Public engagement with genomics.

As detailed in its flagship report, Genome UK, the UK government recognises the vital role that broad public engagement across whole populations plays in the field of genomics. However, there is limited evidence about how to do this at scale. Most public audiences do not feel actively connected to science, are oftenunsure of the relevance to their lives and rarely talk to their family and friends about; we term this dis-connection a 'disengaged public audience'. We use a narrative review to explore: (i) UK attitudes towards genetics and genomics and what may influence reluctance to engage with these topics; (ii) innovative public engagement approaches that have been used to bring diverse public audiences into conversations about the technology. Whilst we have found some novel engagement methods that have used participatory arts, film, social media and deliberative methods, there is no clear agreement on best practice. We did not find a consistently used, evidence-based strategy for delivering public engagement about genomics across diverse and broad populations, nor a specific method that is known to encourage engagement from groups that have historically felt (in terms of perception) and been (in reality) excluded from genomic research. We argue there is a need for well-defined, tailor-made engagement strategies that clearly articulate the audience, the purpose and the proposed impact of the engagement intervention. This needs to be coupled with robust evaluation frameworks to build the evidence-base for population-level engagement strategies.

Current State of Genomics in Nursing: A Scoping Review of Healthcare Provider Oriented (Clinical and Educational) Outcomes (2012-2022).

In the 20 years since the initial sequencing of the human genome, genomics has become increasingly relevant to nursing. We sought to chart the current state of genomics in nursing by conducting a systematic scoping review of the literature in four databases (2012-2022). The included articles were categorized according to the Cochrane Collaboration outcome domains/sub-domains, and thematic analysis was employed to identify key topical areas to summarize the state of the science. Of 8532 retrieved articles, we identified 232 eligible articles. The articles primarily reported descriptive studies from the United States and other high-income countries (191/232, 82%). More than half (126/232, 54.3%) aligned with the "healthcare provider oriented outcomes" outcome domain. Three times as many articles related to the "knowledge and understanding" sub-domain compared to the "consultation process" subdomain (96 vs. 30). Five key areas of focus were identified, including "nursing practice" (50/126, 40%), "genetic counseling and screening" (29/126, 23%), "specialist nursing" (21/126, 17%), "nurse preparatory education" (17/126, 13%), and "pharmacogenomics" (9/126, 7%). Only 42/126 (33%) articles reported interventional studies. To further integrate genomics into nursing, study findings indicate there is a need to move beyond descriptive work on knowledge and understanding to focus on interventional studies and implementation of genomics into nursing practice.

Knowledge, attitudes and decision regret: a longitudinal survey study of participants offered genome sequencing in the 100,000 Genomes Project.

We used cross-sectional surveys to compare the knowledge, attitudes, and decision regret of participants who had consented for genome sequencing (GS) for rare disease diagnosis in the 100,000 Genomes Project (100kGP) across two timepoints (at the time of consenting for GS (T1) and 12-18 months later (T2)). At T1, participants (n = 504) completed a survey that included measures of general knowledge of GS ("Knowledge of Genome Sequencing" (KOGS)), specific knowledge of GS and attitudes towards GS ("General attitudes" and "Specific attitudes"). At T2, participants (n = 296) completed these same assessments (apart from the specific knowledge scale) together with an assessment of decision regret towards GS ("Decisional Regret Scale"). At 12-18 months after consenting for GS, participants' basic knowledge of GS had remained stable. General knowledge of GS varied across topics; concepts underlying more general information about genetics were better understood than the technical details of genomic testing. Attitudes towards GS at T2 were generally positive, and feelings towards GS (both positive and negative) remained unchanged. However, those who were more positive about the test at the outset had greater specific knowledge (as opposed to general knowledge) of GS. Finally, although the majority of participants indicated feeling little regret towards undergoing GS, those with low positive attitude and high negative attitude about GS at T1 reported greater decision regret at T2. Careful assessment of patient knowledge about and attitudes towards GS at the time of offering testing is crucial for supporting informed decision making and mitigating later regret.

