Towards responsible genome-wide screening

Towards responsible genome-wide screening | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Towards responsible genome-wide screening Mirjam Plantinga, M. Corrette Ploem, Sara Soriano Longaron, Jacobien NIebuur, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8743522/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 May, 2026 Read the published version in European Journal of Human Genetics → Version 1 posted 9 You are reading this latest preprint version Abstract Genome-wide screening can be offered at various stages of life and serve multiple purposes, including early detection of treatable conditions, achieving health benefits, or enhancing reproductive choice. Although genome-wide screening offers many advantages and possibilities, deciding which genomic data to analyse, how to interpret results, and how to communicate findings raises significant challenges. In this study, we combine a normative analysis of genome-wide screening in three different settings (population screening, opportunistic screening, and direct-to-consumer genetic testing) with an exploration of stakeholder views. In doing so, we used proportionality as the central normative criterion, and we investigated four key issues in screening: 1) dealing with unsolicited, secondary and uncertain findings, 2) information and consent, 3) privacy, storage, and (re)use of data, and 4) non-participation in screening. Our findings show broad consensus on the need for a cautious approach towards genome-wide screening. The proportionality criterion requires that benefits outweigh harm on both individual and societal level. Although genome-wide testing offers a range of possible expansions of screening, evidence showing that an expansion is proportional is lacking in most cases. The expansion of direct-to-consumer genetic testing raised the most concerns and questions in terms of proportionality. In all screening settings, the position of and advocacy for newborns and children deserve special attention. Given the already scarce resources and personnel in healthcare, responsible implementation of genome-wide screening must be grounded in well-defined normative frameworks, supported by pilot studies that critically evaluate harms and benefits on both individual and societal level. Health sciences/Medical research/Genetics research Scientific community and society/Social sciences/Ethics Health sciences/Health care/Health policy DNA genomics next-generation sequencing newborn screening direct to consumer testing opportunistic screening Q methodology implementation 1. Introduction With the development of next-generation sequencing (NGS) techniques, it has become possible to sequence an individual’s whole exome or genome. Due to decreasing costs of NGS, a true paradigm shift took place from traditional Sanger sequencing‒based genotyping techniques to the use of NGS. While NGS is now widely used in the context of diagnostics, it also offers opportunities for screening [ 1 ]. Although NGS is becoming the standard sequencing technique in diagnostics, usually not all NGS data are subsequently analysed and interpreted. Data analysis is usually restricted to disease gene panels and genome-wide analysis is only performed in specific cases. It remains challenging to decide which part of the sequenced DNA should be analysed, in which context, and when and how test results should be communicated to individuals. This is even more true in the context of screening, where people who have no indication for medical examination are being tested. With ‘screening’ we refer to an offer of medical testing to individuals who are not (yet) experiencing health problems, with the aim to detect a disorder, a genetic predisposition to a disorder, or risk factors that increase the likelihood of (developing) a disorder or having a child with a genetic disorder. Screening can be performed at different life stages, e.g. before pregnancy (preconception), during pregnancy (prenatal), shortly after birth (neonatal), or later in life. It can also have different aims, such as the early detection of treatable or preventable conditions, realising health benefits, or enabling reproductive choices [ 2 ]. The use of NGS in screening is increasing. Several pilot studies, for example in the field newborn screening (NBS), are currently being conducted [ 3 ] in which genome-wide testing and analysis is performed. Several European countries are also using NGS as a first-tier test in their offer of non-invasive prenatal testing to all pregnant women [ 4 ]. In our study, when using the term genome-wide screening we refer to both testing and analysis. Central to the introduction of genome-wide screening is the question how to achieve a “good balance” between maximising the benefits of genome-wide testing and analysis while minimising the risks and burdens for individuals as well as society. In this article, we elaborate on the main results of our study [ 5 ] aiming to identify, in light of the proportionality criterion, the main normative concerns that arise with the introduction of genome-wide screening. In doing so, we paid particular attention to four aspects of screening: 1) dealing with unsolicited, secondary and uncertain findings, 2) information and consent, 3) privacy, storage, and (re)use of data, and 4) non-participation in screening. With these aspects in mind, we examined three screening settings: population screening, opportunistic genetic screening (OGS), and screening based on direct-to-consumer genetic testing (DTC-GT). We also explored the positions and opinions of Dutch stakeholders, using Q methodology, together resulting in considerations for responsible introduction of genome-wide screening. 