Background: Though genomic science has rapidly advanced, efforts to demonstrate the population-level utility of genomics have been slow to follow. It has long been argued that the family is an important unit of significance in genomics, yet it has been challenging to address this in clinical care. This is apparent in how hospital administrators and clinicians in the United States typically approach cascade screening, the process of notifying and offering genetic testing to at-risk relatives of a patient with a hereditary condition. The most common notification approach is proband-led contact, in which the index patient is responsible for communicating a health risk to their relatives. This model has been associated with suboptimal outcomes. In contrast, recent research has shown that system-led contact, in which healthcare or public health institutions initiate communication to relatives with the proband’s consent, has been associated with increased clinical utility and acceptability. Summary: With the needs of hospital administrators and clinicians in mind, we revisit normative questions about the appropriate way to notify relatives about their potentially elevated risk of developing an actionable disease. We review evidence demonstrating that system-led direct contact of relatives is feasible and acceptable. We further argue that system-led contact of relatives eligible for cascade screening is ethically justified if these programs are designed with public input, have an opt-out provision, and are implemented for conditions that meet specific criteria which we propose in this article. Key Messages: In this article, we emphasize the usefulness of public health ethics frameworks to inform the design of system-led contact programs. Beyond this, we make the case that such programs are necessary to realize the population utility of genomic medicine equitably.

A rapid increase in the availability of clinical genetic testing over the last two decades has begun revealing the promise of genomic medicine. The potential to precisely tailor an individual’s healthcare while simultaneously improving population health has provided new opportunities to implement preventive medicine and decrease health disparities [1, 2]. However, efforts to measure and demonstrate the population-level utility of genomics have been slow to follow advancements in genomic science [3]. While large-scale translational efforts are now attempting to evaluate and develop metrics for genomic utility [4‒6], most programs treat either the individual or the population as the unit of significance. This focus on the individual makes it difficult to measure the familial benefits of genomic testing.

It has long been argued that the family is important in matters related to genomics [7, 8]. Genomic medicine and families are inextricably linked. Whether it be risk prediction, diagnostic testing, or healthcare management, disentangling individual patients’ interests from those of their family members is not easy or necessarily desirable [9]. Practically and legally speaking, however, it has been challenging to operationalize healthcare at the level of the family. Clinicians report experiencing ethical tensions when confronting the distinct needs of individual patients compared to relatives, and there is a lack of tools to guide preventive care in relatives [10, 11]. This is most apparent in how clinics typically approach cascade screening, the process of notifying and offering genetic testing to at-risk relatives of a proband (index patient) with a well-characterized and actionable hereditary condition [12].

Cascade screening is an effective method of identifying individuals who may be unknowingly affected with disease (or at risk of developing it). It can result in an earlier diagnosis, inform medical interventions, facilitate appropriate screening, and ultimately extend life expectancy for at-risk relatives [13]. The most common notification approach in the United States (U.S.) is proband-led contact, which has been associated with suboptimal outcomes. In proband-led contact, the index patient in whom a genetic diagnosis is initially found is held responsible for notifying relatives about their potentially elevated risk of a hereditary condition. Recent research challenges this approach by modeling clinical utility at the level of the family [14, 15] and investigating practical, logistical, and legal pathways for healthy systems to directly contact relatives eligible for cascade screening. This emerging evidence invites us to revisit normative questions about the appropriateness of involving health systems and public health organizations in notifying family members about their potentially elevated risk of actionable diseases, including how to solicit relatives’ preferences for learning (or not learning) about their potentially increased risk.

With the needs of hospital administrators and clinicians’ mind, we highlight recent evidence obtained via non-systematic narrative literature review that demonstrates the feasibility and acceptability of system-led direct contact (“system-led contact” hereafter) to patients, their relatives, and providers. We further argue that system-led contact of relatives eligible for cascade screening is ethically justified if these programs are designed with public input, have an opt-out provision, and are implemented for conditions that meet specific criteria which we describe in this article. We also emphasize the usefulness of public health ethics frameworks to inform the design of system-led contact programs. Beyond this, we make the case that such programs are necessary to realize the full utility of genomic medicine in an equitable fashion.