The legacy of language: What we say, and what people hear, when we talk about genomics.

The way we "talk" about genetics plays a vital role in whether public audiences feel at ease in having conversations about it. Our research explored whether there was any difference between "what we say" and "what people hear" when providing information about genetics to community groups who are known to be missing from genomics datasets. We conducted 16 focus groups with 100 members of the British public who had limited familiarity with genomics and self-identified as belonging to communities with Black African, Black Caribbean, and Pakistani ancestry as well as people of various ancestral heritage who came from disadvantaged socio-economic backgrounds. Participants were presented with spoken messages explaining genomics and their responses to these were analyzed. Results indicated that starting conversations that framed genomics through its potential benefits were met with cynicism and skepticism. Participants cited historical and present injustices as reasons for this as well as mistrust of private companies and the government. Instead, more productive conversations led with an acknowledgment that some people have questions-and valid concerns-about genomics, before introducing any of the details about the science. To diversify genomic datasets, we need to linguistically meet public audiences where they are at. Our research has demonstrated that everyday talk about genomics, used by researchers and clinicians alike, is received differently than it is likely intended. We may inadvertently be further disengaging the very audiences that diversity programs aim to reach.

International genetic counseling: What do genetic counselors actually do?

We conducted an exploratory survey of genetic counselors internationally to assess similarities and differences in reported practice activities. Between November 2018 and January 2020 we conducted a mass emailing to an estimated 5600 genetic counselors in different countries and regions. We obtained 189 useable responses representing 22 countries, which are included in an aggregate manner. Data from countries with 10 or more responses, comprising 82% of the total (N = 156), are the primary focus of this report: Australia (13), Canada (26), USA (59), UK (17), France (12), Japan (19) and India (10). Twenty activities were identified as common (≥74%) across these countries, encompassing most subcategories of genetic counseling activity. Activities with most frequent endorsement include: reviewing referrals and medical records and identifying genetic testing options as part of case preparation; taking family and medical histories; performing and sharing risk assessment; and educating clients about basic genetic information, test options, outcomes and implications, including management recommendations on the basis of the test results. Genetic counselors also consistently establish rapport, tailor the educational process, facilitate informed decision making and recognize factors that may impact the counseling interaction. The least endorsed activities were in the Medical History category. Notable differences between countries were observed in the endorsement of 33 activities, primarily in the Contracting and Establishing Rapport, Family History, Medical History, Assessing Patients Psychosocially and Providing Psychosocial Support categories. Generalizations about international practice patterns are limited by the low response rate. However, this study is, to our knowledge, the first to systematically compare the clinical practice and specific activities of genetic counselors working in different countries.

Ethical Challenges Associated with Pathogen and Host Genetics in Infectious Disease.

The Covid-19 pandemic has demonstrated the potential of genomic technologies for the detection and surveillance of infectious diseases. Pathogen genomics is likely to play a major role in the future of research and clinical implementation of genomic technologies. However, unlike human genetics, the specific ethical and social challenges associated with the implementation of infectious disease genomics has received comparatively little attention. In this paper, we contribute to this literature, focusing on the potential consequences for individuals and communities of the use of these technologies. We concentrate on areas of challenges related to privacy, stigma, discrimination and the return of results in the cases of the surveillance of known pathogens, metagenomics and host genomics.

Developing a National Newborn Genomes Program: An Approach Driven by Ethics, Engagement and Co-design.