2. Key topics in screening 2.1 Dealing with unsolicited, secondary, and uncertain findings Genome-wide screening may be associated with unsolicited, secondary, and uncertain findings. Unsolicited (also called incidental or unexpected) findings are potentially pathogenic variants that are unrelated to the original reason for testing that are found accidentally during genetic analysis [ 6 ]. The broader the test, the more unsolicited findings can be expected. In opportunistic screening, which aims to take advantage of the possibility to perform a broader genome analysis than strictly necessary for clinical care or research, i.e. actively searching for additional findings, the term ‘unsolicited findings’ is no longer accurate. In that specific context, these are ‘secondary findings’—potentially disease-causing variants that are looked for intentionally . These additional findings pose a challenge for the provision of responsible genetic screening tests, not only because they raise questions about the proportionality of screening (see section 4 ), but also because they complicate the provision of adequate information and counselling to screening participants and well-balanced decision-making. Genome-wide screening can also identify variants of uncertain significance for which there is insufficient information to classify them as pathogenic or benign. In a clinical setting, phenotypic data can help to better classify variants. In the context of screening, however, phenotypic data is often unavailable, as the screening is offered to individuals who do not have health problems. The lack of phenotypic data therefore makes interpretation and classification of variants more difficult and increases the risk of false (positive) results and overdiagnosis, which negatively affects the quality of screening. 2.2 Information and consent Respect for autonomy is an important principle for any medical procedure, including genome-wide screening [ 7 ]. To enable autonomous decision-making and informed consent, potential participants must be provided with understandable information about the benefits and risks of screening. With the implementation of genome-wide screening, it becomes more difficult to meet the requirement of ‘informed consent’, as a broader analysis of genetic data requires information to be provided on a wider range of possible outcomes, including the possibility of obtaining unsolicited or secondary test results [ 8 ]. It is therefore challenging to balance the need for a proper understanding of risks and benefits against the risk of information overload [ 9 ]. 2.3 Privacy, storage, and (re-)use of data Genome-wide screening involves the collection and processing of enormous amounts of genetic data. This can put fundamental legal and medical-ethical values under pressure, such as the duty of healthcare professionals to maintain medical confidentiality and guarantee privacy. Due to the particularly sensitive nature of genetic data - which is predictive in nature and can have consequences for family members - and because of the scientific importance of being able to share such data, establishing well-balanced privacy rules for this is a delicate matter. Internationally, there is currently an on-going debate about whether special rules are needed for the processing and handling of genetic data within the framework of the European Health Data Space [ 10 , 11 ], and the outcome of this debate will also have important consequences for responsible implementation of genome-wide screening [ 12 ]. An important privacy issue is what screening participants, or their parents when the target group consists of children, have to say about the reuse of the genetic data. Given the highly sensitive nature of these data, it can be argued that genetic data should only be used for secondary purposes if the data subject or their representative has given consent, with minimal scope for exceptions. On the other hand, there is also discussion about data-ownership in the first place, especially in the context of genetics, and moving beyond discussions of ownership to regulations regarding protection of personal health data [ 13 – 15 ]. 2.4 Non-participation in screening Responsible implementation of genome-wide screening also touches on the issue of non-participation, which may be a conscious and well-considered choice on the part of the individual (who may prefer to not know about their genetic predispositions) but also a consequence of other factors influencing participation in screening, such as information barriers, out-of-pockets costs [ 16 ] and low health literacy [ 17 ]. The group of non-participants may also include individuals with a known familial risk who are unaware of their high a priori risk and of the option of cascade testing [ 13 ]. When considering the implementation of genome-wide screening, attention must therefore also be paid to possible reasons and barriers for non-participation. 