Criteria for reporting incidental findings in clinical exome sequencing : a focus group study on professional practices and perspectives in Belgian genetic centres

Background: Incidental and secondary findings (IFs and SFs) are subject to ongoing discussion as potential consequences of clinical exome sequencing (ES). International policy documents vary on the reporting of these findings. Discussion points include the practice of unintentionally identified IFs versus deliberately pursued SFs, patient opt-out possibilities and the spectrum of reportable findings. The heterogeneity of advice permits a non-standardised disclosure but research is lacking on actual reporting practices. Therefore, this study assessed national reporting practices for IFs and SFs in clinical ES and the underlying professional perspectives. Methods: A qualitative focus group study has been undertaken, including professionals from Belgian centres for medical genetics (CMGs). Data were analysed thematically. Results: All Belgian CMGs participated in this study. Data analysis resulted in six main themes, including one regarding the reporting criteria used for IFs. All CMGs currently use ES-based panel testing. They have limited experience with IFs in clinical ES and are cautious about the pursuit of SFs. Two main reporting criteria for IFs were referred to by all CMGs: the clinical significance of the IF (including pathogenicity and medical actionability) and patient-related factors (including the patient's preference to know and patient characteristics). The consensus over the importance of these criteria contrasted with their challenging interpretation and application. Points of concern included IFs' pathogenicity in non-symptomatic persons, IFs concerning variants of uncertain significance, the requirement and definition of medical actionability and patient opt-out possibilities. Finally, reporting decisions were guided by the interaction between the clinical significance of the IF and patient characteristics. This interaction questions the possible disclosure of findings with context-dependent and personal utility, such as IFs concerning a carrier status. To evaluate the IF's final relevance, a professional and case-by-case deliberation was considered essential. Conclusions: The challenging application of reporting criteria for IFs results in diversified practices and policy perspectives within Belgian CMGs. This echoes international concerns and may have consequences for effective policy recommendations

Ethical values supporting the disclosure of incidental and secondary findings in clinical genomic testing : a qualitative study

Background: Incidental findings (IFs) and secondary findings (SFs), being results that are unrelated to the diagnostic question, are the subject of an important debate in the practice of clinical genomic medicine. Arguments for reporting these results or not doing so typically relate to the principles of autonomy, nonmaleficence and beneficence. However, these principles frequently conflict and are insufficient by themselves to come to a conclusion. This study investigates empirically how ethical principles are considered when actually reporting IFs or SFs and how value conflicts are weighed. Methods: A qualitative focus group study has been undertaken, including a multidisciplinary group of professionals from Belgian centres for medical genetics. The data were analysed thematically. Results: All eight Belgian centres participated in this study. Ethical values were frequently referred to for disclosure policies on IFs and SFs. Participants invoked respect for patient autonomy to support the disclosure of IFs and optout options for IFs and SFs, non-maleficence for the professional delineation of reportable IFs and opt-out options for IFs and SFs and (the particular scope of) beneficence for the mandatory reporting of actionable IFs, the delineation of reportable IFs and a current decline of actively pursued SFs. Professional assumptions about patients’ genetic literacy were an important factor in the weighing of values. Conclusions: In line with the traditional bioethical discourse, the mandatory reporting of actionable IFs might be interpreted as a “technological, soft paternalism”. Restricting patients’ choices might be acceptable, but then its motives should be valid and its beneficent outcomes highly plausible. Hence, the presuppositions of technological, soft paternalism - patients’ inability to make informed decisions, normative rationality, the efficacy of beneficent outcomes and the delineated spectrum of beneficence - should be approached critically. Moreover, distributive justice should be considered an important value in the delineation of the current scope of the ethical debate on IFs and SFs. This study of guiding values may stimulate the debate on the ethical grounds for a solid policy on IFs and SFs internationally

The sexual adjustment process of cancer patients and their partners : a qualitative evidence synthesis

