Ethics of early detection of disease risk factors: A scoping review

RESEARCH Open Access © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jansen et al. BMC Medical Ethics (2024) 25:25 https://doi.org/10.1186/s12910-024-01012-4 BMC Medical Ethics *Correspondence: Sammie N. G. Jansen [email protected] 1Centre for Sustainability, Environment and Health, National Institute for Public Health and the Environment, RIVM, P.O. Box 1, Bilthoven 3720 BA, The Netherlands 2Department of Social Sciences, Wageningen University & Research, Hollandseweg 1, Wageningen 6706 KN, The Netherlands 3International Network on Children’s Health, Environment & Safety (INCHES), Ellecom, the Netherlands 4Ethics Institute, Utrecht University, Janskerkhof 13a, Utrecht 3512 BL, The Netherlands Abstract Background Scientific and technological advancements in mapping and understanding the interrelated pathways through which biological and environmental exposures affect disease development create new possibilities for detecting disease risk factors. Early detection of such risk factors may help prevent disease onset or moderate the disease course, thereby decreasing associated disease burden, morbidity, and mortality. However, the ethical implications of screening for disease risk factors are unclear and the current literature provides a fragmented and case-by-case picture. Methods To identify key ethical considerations arising from the early detection of disease risk factors, we performed a systematic scoping review. The Scopus, Embase, and Philosopher’s Index databases were searched for peerreviewed, academic records, which were included if they were written in English or Dutch and concerned the ethics of (1) early detection of (2) disease risk factors for (3) disease caused by environmental factors or gene-environment interactions. All records were reviewed independently by at least two researchers. Results After screening 2034 titles and abstracts, and 112 full papers, 55 articles were included in the thematic synthesis of the results. We identified eight common ethical themes: (1) Reliability and uncertainty in early detection, (2) autonomy, (3) privacy, (4) beneficence and non-maleficence, (5) downstream burdens on others, (6) responsibility, (7) justice, and (8) medicalization and conceptual disruption. We identified several gaps in the literature, including a relative scarcity of research on ethical considerations associated with environmental preventive health interventions, a dearth of practical suggestions on how to address expressed concerns about overestimating health capacities, and a lack of insights into preventing undue attribution of health responsibility to individuals. Conclusions The ethical concerns arising with the early detection of risk factors are often interrelated and complex. Comprehensive ethical analyses are needed that are better embedded in normative frameworks and also assess and weigh the expected benefits of early risk factor detection. Such research is necessary for developing and implementing responsible and fair preventive health policies. Keywords Early detection, Screening, Risk factors, Prevention, Ethics, Scoping review, Environmental health, Public health Ethics of early detection of disease risk factors: A scoping review Sammie N. G.Jansen1,2*, Bart A.Kamphorst2, Bob C.Mulder2, IrenevanKamp1, SandraBoekhold1, Petervan denHazel3 and Marcel F.Verweij4 Page 2 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 Background Early detection of disease risk factors contributes to identifying pathways to prevent disease onset or moderate disease course and thereby decrease associated disease burden, morbidity, and mortality [1, 2]. Making disease predictions based on early risk factors has proven notoriously difficult since most diseases develop through a complex interplay between an individual’s susceptibility or predisposition to a certain disease or disorder and specific environmental exposures over time [3, 4]. New research is pushing the boundaries of understanding the pathways and mechanisms by which various factors interact by utilizing recent advances in computational and biomedical sciences that allow for measuring, modelling, and analyzing increasingly large clusters of environmental factors and linking these to disease outcomes. Initiatives to map the human exposome, i.e. “every exposure to which an individual is subjected from conception to death” [5], aim to uncover new (clusters of) risk factors and corresponding pathways to disease. An example is the Equal-Life project that studies the long-term effects of physical and psychosocial risk factors on children’s mental health and cognitive development [6]. One major practical aim of such initiatives is to enable and strengthen preventive strategies by improving the precision and accuracy of detecting early risk factors and identifying (groups of) people at risk of future disease. The potential benefits of