There are two notification approaches to communicating with at-risk relatives in the process of cascade screening. In proband-led contact, probands (index patients) are responsible for communicating the health risk to relatives. Healthcare providers may supply resources to the proband to aid in this communication, sometimes referred to as “indirect contact” [16]. Multiple studies have shown that proband-led contact leads to relatively low uptake in genetic testing by relatives [17]. While we recognize that test uptake is not always a goal of risk communication to relatives (since some relatives may opt out of testing for personal reasons), it is an indication that risk communication has occurred and therefore a proxy measure of cascade screening success. Even with the assistance of educational or communication resources, proband-led cascade screening methods have been largely ineffective [18]. Estimates of test uptake range from 40 to 60% for hereditary cancer susceptibility and as low as 4–12% in the U.S., where proband-led contact is the norm [19‒26]. Low testing uptake may be further exacerbated among underrepresented minority populations, where inequalities in access to genetic testing have been well characterized [27‒31].

In contrast, system-led contact (or “direct contact”) of relatives has demonstrated effectiveness in increasing cascade screening uptake and subsequent preventative healthcare measures for relatives [12, 16, 32]. With the permission of the proband, this method allows for healthcare and other public health professionals to contact relatives directly to notify them of their risk and offer them the choice to undergo further risk assessment. Multiple system-led contact models have been proposed, which may be orchestrated by healthcare institutions, patient advocacy groups, and public health organizations that work independently or cooperatively to reach cascade screening goals [33‒35].

One system-led, centralized approach to cascade screening for familial hypercholesterolemia (FH) in Australia led to an increase in disease identification of 2–3 more relatives per proband compared to proband-led approaches [33, 34]. In a meta-analysis of cascade screening programs for hereditary cancer syndromes, system-led contact resulted in significantly higher uptake of genetic counseling for relatives compared to proband-led approaches (63% vs. 35%), as well as genetic testing for first-degree relatives (62% vs. 40%) [35]. Increased testing uptake shows that system-led cascade screening is therefore clinically effective, with the ability to prevent morbidity and mortality rates among relatives [33]. Relatedly, increased uptake of cascade testing may modestly improve the cost-effectiveness of screening programs [36‒40].

Another important consideration regarding contact methods is patient preference. Most patients report that sharing genetic risk information with family members is important [41]; however, patients with inherited disease have reported being unsatisfied with current patient-mediated models of familial notification and genetic testing [42]. Support for system-led contact models is rooted in a belief that such programs would allow relatives to more quickly and efficiently learn how to get proper clinical evaluation and genetic testing [43‒45]. Probands report that health system-led programs could help better ensure that genetic risk is not only communicated to relatives but also communicated accurately [13, 43, 46, 47]. This can decrease the burden on probands to communicate this information [48], which may be especially advantageous in situations where family relationships are strained or dynamics are difficult to navigate. Concerns about direct contact being disturbing to family members, which proponents of proband-led contact have raised, seem unfounded in some populations [49, 50]. Family members of probands are largely supportive of direct contact models, citing the desire to know risk information and the resources available to act on it [51].

While healthcare providers have expressed concerns related to direct contact methods, these have largely been based on legal and practical system issues rather than moral or ethical concerns. Research has previously demonstrated that genetic professionals endorse informing relatives of risks because of the duty to warn, yet are conflicted due to unclear policy and legal guidance [52‒55]. One study showed that while most physicians agree that disclosing risk to a patient’s relatives without their consent is unacceptable, a majority express a belief that healthcare providers should be properly trained to disclose relevant results to family members [56]. In the U.S., recent work by Henrikson et al. [57] corrected misunderstandings about the Health Insurance Portability and Accountability Act (HIPAA) and sharing genomic information between family members, highlighting that provider-mediated contact of relatives with proband permission is legally permissible. With the proband’s permission, there is support among healthcare providers for system-led cascade screening and recognition of the ability of such programs to more efficiently identify disease and integrate preventative measures into care. This is especially true for conditions with treatment or management guidelines [58, 59]. Healthcare providers also recognize how the assistance of an expert in communication of risk may improve patient understanding and provide better familial support [60‒62]. Remaining concerns about system-led cascade screening are largely pragmatic, such as how the additional work required to contact relatives may be burdensome to providers and present potential liability concerns [61].

