views on familial disclosure, discuss where they agree on this topic.

Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK).

PURPOSE: Variant classifications may change over time, driven by emergence of fresh or contradictory evidence or evolution in weighing or combination of evidence items. For variant classifications above the actionability threshold, which is classification of likely pathogenic or pathogenic, clinical actions may be irreversible, such as risk-reducing surgery or prenatal interventions. Variant reclassification up or down across the actionability threshold can therefore have significant clinical consequences. Laboratory approaches to variant reinterpretation and reclassification vary widely. METHODS: Cancer Variant Interpretation Group UK is a multidisciplinary network of clinical scientists and genetic clinicians from across the 24 Molecular Diagnostic Laboratories and Clinical Genetics Services of the United Kingdom (NHS) and Republic of Ireland. We undertook surveys, polls, and national meetings of Cancer Variant Interpretation Group UK to evaluate opinions about clinical and laboratory management regarding variant reclassification. RESULTS: We generated a consensus framework on variant reclassification applicable to cancer susceptibility genes and other clinical areas, which provides explicit recommendations for clinical and laboratory management of variant reclassification scenarios on the basis of the nature of the new evidence, the magnitude of evidence shift, and the final classification score. CONCLUSION: In this framework, clinical and laboratory resources are targeted for maximal clinical effect and minimal patient harm, as appropriate to all resource-constrained health care settings.

Couple-based expanded carrier screening provided by general practitioners to couples in the Dutch general population: psychological outcomes and reproductive intentions.

PURPOSE: The aim of expanded preconception carrier screening (ECS) is to inform any couple wishing to conceive about their chances of having children with severe autosomal or X-linked recessive conditions. Responsible implementation of ECS as reproductive genetic screening in routine care requires assessment of benefits and harms. We examined the psychological outcomes of couple-based ECS for 50 autosomal recessive (AR) conditions provided by general practitioners (GPs) to couples from the Dutch general population. METHODS: Dutch GPs invited 4,295 women aged 18-40. We examined anxiety (State-Trait Anxiety Inventory, STAI-6), worry, decisional conflict (DCS) over time in participants declining GP counseling or attending GP counseling with/without testing. RESULTS: One hundred ninety couples participated; 130 attended counseling, of whom 117 proceeded with testing. No carrier couples were identified. Before counseling, worry (median 6.0) and anxiety (mean 30-34) were low and lower than the population reference (36.4), although some individuals reported increased anxiety or worry. At follow-up, test acceptors reported less anxiety than test decliners (mean 29 vs. 35); differences in anxiety after testing compared to before counseling were not meaningful. Most participants (90%) were satisfied with their decision (not) to undergo testing. CONCLUSION: Some individuals reported temporarily clinically relevant distress. Overall, the psychological outcomes are acceptable and no barrier to population-wide implementation.

Using a biomarker acutely to identify babies at risk of serious adverse effects from antibiotics: where is the 'Terrible Moral and Medical Dilemma'?

We thank Parker and Wright for engaging in this roundtable debate in such a spirited way. The 'Pharmacogenetic [test] to Avoid Loss of Hearing' (PALOH) Trial is the first time a genetic point of care test has been applied in the acute neonatal setting; therefore, it is not surprising that questions have been raised which require debate, discussion and clarification. Parker and Wright misattribute several assumptions to the roundtable authors, which we would like to clarify here. Since they raise wider questions about the PALOH trial itself, several of the roundtable discussants have made a joint response.

International perspectives on the implementation of reproductive carrier screening.

Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay-Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X-linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry-based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.

Recent developments in genetic/genomic medicine.

Advances in genetic technology are having a major impact in the clinic, and mean that many perceptions of the role and scope of genetic testing are having to change. Genomic testing brings with it a greater opportunity for diagnosis, or predictions of future diagnoses, but also an increased chance of uncertain or unexpected findings, many of which may have impacts for multiple members of a person's family. In the past, genetic testing was rarely able to provide rapid results, but the increasing speed and availability of genomic testing is changing this, meaning that genomic information is increasingly influencing decisions around patient care in the acute inpatient setting. The landscape of treatment options for genetic conditions is shifting, which has evolving implications for clinical discussions around previously untreatable disorders. Furthermore, the point of access to testing is changing with increasing provision direct to the consumer outside the formal healthcare setting. This review outlines the ways in which genetic medicine is developing in light of technological advances.