avoiding disease onset and corresponding disease burden may be significant. However, prevention of disease by early detection of risk factors also raises ethical concerns. For example, false positive results can lead to unnecessary medical treatment (e.g. biopsies), and, detection techniques can themselves involve risks, as is the case with, e.g., colonoscopies [7]. Moreover, the mere offering of medical preventive interventions can burden people with worries and uncertainties about their health [8]. And labeling environments such as neighborhoods as ‘high-risk’ can have stigmatizing effects that may, for example, affect school careers [9, 10]. Even for many preventive actions that have an obvious positive impact on public health, such as vaccination, only small benefit is expected for each participating individual as most of the participants would never develop the disease or severe complications in their lifetime [11].1 Early detection of disease risk factors likewise invokes ethical concerns. However, the current literature on this subject provides a fragmented and case-by-case picture, and no systematic efforts have been taken to capture the overarching ethical considerations of early detection of disease risk [12–15]. To improve this situation, the 1 This is also known as the Prevention Paradox: “a measure that brings large benefits to the community offers little to each participating individual.” (Rose, 1981, p. 1850). present paper presents a scoping review conducted with the dual aim of (1) providing an overview of the relevant ethical themes related to the early detection of disease risk factors, and (2) identifying potential gaps in the literature. The scoping review method allows for addressing a broad research question and including literature from different study domains and designs. In addition, the scoping review methodology allows for the broad mapping and thematically synthesizing of information, rather than solely summarizing the results [16], which makes it suitable for our aims. This scoping review results in a summary of the characteristics of the included studies and an overview of common ethical themes as discussed in the literature, followed by a discussion of gaps in the literature. These results aim to guide future initiatives into detecting early risk factors and might thus be useful for ethicists, health practitioners and policymakers working in preventive medicine. Methods A scoping review of the ethics literature was performed according to Arksey & O’Malley’s methodological framework [16], using the update by Levac et al. [17]. This review framework includes five main stages that are described below. Furthermore, the PRISMA-ScR guidelines established by Tricco et al. [18] and the PAGER reporting guidelines by Bradbury-Jones et al. were consulted [19]. Identifying the research question The aim of this study was to analyze the ethics literature on early detection of disease risk factors, and to define prominent ethical themes. Our assumption was that identifying such ethical themes could guide new developments in prevention such as exposome research and policies. Identifying relevant studies Before conducting the systematic searches, Google Scholar was used to gather information for determining the appropriate scope, search terms, and feasibility of the search strategy. Two searches were conducted, in Scopus and Embase. Scopus was chosen for its wide range of literature in a wide range of domains. Embase was chosen for its comprehensive coverage of biomedical literature. These searches were performed on April 5, 2022. A third search in the Philosopher’s Index was performed for the same time period in December 2023. Philosopher’s Index was chosen for its disciplinary focus on philosophy and ethics literature. Keywords related to the domain of early detection (e.g. “Early detection” OR “Preclinical detection” OR “Predict*”) were combined with keywords relating to risk factors (e.g. “Risk factor” Page 3 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 OR “Protective factor” OR “Determinant”) or the domain of exposome (e.g. “Exposom*” OR “Multi-expos*” OR “*omic”) and combined with the general domain of ethics (“ethic*”). For the full search strategy, see the supplementary materials. Study selection Articles were included if they (1)discussed ethics of early detection of disease risks, (2)concerned human health, (3)were peer-reviewed and published in academic journals, (4)were written in English or Dutch. Articles were excluded if they (1)discussed a disease risk that is solely genetic (no environmental component), (2) primarily discussed detection of clinical symptoms or predicting treatment response (rather than discussing risk factors that could lead to the development of disease). Although our focus was on early detection of disease risks, papers discussing detection of presymptomatic disease were also included given that the distinction