3. Normative concerns in genome-wide screening 3.1 Proportionality as a central normative criterion The World Health Organisation’s ‘Wilson & Jungner criteria’ [ 2 , 18 ] have long formed the foundation of the normative context for a responsible offer of screening. Over time, these criteria have been amended and updated by, amongst others, the Dutch Health Council [ 19 , 20 ]. The normative core of these criteria is the criterion of proportionality . Screening must be proportional both in the strict sense (the benefits of screening for participants must outweigh the disadvantages they may experience) and in a societal sense (the general benefits to society must outweigh the disadvantages). This latter interpretation also includes the principle of distributive justice, which requires the just distribution of scarce resources for healthcare. 3.2 Population screening Population screening entails the offer of screening to a specific subset of the general population, for example newborns and pregnant women. Several countries are currently exploring the use of genome-wide screening in the context of NBS, aiming to expand the range of conditions included in most NBS programmes from tens to potentially hundreds [ 4 , 21 ]. The major advantage of this expansion would be the timely identification of treatable disorders in a larger number of newborns, thereby better meeting the aim of NBS to serve both the best (medical) interests of these children and public health [ 22 ]. Possible disadvantages, however, include genotype−phenotype correlations that may be unclear [ 23 , 24 ]. This broadening of NBS within its current aim (early detection of treatable disorders) may be proportionate in a strict sense. However, it raises questions in terms of proportionality in a societal sense given the scarcity in personnel and healthcare resources and the substantial needs for labour-intensive, expensive post-test counselling and follow-up that may accompany screening for a higher number of conditions [ 23 , 24 ]. Empirical data are thus needed to get a better understanding of the proportionality of genome-wide NBS. Genome-wide screening may also be used to widen the aim of NBS, for example to include untreatable early-onset conditions with the aim to prevent a long diagnostic odyssey or to allow for reproductive options in subsequent pregnancies. While support is growing for screening for such untreatable but nevertheless ‘actionable’ conditions [ 25 ], it also raises concerns. These include concerns about possible information overload, parental overprotection of children at health risk, potential violation of children’s autonomy rights, negative psychosocial consequences, and the potential negative impact on the high uptake of NBS [ 26 , 27 ]. In 2020, the Dutch Health Council concluded, that although no principal arguments against screening for untreatable conditions exist, to be cautious with expanding the current screening offer to also include untreatable conditions. They questioned whether the potential benefits would be proportional to the burden on parents, professionals and society [ 28 ]. Another possible extension of the current NBS offer and aim that is being investigated, is the offer of a pharmacogenetic passport to newborns [ 29 ]. This provides a DNA-based personalised description of expected drug response and can help in prescribing medicine. Again, the question is what the medical relevance and proportionality of offering such a passport to newborns is or whether it could also be generated when medicine is prescribed for the first time. Each expansion made possible by genome-wide screening will thus require evaluation and assessment in terms of proportionality. 3.3 Opportunistic genetic screening The paradigm example of OGS is the recommendation from the American College of Medical Genetics and Genomics (ACMG) to routinely look for specific genetic conditions in patients for whom an NGS test is conducted for clinical purposes. The ACMG list currently encompasses more than 80 genes associated with predispositions for (mostly) inherited forms of cancer and inherited cardiovascular conditions, and this offer is considered part of physicians’ fiduciary duty [ 30 ]. The OGS argued for by the ACMG has received much critique, including from the European Society of Human Genetics (ESHG). In particular, the presumed high penetrance of some of the listed predispositions in the general population, and their presumed actionability, have been criticised. Both weaken the proportionality of this OGS offer. Furthermore, it has been argued that respect for autonomy requires proper informed consent, rather than the opt-out approach recommended by the ACMG, and that OGS may conflict with the principle of equal access, since individuals not undergoing diagnostic sequencing will not be offered this screening even though they have the same a priori risk as those who do [ 31 ]. Last but not least, the ACMG’s recommendation to also offer OGS to children is at odds with widely accepted guidelines regarding presymptomatic testing for late-onset inherited diseases in children [ 32 , 33 ]. Other forms of OGS than the ACMG offer might, under specific circumstances, also be possible and could justify a different evaluation depending on the content (the list of conditions/genes/gene variants targeted) and the setting in which it