Expanded carrier screening for autosomal recessive conditions in health care: Arguments for a couple-based approach and examination of couples' views.

BACKGROUND: Expanded carrier screening (ECS) is aimed at detecting carrier states for autosomal recessive (AR) or X-linked conditions in couples from the general population planning a pregnancy. ECS is currently usually offered on an individual basis despite the fact that, for AR conditions, only carrier couples are at risk of affected offspring. In this paper, we present a couple-based ECS test-offer for AR conditions, where results are offered as couple-results only, and describe how couples view such an offer. METHODS AND RESULTS: An online survey covering attitudes, perceived difficulty, and intention to take up couple-based ECS was used to examine couples' views. Results show that in 76% of the participating couples there is no objection at all towards receiving couple-results only. Most couples display similar views. Observed discrepancies usually involved one of the couple members having a positive view, whilst the other was neutral. Although views stayed strikingly stable after discussion, the partner's opinion was regarded as important in deciding whether or not to have testing. CONCLUSION: This study shows that most couples do not object to receiving couple rather than individual ECS results, have similar views towards the offer, and are able to discuss differences in views and intentions.

The moral argument for heritable genome editing requires an inappropriately deterministic view of genetics.

Gyngell and colleagues consider that the recent Nuffield Council report does not go far enough: heritable genome editing (HGE) is not just justifiable in a few rare cases; instead, there is a moral imperative to undertake it. We agree that there is a moral argument for this, but in the real world it is mitigated by the fact that it is not usually possible to ensure a better life. We suggest that a moral imperative for HGE can currently only be concluded if one first buys into an overly deterministic view of a genome sequence, and the role of variation within in it, in the aetiology of the disease: most diseases cannot simply be attributed to specific genetic variants that we could edit away. Multiple, poorly understood genetic and environmental factors interact to influence the expression of diseases with a genetic component, even well understood 'monogenic' disorders. Population-level genome analyses are now demonstrating that many genetic 'mutations' are much less predictive than previously thought 1 Furthermore, HGE might introduce new risks just as it reduces old ones; or remove protections not yet clearly delineated.

Is it acceptable to contact an anonymous egg donor to facilitate diagnostic genetic testing for the donor-conceived child?

We discuss a case where medically optimal investigations of health problems in a donor-conceived child would require their egg donor to participate in genetic testing. We argue that it would be justified to contact the egg donor to ask whether she would consider this, despite her indicating on a historical consent form that she did not wish to take part in future research and that she did not wish to be informed if she was found to be a carrier of a 'harmful inherited condition'. We suggest that we cannot conjecture what her current answer might be if, by participating in clinical genetic testing, she might help reach a diagnosis for the donor-conceived child. At the point that she made choices regarding future contact, it was not yet evident that the interests of the donor-conceived child might be compromised by her answers, as it was not foreseen that the egg donor's genome might one day have the potential to enable diagnosis for this child. Fertility consent forms tend to be conceptualised as representing incontrovertible historical boundaries, but we argue that rapid evolution in genomic practice means that consent in such cases is better seen as an ongoing and dynamic process. It cannot be possible to compel the donor to aid in the diagnosis of the donor-conceived child, but she should be given the opportunity to do so.

Familial genetic risks: how can we better navigate patient confidentiality and appropriate risk disclosure to relatives?

This article investigates a high-profile and ongoing dilemma for healthcare professionals (HCPs), namely whether the existence of a (legal) duty of care to genetic relatives of a patient is a help or a hindrance in deciding what to do in cases where a patient's genetic information may have relevance to the health of the patient's family members. The English case ABC v St George's Healthcare NHS Trust and others considered if a duty of confidentiality owed to the patient and a putative duty of care to the patient's close relatives could coexist in this context. This article examines whether embracing the concept of coexisting duties could enable HCPs to respect duties in line with their clinical judgement, thereby providing legal support and clarity to professionals to allow them to provide the best possible genetics service to both the patient and their family. We argue that these dual duties, framed as a novel, composite duty to consider the interests of genetic relatives, could allow HCPs to exercise and act on their professional judgements about the relative value of information to family members, without fears of liability for negligence or breach of confidence.