is not clearcut. First, two reviewers (SJ and IVK) screened all articles for meeting the inclusion and exclusion criteria based on titles and abstracts. All articles were independently (blindly) reviewed; conflicts were resolved by a third reviewer (BK). The remaining articles were screened based on the fulltexts and independently reviewed for meeting the criteria by at least two reviewers (SJ, BK, and BM). Conflicts were resolved by deliberation between the three reviewers. Finally, the reference lists of the included articles were consulted for additional literature. Charting the data For all relevant articles, information was extracted by two authors independently from each other (SJ all articles, BK and BM both half of the articles). The following information relating to the type of article was extracted using a spreadsheet: the aim of the article, the method (empirical or non-empirical), the discussed type of risk factor and measurement method, target population, context (e.g. clinical practice, public health, occupational setting), the disease, and the action perspective of detecting the risk factor (e.g. treatment or other intervention available). For all relevant articles the ethical issues that were discussed substantially were extracted and categorized into either a class of issues related to the individual or familial sphere (e.g. patient informed consent and the duty to share relevant test results with family members), or a class of issues relating to a broader population or societal level (e.g. the issue of medicalization). Ethical issues that were mentioned but not further elaborated or analyzed were noted in a separate column. Collating, summarizing, and reporting the results We present our results in a thematic narrative form [16], supported by an overview of the main themes and subthemes in Table1, and the main themes per article in Table2. For the descriptive analysis, information about the country of the first author, date of publication, the discussed health domain, the broader context of the early detection of risk factors, and the methods were captured. For the thematic analysis, a conventional content analysis approach was used [20]. The descriptive ethical issues extracted from the included articles were inductively coded by SJ. Recurrent coding patterns were identified and grouped into themes and subthemes. In an iterative process, the codes and developing (sub)themes were discussed by the three authors until conceptual stability was reached for the themes. Although the identified (sub) themes presumably have distinct importance and applications for different diseases and in specific situations, the aim was to categorize the most discussed issues and identify the broader ethical themes that arise out of the comparison of these issues. Finally, from the identified themes, literature gaps were identified. Results Descriptive analytics The searches resulted in N = 1201 articles from Scopus, N = 1121 articles from Embase, and N = 118 articles from Philosopher’s Index. Additionally, promising articles identified in the review’s preparational phase were added (N = 37). After removal of duplicates, N = 2034 articles were included for screening based on title and abstract. Abstract and title screening resulted in N = 112 articles that were found eligible for full-text reviewing. Full-text screening resulted in N = 48 articles fulfilling the criteria. Following the searches, we found further relevant articles (N = 7) by consulting the relevant articles’ references lists. A final sample of N = 55 was included in the analysis. See Fig.1. The included articles were published by authors in Europe (N = 31), the United States and Canada (N = 21), and Australia (N = 3). The articles were published between 1990 and 2021, with a peak between 2015 and 2019 (N = 18). A large part of the articles discussed the ethics of early detection of risk factors without focusing on a particular disease (N = 20) and many had a focus on mental health and neurological diseases (N = 25), followed by cancers (N = 8), nutrition (N = 2), and viral infection (N = 1). The articles discussed early detection of risk factors in the context of public health (N = 18), clinical health (N = 10), both public and clinical health (N = 15), occupational (N = 8) and forensic settings (N = 4). The majority of the included articles utilized methods common in applied ethics, including conceptual analysis and critical reflection on and engagement with the empirical literature, instead of conducting empirical research. The articles using empirical methods (N = 5) made use of Page 4 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 focus group discussions [21, 22], interviews [23], ethnographic fieldwork [24], and expert workshops [14]. Analysis of the included articles identified eight common ethical themes: (1) Reliability and uncertainty in early detection, (2) Autonomy, (3) Privacy, (4) Beneficence