Systematic reanalysis of genomic data by diagnostic laboratories: a scoping review of ethical, economic, legal and (psycho)social implications.

With the introduction of Next Generation Sequencing (NGS) techniques increasing numbers of disease-associated variants are being identified. This ongoing progress might lead to diagnoses in formerly undiagnosed patients and novel insights in already solved cases. Therefore, many studies suggest introducing systematic reanalysis of NGS data in routine diagnostics. Introduction will, however, also have ethical, economic, legal and (psycho)social (ELSI) implications that Genetic Health Professionals (GHPs) from laboratories should consider before possible implementation of systematic reanalysis. To get a first impression we performed a scoping literature review. Our findings show that for the vast majority of included articles ELSI aspects were not mentioned as such. However, often these issues were raised implicitly. In total, we identified nine ELSI aspects, such as (perceived) professional responsibilities, implications for consent and cost-effectiveness. The identified ELSI aspects brought forward necessary trade-offs for GHPs to consciously take into account when considering responsible implementation of systematic reanalysis of NGS data in routine diagnostics, balancing the various strains on their laboratories and personnel while creating optimal results for new and former patients. Some important aspects are not well explored yet. For example, our study shows GHPs see the values of systematic reanalysis but also experience barriers, often mentioned as being practical or financial only, but in fact also being ethical or psychosocial. Engagement of these GHPs in further research on ELSI aspects is important for sustainable implementation.

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.

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.

Interventions to support patients with sharing genetic test results with at-risk relatives: a synthesis without meta-analysis (SWiM).

Whilst the finding of heritable susceptibility to disease was once relatively rare, mainstreaming of genetic testing has resulted in a steady increase. Patients are often encouraged to share their genetic test results with relevant relatives, but relatives may not receive this information, leaving them without knowledge of their own risk. Therefore, strategies to help communicate such information are important. This review aimed to explore the efficacy of existing interventions to improve the sharing of genetic test results. A synthesis without meta-analysis design was used. A systematic search of Medline, CINAHL, PsychINFO, and AMED was conducted, and five studies were identified worldwide. Data were extracted for each study regarding study aim, participant characteristics, condition, intervention details, comparison, study duration, outcome measures, theory and behaviour change techniques used. Limited efficacy and application of theory was found. Knowledge, motivation and self-efficacy were not increased in any intervention. No gender differences in communication behaviour were encountered in interventions that recruited men and women. Two studies reported an evaluation of acceptability, which showed that the interventions were well received by patients and health professionals. No study reported the involvement of the target population in any phase of intervention development. Given the lack of health psychology-informed interventions in this area of clinical genetics, we recommend genetic health professionals, health psychologists and patients collaborate on all stages of future interventions that involve the cascading of genetic health information within families. We also provide guidance regarding use of theory and intervention elements for future intervention development.

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.

The environmental impact of data-driven precision medicine initiatives.

Opportunities offered by precision medicine have long been promised in the medical and health literature. However, precision medicine - and the methodologies and approaches it relies on - also has adverse environmental impacts. As research into precision medicine continues to expand, there is a compelling need to consider these environmental impacts and develop means to mitigate them. In this article, we review the adverse environmental impacts associated with precision medicine, with a particular focus on those associated with its underlying need for data-intensive approaches. We illustrate the importance of considering the environmental impacts of precision medicine and describe the adverse health outcomes that are associated with climate change. We follow this with a description of how these environmental impacts are being addressed in both the health and data-driven technology sector. We then describe the (scant) literature on environmental impacts associated with data-driven precision medicine specifically. We finish by highlighting various environmental considerations that precision medicine researchers, and the field more broadly, should take into account.

"A very big challenge": a qualitative study to explore the early barriers and enablers to implementing a national genomic medicine service in England.