is offered [ 34 ]. For example, if OGS would focus solely on screening pathogenic gene variants for actionable conditions with proven high penetrance in the general population, this could positively impact its proportionality in the strict sense. Another example that could meet the proportionality criterion in practice is pharmacogenetic screening, although questions remain about its cost-effectiveness and equal access, which raises concerns regarding proportionality in a societal sense [ 35 ]. There is also discussion about offering OGS (for example for genes from the ACMG list) in the context of prenatal diagnostic sequencing. This form of OGS is being questioned since it would burden pregnant couples with additional, highly complex decisions that are not linked to the already difficult and complex (decision-making) situation that led to the initiation of diagnostic genetic testing [ 36 ]. 3.4 Direct-to-consumer genetic testing Multiple concerns are raised with the introduction of genome-wide tests in the context of DTC-GT. First, although DTC-GT may have advantages at individual level, it raises concerns in terms of respect for people’s autonomy, especially that of children whose right to an open future is compromised if their parents submit their DNA for testing for later-onset disorders that does not serve the child’s imminent medical interests [ 37 ]. Concerns have also been expressed about the provision of information and pre-test counselling by DTC-GT providers, which has sometimes been found to be inadequate or even misleading. Another concern is that the companies offering these tests are not always transparent about the further processing (storage, sharing, and (re)use of data), thereby undermining informed consent and screenees' right to privacy [ 38 ]. When ordering a test, participants often, mostly unconsciously, consent to sharing and selling their data to third parties, such as other companies, located in different countries. Lastly, although DTC-GT takes place outside the regulated healthcare domain, a DTC-GT screening offer may still impact healthcare since screening participants may turn to the regulated healthcare sector due to concerns, anxiety, or questions raised by their DTC-GT results, further increasing the current pressure on the healthcare system [ 39 ]. DTC-GT screening could therefore conflict with societal interests making the proportionality of DTC-GT in a societal sense also a point of attention. 4. Stakeholder views 4.1 Study design and participants We explored stakeholders’ views towards genome-wide screening and the requirements they bring forward for responsible implementation using Q methodology, an approach that uses a mix of qualitative and quantitative data to identify different individual perspectives towards a certain topic [ 40 ]. Two Dutch stakeholder groups were included: professionals and potential users of screening. Statements describing different requirements for responsible implementation of genome-wide screening were developed through a literature review and two online focus group discussions (one with professionals and one with potential users) using the FocusGroupIt platform [ 41 ]. Based on the findings from the literature and focus groups, the research team formulated 35 requirements for responsible implementation (see Supplementary Table S1 ). Participants were asked to sort these requirements in terms of importance through the Q-method platform. In the sorting process, each participant had to place all requirements in a bell-shaped grid with anchors from least important to most important (see Supplementary Figure S1 ). Participants were recruited by snowball sampling through the network of the project team. In total, 40 stakeholders (25 professionals and 15 potential users) participated in the online sorting exercise. Participant characteristics are provided in the Supplementary Table S2. 4.2 Results 4.2.1. Requirements for responsible implementation The sorting of the requirements for responsible implementation showed that, overall, participants (both professionals and potential users) considered the fact that potential users can make informed decisions very important. This is shown by requirement 5 ( possible consequences are sufficiently explained to screening participants ) being attributed most importance, followed by requirement 1 ( making sure the screening participant is well informed about the screening ) and requirement 6 ( possible consequences are sufficiently understood by screening participants ). The requirements considered least important by both stakeholder groups were 25 ( the collected data are destroyed after analysis ), 31 ( participants have indicated in advance that they will inform their family members when they receive feedback on results that may be relevant to them ), and 18 ( the government determines which genetic results may or may not be reported back to participants ) (see Supplementary Table S1 ). 