and Non-maleficence, (5) Downstream burdens on others, (6) Responsibility, (7) Justice, (8) Medicalization and conceptual disruption. For an overview of these themes and the covered subthemes, see Table 1. The themes are in many ways interconnected, but for the sake of clarity will be discussed separately below. See Table2 for the patterning chart of the main themes. Reliability and uncertainty in early detection Reliability and uncertainty of early risk information are frequently discussed as important ethical considerations for detecting early disease risk factors [see Table2, column Reliability and uncertainty]. The efficacy and accuracy of detecting the risk that is investigated are, for example, often discussed. Where diagnostic tests provide binary outcomes (a disease is present or not present), the factors detected with methods to determine and predict disease risk provide probabilistic outcomes from 0 to 100% risk for the disease to develop, where the low and high extremes are very rare for most diseases as many biological and environmental factors affect the risk score [4, 15, 25]. In risk screening tests, reliability and uncertainty are often discussed in terms of validity, i.e. sensitivity and specificity, of the test [26, 27]. Sensitivity refers to the chance that the test returns a positive result in people that are at risk (true positive rate) whereas specificity refers to a negative result in people that are not at risk (true negative rate). Tests with a low validity, therefore, Fig. 1 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) flowchart of article screening phases Page 5 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 return more false-positive and false-negative results. The predictive value of a test also depends on the disease prevalence in the target population. For example, if the prevalence of a risk factor is very low, even a test with high sensitivity and specificity will have a low positive predictive value. Furthermore, the analytical validity of the test does not necessarily mean clinical validity and utility, i.e. how well the test correlates with clinical responses and treatments [21]. Depending on these latter two, the number of at-risk people that need to be correctly detected and treated to prevent one person from developing the disease (“number needed to treat”) varies for different diseases and detection methods [28]. As preventive medicine is turning towards detecting and preventing more complex, multifactorial diseases, authors2 warn that the predictive value and reliability of the detection methods need to be carefully monitored and balanced against other aspects such as the costeffectiveness and actionability of the risk information (see the sections on, respectively, justice and beneficence & non-maleficence). Furthermore, non-genetic risk factors, including epigenetic factors [21, 29, 30], can change over time and interactions with different environmental 2 Throughout the manuscript, the term “authors” always refers to the authors of included articles discussed in that paragraph. factors and conditions can produce different outcomes. This increases the uncertainty associated with risk predictions [4, 25, 27, 31, 32], but also provides opportunities for preventive interventions to decrease risk dispositions and modify the disease course [43]. Early detection of disease risk factors can be affected by, and play into, various biases that decrease the reliability of test results and increase uncertainty in risk predictions. Frequently mentioned is the way in which selection bias in the development and validation phases of detection methods (e.g., due to non-representative study samples) can limit the generalizability of these detection methods [33, 34]. In the other direction, the ability to detect risk factors and abnormalities in increasingly early phases can play into lead-time bias (where earlier detection leads to a mistaken sense of increased survival time), length bias (where the effectiveness of a test is overestimated because it over-identifies slow-developing, less aggressive diseases), and overdiagnosis bias (where many people are identified as high risk for a disease that will never develop during their lifetime [35]). (For overdiagnosis, also see the section on medicalization and conceptual disruption.) To overcome potential biases and improve the predictive value and reliability of early screenings the use of big data approaches is sometimes proposed as a solution. However, authors warn that “it is not always the case that more data will lead to better predictive models” [28, p. 124] as it can also increase the complexity and degree of uncertainty by increasing the variance of the results (and thereby causing loss of precision). Moreover, it does not necessarily solve other issues discussed in this section or the thematic sections below [24, 36, 37]. Autonomy A commonly mentioned set of issues centers around