When confronted with cancer, a prominent challenge for patients and their partners is their changed sexual relationship. An empirically based theoretical model of the sexual adaptation process during cancer might be helpful in guiding the development of adequate interventions for couples who struggle with their sexual relationship. Therefore, the purpose of this study was to synthesize evidence from primary qualitative research studies and to arrive at a detailed description of the process of sexual adjustment during cancer. We conducted a qualitative evidence synthesis of a purposeful sample of 16 qualitative papers, using the meta-ethnography approach to synthesis. We found that the subsequent studies used different theoretical approaches to describe the sexual adaptation process. This led to three divergent sexual adaptation processes: (1) the pathway of grief and mourning, depicting sexual changes as a loss; (2) the pathway of restructuring, depicting the adjustment process toward sexual changes as a cognitive process with a strong focus on the social and cultural forces that shape the values and experiences of sexuality; and (3) the pathway of sexual rehabilitation, depicting sexual changes as a bodily dysfunction that needs treatment and specific behavioral strategies. All three pathways have their own opportunities and challenges. A greater awareness of these different pathways could help healthcare providers to better understand the ways a particular couple might cope with changed sexuality, offering them opportunities to discover alternative pathways for sexual adjustment

Disclosing incidental and secondary findings in clinical genomics : professional practice, patient experience and ethical reflection

Background and research objectives Genetic testing is becoming a standard procedure in clinical care. Whereas previous methods of diagnostic testing were mainly focussed on disease-specific genes, current methods are often genome-wide. This implies that diagnostically unrelated findings may be unintentionally revealed (as incidental findings or IFs) and/or that they may be actively pursued as secondary findings (SFs). IFs and SFs can allow for preventive or therapeutic actions but they may also result in distress or harmful interventions. International advisory boards, professional organisations and patients have expressed different views on these potential findings. The main objective of this dissertation is to examine practices and perspectives concerning the meaning and disclosure of IFs and SFs in a context of clinical testing in adults. This objective is realised by means of an empirical, qualitative research approach that captures both professional and patient voices and that covers both policy and ethical concerns. More specifically, this dissertation focusses on professional disclosure practices and policies in Belgian centres for medical genetics (CMGs) and on the meaning of potential IFs and SFs from a patient perspective. Results A focus group study with genetic professionals in Belgian CMGs indicated that the clinical significance of an IF is a major criterion for disclosure. This means that reported IFs should be pathogenic and actionable. However, these criteria are difficult to interpret unambiguously. Secondly, a diversified practice, based on clinical, practical and ethical arguments, concerning a patient opt-out of medically actionable IFs was revealed across Belgian CMGs. Finally, an interaction between particular patient characteristics and the significance of a specific IF can affect disclosure, which creates the need for deliberation and a tension between general guidelines and case-by-case decisions. At value level, Belgian professionals frequently called upon respect for patient autonomy, non-maleficence and beneficence to support disclosure practices. With respect to medically actionable IFs, some professionals considered the value of patient autonomy as superseded by the professional duties of care and avoiding harm, which may result in a mandatory disclosure of these findings. This missing opt-out possibility can be conceptualised as technological soft paternalism. Its arguments and consequences, including assumptions about patients’ genetic literacy, a normative rationality and beneficent outcomes, are critically questioned. The value of distributive justice is additionally included as an important factor concerning the scope of the debate on IFs and SFs. Subsequently, this dissertation thoroughly examines the perspective of adults with an inherited retinal disease (IRD) on the meaning of IFs. An interview study showed that these patients assign a complex meaning to IFs that largely transcends clinical, result-centred components such as actionability or psychological consequences. Instead, also lived experiences of an IRD, patients’ family embedding and a family history of disease affect the interpretation of IFs. This nuanced meaning structure of IFs should be taken into account in the development of effective counselling procedures. Given the nuanced interpretation of IFs and SFs, both genetic professionals and patients may experience uncertainty concerning the meaning and potential disclosure of IFs and SFs. However, the causes and consequences of these uncertainties diverge. Whereas professionals are more concerned about epistemic causes and scientific consequences of uncertainty, patients mainly focus on lived experiences and personal consequences of uncertainty. A rapprochement of these uncertainties may result in a conjointly constructed and case-specific meaning of IFs and SFs that can contribute to an efficient policy

Expanding citizen engagement in the secondary use of health data: an opportunity for national health data access bodies to realise the intentions of the European Health Data Space