Despite all of these issues, system-led pilot programs have been implemented with success outside of the U.S., including in Australia, Korea, and across Europe. In the Netherlands, direct contact programs for FH have been in place since the early 2000s, showing increased uptake in disease screening and identification of disease [63] and projected cost savings to the healthcare system at an estimate of USD 8,700 per life-year gained [64]. Similar approaches using a health system-led registry have been effective in the U.K. [65], Spain [66, 67], and Australia [68]. Models have also extended to hereditary cancer syndromes. In the U.K., a direct contact approach to unaffected relatives of probands with positive BRCA1/2 results revealed a significant uptake in testing compared to usual care [69]. In Brussels, a pilot showed that direct contact not only doubled the number of relatives tested but was also psychologically safe to family members and probands [70]. Programs have expanded to use digital health tools to facilitate familial communication broadly, most notably in the International CASCADE Consortium [71, 72].

While these studies were largely implemented in countries with national healthcare systems, multiple studies have now been deployed as effective proofs of concept of system-led models in the U.S. The FH Foundation has shown the feasibility of system-led cascade screening approaches through an adoption of the Dutch model, contacting eligible relatives with proband permission to coordinate screening [73]. Further innovation using digital tools to systematically implement direct contact is also underway [24]. Similar to European studies, a feasibility trial of direct contact of relatives for probands with inherited cancer syndromes in the U.S. showed favorable outcomes, including low levels of anxiety and high levels of satisfaction among relatives [74]. Studies have shown that when presented with concrete programs, clinicians and patients alike have been supportive and find them feasible in the U.S. healthcare context [75]. Multiple clinical trials are ongoing, including programs to identify and communicate familial risk for FH [24, 76], hereditary breast and ovarian syndrome [77], Lynch syndrome [78], and Long QT syndrome [79].

This body of evidence – which cites the clinical utility, personal utility of patients and providers, and the economic utility of direct contact models – suggests that the principles traditionally used to assess system-led cascade screening may be poorly suited to evaluate the full range of ethically relevant considerations in this situation (Table 1). Next, we review and critique the various ethical frameworks that have been proposed for evaluating ways to notify relatives about a potentially elevated genetic risk of disease. Drawing upon this analysis, we then propose a new approach that is better suited for evaluating the rights and responsibilities of all parties in the cascade screening process.

Table 1.

Comparison of two cascade screening contact models

Proband-led contactSystem-led contact
Also known as… Patient-mediated contact or “indirect contact” Provider-mediated contact or “direct contact” 
Burden of disclosure On affected probands and healthcare providers On system (healthcare, public health, etc.) and healthcare providers 
Cost-effectiveness Suboptimal Optimal 
Patient preference Unsatisfied. Burden of disclosure is high Accepted and favored. Decreases burdens, increases satisfaction with the healthcare system 
Provider preference Unsatisfied. Recognized limitations of contact method to increase testing uptake With proper support to operationalize, accepted 
Uptake of genetic testing among relatives Lower; fewer at-risk relatives identified Higher; more at-risk relatives identified 
Principles prioritized Proband autonomy and confidentiality Proband autonomy and confidentiality balanced against relatives’ and societal interests 
Current ethical frameworks used Limited duty to warn Joint accountability model 
Proband-led contactSystem-led contact
Also known as… Patient-mediated contact or “indirect contact” Provider-mediated contact or “direct contact” 
Burden of disclosure On affected probands and healthcare providers On system (healthcare, public health, etc.) and healthcare providers 
Cost-effectiveness Suboptimal Optimal 
Patient preference Unsatisfied. Burden of disclosure is high Accepted and favored. Decreases burdens, increases satisfaction with the healthcare system 
Provider preference Unsatisfied. Recognized limitations of contact method to increase testing uptake With proper support to operationalize, accepted 
Uptake of genetic testing among relatives Lower; fewer at-risk relatives identified Higher; more at-risk relatives identified 
Principles prioritized Proband autonomy and confidentiality Proband autonomy and confidentiality balanced against relatives’ and societal interests 
Current ethical frameworks used Limited duty to warn Joint accountability model 

As the preceding evidence review shows, there are several parties whose interests are relevant when considering whether and how to notify relatives about their potentially elevated disease risk: the proband, their relatives, members of the healthcare team, the health system, and more collectively, families and communities impacted by heritable conditions. The fact that so many parties have interests in the way cascade risk notification and screening occur suggests that these interests need to be weighed and balanced against one another, necessitating a robust ethical framework to guide program design. Over the years, theorists have conceptualized and weighed the interests of these parties differently, leading to inconsistent conclusions about the best course of action in specific cases. In what follows, we review some of the contributions and shortcomings of existing ethical frameworks that have been, or could be, used to justify or prohibit the use of direct contact for cascade screening.