the notion of personal autonomy [see Table2, column Autonomy], which we understand here in the broad sense of being able to “lead one’s life in a way that accords with what one genuinely cares about” [38, p. 5]. In the surveyed papers, autonomy considerations about having the capacities and opportunities to make one’s own choices are mostly discussed in the context of informed consent. There is broad consensus among authors that informed consent should contain information about the expected benefits and possible medical and psychosocial risks [39], about who can use and access the data (e.g. secondary uses by third parties [40]), and about the possibility of incidental findings that may be sensitive as they might unveil environmental and lifestyle exposures [21]. The extensive and complex nature of the information required for truly informed consent, however, requires a level of health literacy that for many individuals may not be attainable [23]. For example, worries are expressed Table 1 Key ethical themes and subthemes for the early detection of disease risk factors Main themes Sub themes Reliability and uncertainty in early detection Validity, sensitivity, and specificity of the detection methods Predictive value and reliability of the detection methods Data biases The complexity of big data Autonomy Informed consent Health competencies Empowerment and responsibility for health Privacy Data protection Confidentiality Beneficence and non-maleficence Harmful psychological effects False-positive and false-negative results Actionability of test results Behavior and lifestyle change Risk communication Downstream burdens on others Changing perceptions of “at-risk individuals” Direct and indirect implications for family and significant others Responsibility Individual responsibilities for health Collective and societal responsibilities for health Justice Stigmatization and discrimination Health inequities Equitable and efficient use of financial resources Medicalization and conceptual disruption Reconceptualization of health and disease Overdiagnosis and overtreatment Page 6 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 Themes in the Ethics of Early Detection of Disease Risk Factors Paper ID Reliability & uncertainty Autonomy Privacy Beneficence & non-maleficence Downstream harms to others Responsibility Justice Medicalization & conceptual disruption Ahlgrim et al. 2019 x x x x x x Almond 2006 x x x x x x x Bolt et al. 2021 x x x x x Bunnik & Bolt 2021 x x x x x x CalzÃet al., 2015 x x x x Chowdhury et al. 2013 x x x x x Christiani et al. 2001 x x x x x Corcoran et al. 2005 x x x x x x DeCamp & Sugarman 2004 x x x x x Dhondt 2010 x x x x x x Frank 1996 x x Frank 2001 x x x x x Gershon & Alliey-Rodriguez 2013 x x x x x x Glenn 2019 x x x x x Green & Hillersdal 2021 x x x x x Green & Vogt 2016 x x x x x x x Hall et al. 2014 x x x x x x x Hall et al. 2004 x x x x Hall et al. 2008 x x x x x Hoge & Appelbaum 2012 x x x x x x x Holzman 1996 x x x x Horstkötter et al., 2021 x x x x Hurlimann et al. 2017 x x x x x Illes et al. 2007 x x x x x x x Jenkins et al. 2008 x x x x Jurjako et al. 2019 x x x x x x Lawrie et al. 2019 x x x x x Lewis 2018 x x x x Meager et al. 2017 x x x x x x McKeown et al. 2021 x x x x x x Paul et al. 2014 x x x x x x Plutynski 2012 x x x x x x Prainsack 2019 x x x x x Press et al. 2000 x x x Quattrocchi et al. 2019 x x x Rawbone 1999 x x x x x Roberts et al. 2013 x x x Salamanca-Buentello et al. 2020 x x x x Schermer & Richard 2019 x x x x Schicktanz et al. 2014 x x x x x x x Singh & Rose 2009 x x x x x x Specker & Schermer 2021 x x x x Specker & Schermer 2017 x x x x x Spriggs et al. 2008 x x x x x x Stol et al. 2016 x x x x x x Table 2 Key ethical themes and patterning chart Page 7 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 that complex health information can overwhelm people and compromise their capacity for autonomous decision making [41], that it is difficult for many people to understand the difference between absolute and relative risk [35], and that people might have unrealistic ideas about the explanatory power of early disease risk factors [42]. Concerns about (lack of) health-related competencies are especially prominent in the surveyed literature. Dilemmas can arise when early detection takes place early in life and consent had to be given by legal proxies (parents or legal guardians). One issue here is that preventive testing in children might deprive them of their ‘right not to know’, in which case it could be preferable to postpone testing until the young person has developed sufficient competency to make their own decision. However, waiting can also deprive the same person of the opportunity to make choices that can affect their disease risk, or compromise their health and potentially the development of necessary competencies by allowing the disease to develop [13, 15, 30, 39, 43–45]. Competencies for informed consent in