4.2.2. Different perspectives towards responsible implementation Analysis of the Q-sort grids (see Supplementary Figure S1 ) showed that three different perspectives could be distinguished among the participants regarding the requirements they bring forward as most important for responsible implementation of genome-wide testing in the context of screening (see Supplementary Table S3). The attribution of participants to the three perspectives is provided in the Supplementary Table S4. Perspective 1: Regulated implementation One group of stakeholders, consisting almost exclusively of professionals, attributed a leading role to regulation in enabling participants to make informed decisions about screening as well as in securing a good quality of screening (see Supplementary Table S3). This group displayed a strong focus on information provision as well as formalised and explicit regulations to ensure a responsible screening offer. Perspective 1 can thus be interpreted as a perspective that advocates for regulated implementation of genome-wide testing in screening to protect the provision of information and quality of screening. Perspective 2: Autonomous decision-making by screening participants A second group of stakeholders consisting of an equal number of professionals and potential users positioned the potential users of screening at the centre of the requirements for responsible implementation. They considered requirements relating to securing informed decision-making and control over private data most important and granted least importance to requirements constraining participants’ access to data (see Supplementary Table S3). These rankings underscore the importance stakeholders in this group attribute to autonomous decision-making by screening participants and to providing them with the information that enables them to do so. Perspective 3: Cautious information provision and minimising incidental findings Similarly to Perspective 1, this perspective gives high importance to enabling informed decision-making and securing high-quality screening. However, representatives of Perspective 3, consisting mostly of professionals, placed no emphasis on formalised and explicit regulations to meet these goals. They prioritised the importance of explaining and understanding possible consequences of genome-wide testing, minimizing the chance of detecting incidental findings, protecting children's right not to know, and ensuring that genome-wide testing does not come at the expense of proven (cost-)effective traditional methods of screening analysis. As such, Perspective 3 combines elements of Perspectives 1 and 2 and can be interpreted as a perspective that argues for cautiousness in information provision and minimising incidental findings. 5. Discussion and Conclusion With the introduction of next-generation sequencing techniques, it has become possible to read and interpret a large portion of an individual’s DNA with a single test. This offers possibilities for genome-wide screening, which can offer advantages, such as expanding reproductive choice (before and during pregnancy), enabling early detection of (un)treatable conditions and thereby achieving health benefits, reducing the diagnostic odyssey, or improving the prescription of medicines (pharmacogenetics). Genome-wide screening, however, also presents challenges, such as realising informed decision-making and handling an increasing number of unsolicited findings. We argue, in line with others [ 42 ], that an offer of genome-wide screening requires justification and consideration of already existing and applied screening criteria, including the consideration of the overarching criterion of proportionality. Proportionality in the strict sense requires that the benefits and advantages outweigh the risks and disadvantages for individual screening participants and includes a reflection on issues such as informed decision-making, consent, and unsolicited findings. Proportionality in the broad sense requires a reflection on issues such as securing privacy, responsible storage and (re-)use of data, and the impact of non-participation in screening. Moreover, it requires a positive balance of the impact of screening on society, such as the impact on the availability and provision of good-quality healthcare, including considering the costs (as well as possible cost-savings) of screening and the financial and personnel scarcity in current healthcare systems. Responsible implementation of genome-wide screening thus requires a normative evaluation and critical reflection balancing the possible pros and cons—for both individuals and society at large—of expanding the current screening offer. Wider genome analysis within NBS’s traditional aim of ‘early detection and timely treatment’ could, for example, better serve its public health aim than NBS for early-onset un treatable conditions only. However, evidence showing the proportionality of possible expansions is needed. Moreover, expansion of screening may also complicate counselling, generate information overload, and increase medicalisation, possibly undermining rather than serving the aim of the screening. In addition, in the OGS and DTC-GT context, a critical assessment is required of whether the benefits of early detection of hereditary disorders outweigh possible disadvantages, including taking into consideration the criterium of proportionality in a broad sense and the existing pressure on healthcare and healthcare providers [ 43 ]. Our stakeholder analysis, investigating how a broad group of screening professionals and potential users of screening view genome-wide screening and what requirements for responsible implementation they prioritise, showed that there is much overlap