Abstract The European Health Data Space (EHDS) aims to make the primary use of health data for healthcare provision more continuous, effective, and (cost) efficient. Moreover, it pursues to facilitate the secondary use of health data for purposes such as research, innovation, and policy making. In the context of secondary use, the EHDS legislative proposal (published on 3 May 2022) argues that Member States should develop Health Data Access Bodies (HDABs) whose responsibilities include facilitating the secondary use of health data, issuing data permits, and implementing high levels of accountability and security. In Belgium, the setup in 2023 of a federal Health Data Agency (HDA) that is developing and implementing a policy strategy and framework for the secondary use of health data, aligns well with the responsibilities set out for HDABs. Even though the EHDS aspires the empowerment of citizens, for instance by giving them access to their health data and control over the healthcare professionals who can consult these data, this call for citizen empowerment resonates less loudly regarding secondary use. We think, however, that elaborating and implementing citizen engagement in the domain of secondary use is required to align secondary use with socio-ethical sensitivities, preferences, and values and to provide social legitimacy and ethical solidity to a health data governance system. When implementing the EHDS legislation on a national level, the Belgian HDA and the future HDABs in general might be excellent opportunities to realise this ambition of citizen involvement and empowerment. More specifically, we urge HDABs, firstly, to expand the field of citizen engagement towards the domain of secondary use and, secondly, to respect and facilitate the diversity of citizen engagement. This would offer citizens genuine, continuous and diversified possibilities of involvement and co-creation concerning the development of a solid ethical governance framework for health data

Incidental findings : inherent part of patients’ identity or unwillingly imposed digitalization?

Incidental findings, results that exceed the initial indication for a medical test, are of the most contested topics in current debates on genetic testing. Geneticists stress the inevitably increasing number of incidental findings in the rapidly evolving technique of Next Generation Sequencing (NGS). Whole exome or even whole genome sequencing (WES/WGS) scan the human genetic data to the fullest, allowing a faster and better detection of illness-causing and sought-for mutations. However, they might also reveal supplementary and unsought-for health risks. Therefore, various guidelines have been published on how to handle this additional yet unsolicited medical information (Green et al., 2013). Simultaneously, numerous ethical debates have been raised on whether these incidental findings are an opportunity of self-governance for the patient or, in contrast, a risk towards personal decision-making and autonomy. Up till now, one voice has remained remarkably silent in this debate, i.e. the voice of the patient himself. Despite the advice of geneticists and the arguments of ethicists, little attention has been paid to the experience of the patient who actually gets confronted with incidental findings, as an inherent possibility of WES/WGS. To fill this scientific gap, we will, firstly, argue why practice and policy guidelines for incidental findings are in absolute need of an empirical basis in patients’ lived experience. Secondly, we will present the first results of our qualitative research project in which we interview patients with a Mendelian disease about their experiences and preferences concerning genetic testing and, more specifically, incidental findings. We will investigate the particular meaning of incidental findings and the impact they have on patients’ personal identity and on their psychosocial and family life. Do patients consider incidental findings as a positive side-effect of genetic testing, as an opportunity for knowledge and action (towards themselves, their future and their family), as an inherent part of their identity? Or do they also fear incidental findings as disturbing information they did not ask for, as a possible cause of worries and anxiety, as digital data they cannot control? Leaving the polarization of advocating versus inhibiting incidental findings behind, we aim for an experience-based and contextualized comprehension of incidental findings, as the necessary ground for future guidelines and practice

Incidental findings : an opportunity for autonomy or a case of hidden heteronomy?

Genetic testing is expanding at high speed. Whole Genome Sequencing (WGS) permits detecting mutations in the entire human genome, resulting in a better diagnosis of (rare) hereditary disorders and a more accurate personalized medicine. However, sequencing the whole genome can also reveal medical information a patient did not ask for, the so called “incidental findings” or “surprise discoveries”. The consequences of these supplementary detected mutations can vary from disorders with a mild pathological phenotype to severe illness. The wide spectrum of incidental findings and their different implications (chance of developing the disorder, pathological impact, time of onset, treatability, … of the disorder) raise the question of when incidental findings are good to know and when they better stay undisclosed. Incidental findings can be an opportunity for enhanced autonomy but can also lead to more heteronomy, where suddenly revealed risks turn a person’s life upside down and have a substantial impact on the future actions and decisions (s)he makes during his/her lifespan. Therefor we should raise the question when and how incidental findings do provide an opportunity for relevant and (in multiple meanings) useful knowledge and when they mainly generate uncertainty, resulting in fear and worries. Moreover, we should wonder who is qualified to make this distinction: patients themselves, who are probably most capable to evaluate their own situation or genetic experts and counselors, with education and expertise in interpreting incidental findings and their consequences? We will present the outline of our qualitative research project, in which we try to answer all of these questions, and we will illustrate its twofold design. On the one hand, we will empirically investigate the current practice, lived experiences of patients and advice of experts concerning genetic testing and the return of incidental findings in a clinical context. We will realize this by in-depth interviews with patients, physicians, genetic counselors, … On the other hand and by a more normative reflection, we want to consider these different perspectives in the context of ethical notions such as patient autonomy, personal responsibility and medical paternalism concerning genetic knowledge. This way, we want to contribute to the development of a best practice in one of the most challenging disciplines in current medicine