adults is mostly discussed for individuals atrisk of mental health disorders [39, 46]. Developing mental disease symptoms can increasingly compromise the required competencies such that “a fully competent and autonomous patient at the beginning of a study may progress to a point of diminished capacity and autonomy” [12, p. 7]. Another subtheme related to autonomy that several authors critically discuss is empowerment, in particular the idea that early detection can empower people to take control of their health and to plan their future. It is also discussed that there is a risk that the underlying assumption is that individuals “can (and should) be held morally responsible for their health outcomes” [47, p. 77]. As social and moral norms promoting responsibility for health can put pressure on individuals and groups to conform, several authors worry that the narrative of empowerment might compromise the voluntariness of the decision to take an early detection test [28, 29, 48–51], as well as downstream decisions about lifestyle choices [32]. Privacy Early detection of health-related risks generates sensitive information about a person’s susceptibility to a variety of diseases [see Table2, column Privacy]. Moreover, the information that is collected in the service of such an assessment can potentially contain indicators of a person’s (past) lifestyle and environmental exposures that also warrant protection (e.g. via epigenetic changes) [4, 21, 29]. Therefore, confidentiality of tests and results is considered an important component of protecting sensitive data and preserving individual privacy, but ensuring confidentiality becomes increasingly difficult when a broad range of data is collected and possibly shared or linked to other (public) data sources [4, 21]. Linking datasets increases the risk of identification of individuals in the datasets [4, 14, 21, 22]. Pooling or aggregating data before sharing reduces the risk of identification, but also decreases the richness of the dataset and its (clinical) utility [15]. For the informed consent procedure (also see the section Autonomy), clarity about individual privacy, data confidentiality, and data storing and sharing are frequently mentioned [13, 21, 33, 42, 44, 52, 53]. As individuals might worry about (future) disclosure of their risk information, information about potential risks to privacy and how institutions deal with potential privacy breaches are important for valid informed consent. A lack of confidentiality, or a lack of trust in confidentiality, might lead to people not participating in early detection efforts that can benefit them [54, 55]. Legislation to protect sensitive personal information can provide reassurance [33]. Themes in the Ethics of Early Detection of Disease Risk Factors Paper ID Reliability & uncertainty Autonomy Privacy Beneficence & non-maleficence Downstream harms to others Responsibility Justice Medicalization & conceptual disruption Stol et al. 2017 x x x x x x Stol et al. 2018 x x x x x x Svensson & Sandlund 1990 x x x x Tabery 2009 x x x x Thomas 2015 x x x x Tromp et al., 2021 x x Van Damme et al. 1995 x x x x x x Vineis 1997 x x x x x Vineis & Schulte 1995 x x x x x Vogt et al. 2019 x x x x Table 2 (continued) Page 8 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 Some authors hold that confidentiality might be rightfully breached in certain cases, such as when parents are acting as a proxy for their child [15] or when the risk information is relevant to others as well, such as (future) caretakers and family members who potentially carry the same risk factors. However, hesitance was observed in the literature with respect to assigning a moral duty to physicians or at-risk individuals to share a risk status with relevant others as this would harm their right to autonomy [44, 45, 52]. Broad consensus was observed about the importance of protecting privacy and confidentiality against third parties such as insurers and employers. Worries exist that third parties can misuse risk information to discriminate or stigmatize individuals who have been labeled as being high risk of disease [13, 27, 30, 35, 43, 48, 56, 57]. (See also the section on Justice.) Beneficence and non-maleficence In healthcare, the principles of beneficence (“do as much good as possible”) and non-maleficence (“do no harm beyond what is proportionate”) are important moral guiding principles [58] for striking a positive balance between an intervention’s benefits and inflicted harms for the individual. While the principles themselves are mentioned relatively infrequently in the surveyed literature (but see [27, 35, 40]), they are implicitly present in the background of many discussions about the potential benefits and harms of the early detection of disease risks [see Table 2, column Beneficence & non-maleficence]. For example, multiple authors argue that the ‘latent period’ between detecting a risk and potential disease