Background: The Genomic Medicine Service (GMS) was launched in 2018 in England to create a step-change in the use of genomics in the NHS, including offering whole genome sequencing (WGS) as part of routine care. In this qualitative study on pediatric rare disease diagnosis, we used an implementation science framework to identify enablers and barriers which have influenced rollout. Methods: Semi-structured interviews were conducted with seven participants tasked with designing the GMS and 14 tasked with leading the implementation across the seven Genomic Medicine Service Alliances (GMSAs) and/or Genomic Laboratory Hubs (GLHs) between October 2021 and February 2022. Results: Overall, those involved in delivering the service strongly support its aims and ambitions. Challenges include: 1) concerns around the lack of trained and available workforce (clinicians and scientists) to seek consent from patients, interpret findings and communicate results; 2) the lack of a digital, coordinated infrastructure in place to support and standardize delivery with knock-on effects including onerous administrative aspects required to consent patients and order WGS tests; 3) that the "mainstreaming agenda", whilst considered important, encountered reluctance to become engaged from those who did not see it as a priority or viewed it as being politically rather than clinically driven; 4) the timelines and targets set for the GMS were perceived by some as too ambitious. Interviewees discussed local adaptations and strategies employed to address the various challenges they had encountered, including 1) capacity-building, 2) employing genomic associates and other support staff to support the consent and test ordering process, 3) having "genomic champions" embedded in mainstream services to impart knowledge and best practice, 4) enhancing collaboration between genetic and mainstream specialties, 5) building evaluation into the service and 6) co-creating services with patients and the public. Conclusion: Our findings highlight the challenges of implementing system-wide change within a complex healthcare system. Local as well as national solutions can undoubtedly address many of these barriers over time.

Mixed-methods evaluation of the NHS Genomic Medicine Service for paediatric rare diseases: study protocol.

Background: A new nationally commissioned NHS England Genomic Medicine Service (GMS) was recently established to deliver genomic testing with equity of access for patients affected by rare diseases and cancer. The overarching aim of this research is to evaluate the implementation of the GMS during its early years, identify barriers and enablers to successful implementation, and provide recommendations for practice. The focus will be on the use of genomic testing for paediatric rare diseases. Methods: This will be a four-year mixed-methods research programme using clinic observations, interviews and surveys. Study 1 consists of qualitative interviews with designers/implementers of the GMS in Year 1 of the research programme, along with documentary analysis to understand the intended outcomes for the Service. These will be revisited in Year 4 to compare intended outcomes with what happened in practice, and to identify barriers and facilitators that were encountered along the way. Study 2 consists of clinic observations (pre-test counselling and results disclosure) to examine the interaction between health professionals and parents, along with follow-up interviews with both after each observation. Study 3 consists of a longitudinal survey with parents at two timepoints (time of testing and 12 months post-results) along with follow-up interviews, to examine parent-reported experiences and outcomes. Study 4 consists of qualitative interviews and a cross-sectional survey with medical specialists to identify preparedness, facilitators and challenges to mainstreaming genomic testing. The use of theory-based and pre-specified constructs will help generalise the findings and enable integration across the various sub-studies. Dissemination: We will disseminate our results to policymakers as findings emerge, so any suggested changes to service provision can be considered in a timely manner. A workshop with key stakeholders will be held in Year 4 to develop and agree a set of recommendations for practice.

BACKGROUND AND AIMS: Genome sequencing (where a person's entire genetic code is mapped) is set to dramatically transform patient care and medical outcomes. Recently, genome sequencing was introduced as part of routine clinical care in the NHS, through the Genomic Medicine Service (GMS). The aim of this research is to understand how genome sequencing is being delivered in the first few years of the Service, in particular what the barriers and enablers are to successful delivery. The focus of the study will be the use of genome sequencing for children with undiagnosed conditions. STUDY DESIGN: This is a four-year study in which we will conduct: observations of clinic appointments; interviews with policy makers and health professionals designing and implementing the new service; and surveys/interviews with parents of patients undergoing genomic testing. By the end of this study we will have: - a better understanding of the intended vs actual outcomes of the GMS,- insights into what happens during clinical encounters,- understand what the entire testing process is like for parents from being offered genomic testing to receiving their results and beyond, including the clinical as well as emotional and practical outcomes, and- understand how healthcare professionals feel about delivering the GMS, particularly those that are non-genetic specialists, including how prepared they feel to deliver genomic testing. Patient and public involvement: Parents of children who have been through the testing process have helped us design this study. They have inputted into surveys and topic guides, and will be involved throughout the study as members of the advisory team so that we can ensure the findings are used to improve the quality of care patients and families receive. DISSEMINATION: The findings from this research will be shared with organisations such as NHS England and NHS Improvement so that recommendations can be implemented swiftly.

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.

Cognitive and affective outcomes of genetic counselling in the Netherlands at group and individual level: a personalized approach seems necessary.