Incidental or secondary findings in genetics : stairways to a life of certainty?

Since science started to unravel the human genome, the idea has risen that we are discovering the building blocks and the blueprint of life. Physical qualities, health and illness and even character traits turned out not to be determined by accident or fate, but to be the result of a constant interaction between behavior, environmental factors and very specifically organized DNA strands. As genetic knowledge still increases at high speed and more genes and their function get revealed, the human possibilities for action and prevention, also on the level of healthcare, keep on growing. In some cases, illness can even be prevented, which might create the impression of a predictable health trajectory. If, despite this promising evolution, illness strikes, patients’ questions are tried to be answered as good as possible, i.a. by use of genetic testing. Over the last few years, the technology of Next Generation Sequencing (NGS), by means of which the whole exome or genome is analyzed, has been introduced in the diagnostic context and it is most likely that NGS’s application as a diagnostic tool will only increase in the future. However, NGS might not only answer the initial questions but it might also reveal additional information and (initially) unsought-for health risks, as incidental or secondary findings (ISFs). According to the (currently utopian) dream of a perfectly predictable future, genomic information seems to be a valuable tool. This genetic knowledge might raise the idea that it will be possible to predict which illness one will get, at what time the first symptoms will appear and which prevention or treatment will be most effective. ISFs can stimulate this feeling of knowledge and control, as they might offer an extra chance to avoid serious morbidity or to prepare for future health evolutions. However, one might wonder if this feeling of certainty and control is legitimate and whether the utopian dream can ever be realized. Currently, scientific knowledge is lacking on many genes’ function and on the actual pathogenicity of many variants. Moreover, due to incomplete penetrance and variable expression, pathogenic variants do not indicate a delineated truth but a wide spectrum of possible futures, while also many environmental factors can influence the final outcome. Therefore, ISFs might not only be a way towards certainty and security but also towards doubts, uncertain knowledge, hesitation and worries. To realize a better understanding of the status of ISFs, we have set up a qualitative study and we have been interviewing patients with a Mendelian disease about their experience with NGS and the meaning they ascribe to ISFs. In our presentation, we will focus on patients’ ideas regarding the possible knowledge of additional genetic predispositions. How is this information perceived as contributing to a feeling of certainty? Are ISFs hidden stairways to control? Or will patients get off-road, confused by the many possible ways to go

Incidental or secondary findings : an integrative and patient-inclusive approach to the current debate

Incidental or secondary findings (ISFs) in whole exome or whole genome sequencing have been widely debated in recent literature. The American College of Medical Genetics and Genomics' recommendations on diagnostic ISFs have strongly catalyzed the discussion, resulting in worldwide reactions and a variety of international guidelines. This article will outline how propositions on levels of terminology, policy, and underlying values are still internationally criticized and adjusted. Unsolved questions regarding ISFs include a suitable terminology, adequate counseling or informed consent procedures, opt-out possibilities, reporting ISFs to (parents of) minors and values regarding professional duty, patient autonomy, and actionability. These questions will be characterized as intrinsically related and reciprocally maintained and hence, symptomatic, single-level reflections will be marked as ineffective. Instead, a level-integrative approach of the debate that explicitly acknowledges this interaction and considers a balance between internationally significant and case-specific solutions, will be advocated. Second, the inclusion of a patient perspective will be strongly encouraged to complement the professional preponderance in the current debate. The examination of lived patient experiences, a qualitative focus on the subjective meaning of ISFs, and a contextualization of meaning processes will be suggested as specific concretizations. This integrative and inclusive approach aims for a more comprehensive understanding of ISFs, a consideration of all relevant stakeholders' perspective and, ultimately, an effective health-care policy