occurrence can also be a period of uncertainty and anxiety. They question whether early knowledge about being at heightened risk is more beneficial to an individual than spending the interim time in ‘normalcy’, especially when no preventive actions are currently available [13, 32, 39]. Most discussed are the ways in which a high-risk classification may lead to worries and anxieties for developing disease [2, 13, 22, 23, 28, 32, 44–48, 59] and can have negative effects on self-image [22, 31, 32, 45, 46]. Authors note that the effects on self-image might lead to depression [33] and even suicide [12, 46], although these effects are generally considered rare [49]. Another possible harmful psychological effect might be that positive test results lead to a perceived lack of control and decreased motivation for a future that “threatens to be taken away by illness”, possibly influencing important life decisions such as family planning [39, p. 6]. Knowing one is at greater risk for disease can also cause feelings of being fragile or ‘defected’ [4, 39, 54]. Such knowledge can also contribute to a self-fulfilling prophecy [12, 15, 31, 60] when the (anticipated) risk status leads to stress and anxieties that subsequently affects cognitive functioning [12], which in turn promotes risk-increasing behaviors [15]. Harmful impacts of early detection of disease risk factors are especially problematic and unjustified when results are incorrect. Authors warn that false-positive results can lead to unnecessary labeling and interventions [15, 27, 28, 39, 41, 44, 60]. Likewise, false-negative results can deprive patients from beneficial early interventions and provoke unjustified feelings of security [27, 28, 47, 60], possibly leading to the neglect of early symptoms (“They said everything was okey”) [2, p. 278]. (Also see the section Reliability and uncertainty). Advances in research methods, however, promise to increase the precision of screening tests and thereby decrease mis-categorizations [61]. In short, it is not always beneficial for individuals to participate in early detection programs and undergo (sometimes unnecessary) follow-up examinations and interventions [35]. Though transparency and truth telling by disclosing test results and possible incidental findings are valued as providing respect for autonomy, consensus within the medical community is at present against disclosure of risk information with uncertain predictive value, justified by the principle of non-maleficence [39, 49]. Many authors acknowledge that if early knowledge is to be beneficial to individuals, the screening results should be ‘actionable,’ in the sense that they present (viable) options open to individuals to change their situation and health prospects. The existence of an “effective intervention to prevent the disorder in those who are identified as being at risk” is even identified by some as a prerequisite for the ethical acceptability of early screening tests [57, p. 352], especially when it concerns children who cannot yet decide for themselves [45]. Apart from early interventions to fully prevent disease occurrence several other preventive actions are mentioned that can be considered important for beneficence, including providing reassurance when a test is negative [14, 15, 46, 49], offering support in planning one’s life for a future disease [45, 46], supporting reproductive decisions [32, 41, 43, 62, 63], and giving advice on modifying health behaviors and lifestyle [15, 32, 41, 47, 51, 64]. Promoting healthy lifestyles and health-positive behaviors are mentioned in particular as important interventions to mitigate disease risk and support beneficence [12, 29, 32, 51, 59]. The assumption that individuals can and will successfully implement the provided lifestyle and health behavior advice is, however, questioned and criticized by several authors. Social science studies indicate that changing health behaviors is difficult [28] and the lack of direct experience of symptoms, uncertainty about whether symptoms will materialize, and Page 9 of 16Jansen et al. BMC Medical Ethics (2024) 25:25 uncertainty about the effectiveness of changing lifestyle are mentioned as possible demotivating factors [2]. The harmful psychological effects discussed above can also be barriers to effective behavior change [2, 4]. Even when risk information effectively motivates some individuals to change health behaviors, it should not be assumed to motivate a particular individual [43]. Other barriers to adopting healthy lifestyles that are mentioned are low health literacy, low socio-economic status, and restricted access to healthcare. The implications of these inequalities between individuals and social groups are discussed in the theme on Justice. To achieve the proposed benefits and minimize the harms, adequate communication about risks is discussed as crucial. Participants of preventive interventions should be informed about, among