between the pros and cons brought forward in the literature and those mentioned by stakeholders. Although stakeholders displayed different views towards genome-wide screening, with some more open to expansion of screening than others and some emphasising the importance of regulation while others argued in favour of decisional autonomy, the majority were in favour of a cautious approach towards expansion of current screening. Our study also shows that concerns and requirements for responsible implementation differ for different screening contexts, where responsible implementation of genome-wide screening is expected to be best ensured within the setting of population screening and least ensured within the setting of DTC-GT. Responsible implementation of genome-wide screening requires, amongst others, appropriate information and consent procedures and fair policies on privacy, storage, and (re)use of data. The availability and quality of these provisions raise more concern in the DTC-GT context compared to the OGS and population screening context. Moreover, compliance with these requirements, especially the proportionality criterion and the rules of privacy and informed consent, is more difficult to monitor in the DTC-GT context, especially when the screening is offered by a foreign DTC company or when the genomic test is conducted in another country, since national regulation and oversight do not apply in these situations. Although European regulation sets rules for the quality and safety of medical products offered within Europe, there is no separate European regulation for medical screening. Some limitations of this study should be acknowledged. First, the study was limited to three specific screening settings and four key topics in screening (dealing with unsolicited, secondary and uncertain findings; information and consent; privacy, storage, and (re)use of data; and non-participation). Second, only Dutch stakeholders were included, and the recruitment strategy may have resulted in selection bias, as individuals with a particular interest in the topic were more likely to participate and only a small number of participants were involved. This limits the generalisability of the findings of the stakeholder analysis. Nevertheless, two general considerations for responsible implementation of genome-wide screening might be derived from our study. First, that in all screening settings special attention deserves to be given to the position of and advocacy for (future) newborns and children, who have their future still ahead and may want to decide for themselves about what and what not to test for once reached a certain age. This is particularly important because balancing the child’s informational and medical interests, discussing unsolicited, secondary and uncertain findings, obtaining parental consent, and providing child-centred counselling are additional challenges in these settings. There is therefore much to be said for a careful approach to expanding genetic testing in this vulnerable group. Second, at a time when our healthcare system is already struggling with shortages, an evaluation of the proportionality of genome-wide screening in a broad sense is paramount for responsible implementation. This underlines the importance of proper pilot and evaluation studies for keeping sight of not only the possible benefits, but also the possible burdens and risks, of introducing genome-wide screening. Declarations Ethical approval Ethical approval was obtained from the Central Ethics Review Board of the University Medical Hospital of Groningen (Research Register Number: 16042). Competing interests The authors declare no competing interests. Funding This study was funded by the Netherlands Organisation for Health Research and Development (ZonMw, project number: 08540022140002). Author contributions CP: conceptualisation, methodology, writing. GdW: conceptualisation, methodology, writing - review and editing. SSL: methodology, data analysis, writing – review and editing. JN: methodology, data collection, writing – review and editing. IC: methodology, writing – review and editing. EB: methodology, writing – review and editing. LH: methodology, writing – review and editing. TR: methodology, writing – review and editing. MC: methodology, writing – review and editing. DS: data collection, writing – review and editing. HY: methodology, writing – review and editing. SvdH: methodology, writing – review and editing. MP: conceptualisation, methodology, supervision, writing. 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Additional Declarations There is no duality of interest Supplementary Files supplementaryinformation.pdf Supplementary information Cite Share Download PDF Status: Published Journal Publication published 22 May, 2026 Read the published version in European Journal of Human Genetics → Version 1 posted Editorial decision: revise 16 Mar, 2026 Review # 1 received at journal 16 Mar, 2026 Review # 2 received at journal 04 Mar, 2026 Reviewer # 2 agreed at journal 17 Feb, 2026 Reviewer # 1 agreed at journal 16 Feb, 2026 Reviewers invited by journal 16 Feb, 2026 Submission checks completed at journal 03 Feb, 2026 First submitted to journal 30 Jan, 2026 Editor assigned by journal 30 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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