The transformative potential of whole genome sequencing (WGS) as a diagnostic tool in healthcare has been demonstrated by initiatives including the 100,000 Genomes Project and is now offered to certain patients in the National Health Service (NHS) in England. Building on these foundations, the utility of WGS in the newborn period can now be explored. Genomics England is working in partnership with NHS England and NHS Improvement and other healthcare, patient and public interest groups to design a research program embedded in the NHS to explore the potential challenges and implications of offering WGS in all newborns. The program will aim to: 1) evaluate the feasibility, utility and impact on the NHS of screening for childhood-onset rare actionable genetic conditions; 2) understand how, with consent, genomic and healthcare data could be used to enable research to develop new diagnostics and treatments; and 3) explore the implications of storing an individual's genome for use over their lifetime. Recognizing the important practical, scientific and ethical questions that we must explore in dialogue with the public and experts, we are taking a collaborative, evidence-based and ethically deliberate approach to designing the program. An iterative co-design process including a nationwide public dialogue has identified emergent themes and ethical considerations which are the focus of the program's design. These themes will be further developed through continued engagement with healthcare professionals, researchers, ethics experts, patient groups and the public, with an ongoing commitment to embedding ongoing ethics research and co-design into the delivery of the program.

Co-designing models for the communication of genomic results for rare diseases: a comparative study in the Czech Republic and the United Kingdom.

The communication of genomic results to patients and families with rare diseases raise distinctive challenges. However, there is little evidence about optimal methods to communicate results to this group of service users. To address this gap, we worked with rare disease families and health professionals from two genetic/genomic services, one in the United Kingdom and one in the Czech Republic, to co-design that best meet their needs. Using the participatory methodology of Experience-Based Co-Design (EBCD), we conducted observations of clinical appointments (n=49) and interviews with family participants (n=23) and health professionals (n=22) to gather their experience of sharing/receiving results. The findings informed a facilitated co-design process, comprising 3 feedback events at each site and a series of meetings and remote consultations. Participants identified a total of four areas of current service models in need of improvement, and co-designed six prototypes of quality improvement interventions. The main finding was the identification of post-test care as the shared priority for improvement for both health professionals and families at the two sites. Our findings indicate the need to strengthen the link between diagnostics (whether or not a pathogenic variant is found) and post-test care, including psychosocial and community support. This raises implications for the reconfigurations of genomic service models, the redefinition of professional roles and responsibilities and the involvement of rare disease patients and families in health care research.

Whole-genome sequencing reveals host factors underlying critical COVID-19.

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2-4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Participant experiences of genome sequencing for rare diseases in the 100,000 Genomes Project: a mixed methods study.

In this mixed methods study, a survey and in-depth interviews were used to explore whether decision regret and the psychological impact of receiving genome sequencing (GS) results differed between parents and patients, and between those who received a genetic diagnosis and those who did not. Participants (n = 77) completed a survey that included the Decisional Regret Scale (DRS) and an adaptation of the Multidimensional Impact of Cancer Risk Assessment (MICRA) at least 12 months after consenting for GS for rare disease diagnosis in the 100,000 Genomes Project. Survey participants were invited to take part in an interview and 39 agreed; 12 with a diagnosis, 5 with variants of uncertain significance, and 19 with no pathogenic findings identified. Both survey and interview findings indicated that decision regret was low. DRS scores revealed no differences in levels of regret between parents and patients, or between those with a diagnosis and those without. Though MICRA scores indicated minimal evidence of negative psychological impacts of receiving GS results, subscale analysis revealed greater distress and uncertainty for parents compared to patients. Receiving a diagnosis was found not to influence MICRA scores, supporting interview findings of both positive and negative emotional and psychological impacts irrespective of a genetic diagnosis. Our findings have implications for policy and practice as GS is integrated into the UK and worldwide; notably, that expectation-setting is critical when offering GS, and that post-test counselling is important regardless of the GS result received, with parents perhaps needing additional emotional support.

Towards equitable and trustworthy genomics research.

The representation of traditionally scientifically underserved groups in genomic research continues to be low despite concerns about equity and social justice and the scientific and clinical need. Among the factors that account for this are a lack of trust in the research community and limited diversity in this community. The success of the multiple initiatives that aim to improve representation relies on the willingness of underrepresented populations to make data and samples available for research and clinical use. In this narrative review, we propose that this requires building trust, and set out four approaches to demonstrating trustworthiness, including increasing diversity in the research workforce, and meaningful engagement with underrepresented communities in a culturally and linguistically appropriate manner. Capacity building globally will ensure that actual and perceived exploitation and 'helicopter' research could be eliminated.