We performed a large outcome study at group and individual level in which the goals of genetic counselling were operationalized into cognitive and affective outcomes: empowerment, perceived personal control and anxiety. We then examined which socio-demographic and clinical variables were associated with changes in these outcomes. Data came from 1479 counselees who completed questionnaires (GCOS-18, PPC and STAI) at three time points: before the start of genetic counselling, after the first consultation and after the results of genetic counselling were disclosed. Results showed that at group level empowerment, perceived personal control and anxiety improved significantly after the whole genetic counselling process. Effect-sizes were medium for empowerment and small for the other outcomes. At individual level, 48% of counselees improved in empowerment, 21% in perceived personal control and 17% in anxiety. Around 10% of counselees worsened on all outcomes. Only 'reason for referral' and 'genetic test result' were significantly associated with changes in outcomes. This study demonstrated improvements among counselees in cognitive and affective outcomes after genetic counselling at group level. However, our results also suggest that there are opportunities for improvement at individual level, as many counselees remained stable and some even worsened on all outcomes. Routine outcome monitoring could help to explore the needs of counselees and could help to identify counselees who worsen.

Exploring broad consent in the context of the 100,000 Genomes Project: a mixed methods study.

The 100,000 Genomes Project (100kGP)-a hybrid clinical-research initiative-was set up to analyse whole-genome sequences (WGS) from patients living with a rare disease or cancer. The project positioned participant consent as being of central importance, but consent in the context of genomic testing raises challenging issues. In this mixed method study, we surveyed 1337 100kGP participants regarding their experiences of taking part in the project and conducted in-depth interviews with 24 survey respondents to explore these findings further. Survey responses were analysed using descriptive statistics and interview data were analysed thematically. The consent approach of the 100kGP resulted in a proportion of our study's participants not understanding the complexities of the project and what types of results they might receive; for example, 20% of participants who we surveyed from the cancer arm did not recall what decisions they had made regarding additional findings. It is not surprising that a project such as this, with such diverse aims and participant groups, would throw up at least some challenges. However, participants reported being satisfied with their experience of the project to date. Our study highlights that in the context of consent for more complex endeavours, such as the 100kGP, it is important to assess (and document) an agreement to take part, but complicated decisions about what and when to communicate may need revisiting over time in response to changing contexts. We discuss the implications of our findings with reference to participants of the 100kGP and the newly formed NHS Genomic Medicine Service.

Genome sequencing in healthcare: understanding the UK general public's views and implications for clinical practice.

Technological advances have seen the offer of genome sequencing becoming part of mainstream medical practice. Research has elicited patient and health professional views on the ethical issues genome sequencing raises, however, we know little about the general public's views. These views offer an insight into people's faith in such technologies, informing discussion regarding the approach to consent in clinic. We aimed to garner public views regarding genome sequencing, incidental findings (IFs), and sharing genetic information with relatives. Participants (n = 1954) from the British general public completed a survey, distributed via email. Overall, the public had a positive view of genomic sequencing, choosing 'informative' as the most popular word (52%) and 'family legacy' as the most popular analogy (33%) representing genomic sequencing for them. Fifty-three percent  agree that their relative had the right to be told about genetic information relevant to them. Fifty-four percent would expect to be told about IFs whether they had asked for them or not. Clinical practice needs to acknowledge these perspectives and expectations in order to facilitate meaningful discussion during the consent process for genomic tests. We suggest that: (a) optimistic perspectives on the usefulness of genomic tests need to be tempered by discussion in clinic about the likelihood that genomic results might be uninformative, uncertain or unexpected; (b) discussions regarding the familial nature of results are needed before testing: the majority of patients will welcome this and any concerns can be explored further; and (c) a wider discussion is required regarding the consent approach for genomic testing.

Genomic variant sharing: a position statement.

Sharing de-identified genetic variant data is essential for the practice of genomic medicine and is demonstrably beneficial to patients. Robust genetic diagnoses that inform medical management cannot be made accurately without reference to genetic test results from other patients, as well as population controls. Errors in this process can result in delayed, missed or erroneous diagnoses, leading to inappropriate or missed medical interventions for the patient and their family. The benefits of sharing individual genetic variants, and the harms of not sharing them, are numerous and well-established. Databases and mechanisms already exist to facilitate deposition and sharing of pseudonomised genetic variants, but clarity and transparency around best practice is needed to encourage widespread use, prevent inconsistencies between different communities, maximise individual privacy and ensure public trust. We therefore recommend that widespread sharing of a small number of individual genetic variants associated with limited clinical information should become standard practice in genomic medicine. Information robustly linking genetic variants with specific conditions is fundamental biological knowledge, not personal information, and therefore should not require consent to share. For additional case-level detail about individual patients or more extensive genomic information, which is often essential for clinical interpretation, it may be more appropriate to use a controlled-access model for data sharing, with the ultimate aim of making as much information as open and de-identified as possible with appropriate consent.

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.

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.