other things, the expected benefits and harms and the actionability of the risk information (also see the section on informed consent within the theme Autonomy). It may be difficult, however, for both professionals and laypersons to adequately grasp the difference between susceptibility and disease, and to understand probabilistic and relative risk data [35, 39, 43, 50, 59]. Some authors recommend avoiding complex medical terminology and contextualizing the provided information in relation to the patient’s situation [12, 53]. Misinterpretation of test results and unsubstantiated expectations for the explanatory power and actionability of the information (therapeutic misconception) are widely discussed as harmful implications of inadequate communication of risk information [12, 42, 46, 47, 49, 59, 63]. An example by Schermer & Richard [53, p. 143] is that “the emotional and social effects of terms chosen to communicate with lay-people can be considerable; being told one is ‘at risk’ for developing AD [Alzheimer’s disease] is different from being told one has preclinical or asymptomatic AD – although the situations these terms aim to describe may be exactly the same”. Educating patients using simple support aids [45], offering counseling [39, 43], and training healthcare professionals in patient communication are discussed as benefitting risk communication [44, 49]. Downstream burdens on others Besides the harms and benefits of early risk factor detection for the individuals who consent to screening procedures, authors frequently mention the downstream effects that screening participation may have for, and in relation to, friends and family [see Table2, column Downstream burdens on others]. Though these downstream effects to a certain extent relate to the bioethical principles of beneficence and non-maleficence as well (e.g., consider the social harms that may befall individuals through stigmatization; see also Justice), we discuss them separately because they also relate to broader ethical questions about how to strike a balance between diverging interests of multiple individuals. In this context, authors mention that family and others around “at-risk individuals” might think of them “as in some sense already impaired” [43, p. 69] and treat them differently [42, 61, 63]. For example, children might be treated differently at school [39]. This does not need to be harmful per se, but authors warn that it can have adverse impacts on relationships [15], cause conflicts with the family [13, 45, 52], and contribute to possible self-fulfilling prophecies [15, 43, 53] (see also section Beneficence and Non-Maleficence). To prevent conflicts or misunderstandings within families and relationships, providing adequate risk information and an explanation of what a disease risk means for the screened individual and relevant others is important. Multiple authors propose that family counseling should be offered when conflict is probable [39, 47, 52]. Risk information can also have direct consequences for relatives when the risk is inheritable or when parents need to take decisions on behalf of their child, for example. Interests of family or significant others can create tensions between the individual’s right to keep risk information confidential and opportunities to reduce risk for others (the principle of non-maleficence). This raises questions about the duties of the patient and his or her physician towards other persons at risk [40, 45, 52]. Responsibility Responsibilities for health outcomes and the development and prevention of illness are discussed in the majority of the included articles [see Table2, column Responsibility]. As was touched upon in the themes of Autonomy and Beneficence and Non-maleficence, empowerment of people to use risk information to make health decisions and manage their well-being is an important driver for the early detection of disease risk factors. Although some authors mention the possibility that detection of risk factors, especially biological factors, might lead to ascribing decreased responsibility to individuals for ill health [4, 31], most authors discuss that individual responsibilities for health and well-being are increasing due to a focus on personalized disease risks, leading to individuals also increasingly being held accountable for their illhealth [22, 24, 28, 29, 32, 47, 50, 51, 55, 59, 62]. However, emphasizing individual responsibility for health and well-being might overburden individuals and suggest they are to blame for outcomes that are not always within their control. Such lack of control can be caused by the amount and complexity of health-related information [41] or the lack of means and resources to be proactive about health [37, 42, p. 204]. Authors warn that if such responsibility shifts towards the individual occur, individuals or parents who are not Page 16 of 16Jansen et al. 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