Return of genomic results does not motivate intent to participate in research for all: Perspectives across 22 countries.

PURPOSE: The aim of this study was to determine how attitudes toward the return of genomic research results vary internationally. METHODS: We analyzed the "Your DNA, Your Say" online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle-, and high-income countries, and these were gathered in 15 languages. We analyzed how participants responded when asked whether return of results (RoR) would motivate their decision to donate DNA or health data. We examined variation across the study countries and compared the responses of participants from other countries with those from the United States, which has been the subject of the majority of research on return of genomic results to date. RESULTS: There was substantial variation in the extent to which respondents reported being influenced by RoR. However, only respondents from Russia were more influenced than those from the United States, and respondents from 20 countries had lower odds of being partially or wholly influenced than those from the United States. CONCLUSION: There is substantial international variation in the extent to which the RoR may motivate people's intent to donate DNA or health data. The United States may not be a clear indicator of global attitudes. Participants' preferences for return of genomic results globally should be considered.

Decision-making, attitudes, and understanding among patients and relatives invited to undergo genome sequencing in the 100,000 Genomes Project: A multisite survey study.

PURPOSE: The purpose of this study was to assess decisions, attitudes, and understanding of participants (patients, parents, relatives) having genome sequencing for rare disease diagnosis. METHODS: This study involved a cross-sectional observational survey with participants in the 100,000 Genomes Project. RESULTS: Survey response rate was 51% (504/978). Most participants self-reported that they had decided to undergo genome sequencing (94%) and that this was an informed decision (84%) with low decisional conflict (95%). Most self-reported that they had chosen to receive additional findings (88%) and that this was an informed decision (89%) with low decisional conflict (95%). Participants were motivated more by the desire to help others via research than by the belief it would help them obtain a diagnosis (Z = 14.23, P = 5.75 × 10-46), although both motivations were high. Concerns were relatively few but, where expressed, were more about the potential psychological impact of results than data sharing/access (Z = 9.61, P = 7.65 × 10-22). Concerns were higher among male, Asian or Asian British, and more religious participants. General and context-specific understanding of genome sequencing were both moderately high (means 5.2/9.0 and 22.5/28.0, respectively). CONCLUSION: These findings are useful to inform consent guidelines and clinical implementation of genome sequencing.

Return of individual research results from genomic research: A systematic review of stakeholder perspectives.

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants.

Demonstrating trustworthiness when collecting and sharing genomic data: public views across 22 countries.

BACKGROUND: Public trust is central to the collection of genomic and health data and the sustainability of genomic research. To merit trust, those involved in collecting and sharing data need to demonstrate they are trustworthy. However, it is unclear what measures are most likely to demonstrate this. METHODS: We analyse the 'Your DNA, Your Say' online survey of public perspectives on genomic data sharing including responses from 36,268 individuals across 22 low-, middle- and high-income countries, gathered in 15 languages. We examine how participants perceived the relative value of measures to demonstrate the trustworthiness of those using donated DNA and/or medical information. We examine between-country variation and present a consolidated ranking of measures. RESULTS: Providing transparent information about who will benefit from data access was the most important measure to increase trust, endorsed by more than 50% of participants across 20 of 22 countries. It was followed by the option to withdraw data and transparency about who is using data and why. Variation was found for the importance of measures, notably information about sanctions for misuse of data-endorsed by 5% in India but almost 60% in Japan. A clustering analysis suggests alignment between some countries in the assessment of specific measures, such as the UK and Canada, Spain and Mexico and Portugal and Brazil. China and Russia are less closely aligned with other countries in terms of the value of the measures presented. CONCLUSIONS: Our findings highlight the importance of transparency about data use and about the goals and potential benefits associated with data sharing, including to whom such benefits accrue. They show that members of the public value knowing what benefits accrue from the use of data. The study highlights the importance of locally sensitive measures to increase trust as genomic data sharing continues globally.