Limited Duty to Warn

Rothstein [80] has argued that physicians have a primary duty to maintain their patients’ confidentiality, a duty which is not consistent with a broad responsibility to notify their patients’ relatives about the existence of a genetic disease risk in the family. The widely accepted belief that physicians have a very limited duty to warn a patient’s at-risk relatives draws upon primarily legalistic rather than ethical arguments. Upon closer scrutiny, we find that this belief is supported by some potentially unfounded assumptions.

One such assumption is that in many situations a patient would not wish to inform relatives about their genetic diagnosis. As current literature demonstrates, however, there is scant evidence that this is in fact a common situation [41]. A second assumption is that patients will typically be better off because of a physician’s lack of information disclosure to relatives, a claim that contradicts evidence that patients frequently welcome help from healthcare providers when communicating with relatives about genetic information [43]. The reasoning underpinning this framework relies on a zero-sum view of patients’ and relatives’ interests, with no acknowledgment of their shared interests in learning about and adapting to familial disease and/or disease risk together. While Rothstein’s framework also points out that contacting a patient’s relatives can be burdensome for physicians, it does not recognize that this burden can be more readily absorbed by healthcare institutions and/or teams, rather than individual providers, and that there is an array of new information-sharing tools available and system-led models proposed which can lessen this burden [81].

The view that physicians have a limited duty to warn a patient’s at-risk relatives also ignores that genetic conditions vary tremendously in terms of their symptom profiles, penetrance, preventability, and therapeutic actionability, all of which are considerations that might strengthen or weaken the case for or against disclosure. In addition, the duty-to-warn framework operates under the assumption that HIPAA does not allow for the direct disclosure of protected health information except under very limited circumstances, whereas recent work has shown that HIPAA does not prevent physician disclosure with proband consent [57]. In light of emerging evidence showing the feasibility of system-led cascade screening in the U.S., this framework unjustifiably forecloses a meaningful engagement with ethical questions about what specific circumstances might warrant a system-led approach.

The Joint Account Model

In contrast to Rothstein, Parker and Lucassen’s 2004 “joint account” model begins with the question of who “owns” genetic information and concludes that it should be conceptualized similarly to a family’s joint bank account rather than as a type of personal information [82]. Given the unavoidably familial nature of most genetic information, Parker and Lucassen assert that it is unjustifiable for one family member to benefit from it and exclude others from access to such benefits for the arbitrary reason that they came to medical attention first. The animating principles underlying this view are justice and reciprocity among family members as well as that of benefit maximization for patients and the healthcare system. These values support a presumption that all relatives have equal rights to benefit from their shared genetic information by default. The joint account model places the burden of proof on patients to articulate concrete reasons for overriding this default presumption in cases where they wish to opt out of familial information sharing.

A strength of the joint account model is that it treats the family as the primary unit of significance in healthcare. It is compelling because it challenges many of the unsupported assumptions of the limited duty-to-warn framework, including the assumption that most patients do not wish to share information about their genetic diagnosis with relatives. However, like the limited duty-to-warn view, the joint account model does not distinguish between different kinds of genetic information or delineate differing levels of responsibility to share information about a diagnosis in families based on the predictive power, preventability, or the therapeutic actionability of a particular genetic test result. Furthermore, the joint account model includes few details about its practical implications for healthcare providers and is especially silent about how privacy and confidentiality concerns should be navigated. Parker and Lucassen suggest that genetic information could be routinely stored in family registries without elaborating how these registries would be controlled and stewarded, what kinds of informed consent requirements would be waived or deemed appropriate for this type of information storage, and what levels of data access would be available to whom, for how long, and for what purposes.

Public Health Ethics Frameworks

Public health ethics emerged in the 1990s as a subfield within bioethics, primarily in response to the limitations of the medical models of bioethics which is not sensitive to the goals and contexts of public health practice [83]. The central concern of public health is the health and well-being of populations, rather than individuals. The impetus behind public health ethics was that clinical ethics, with its central focus on patient-provider relationships, did not hold space for the full range of considerations and values that are relevant when conducting interventions that affect groups or which involve shared resources.

Owing to the breadth and diversity of global public health interventions and contexts, public health ethics has evolved into a heterogeneous field of scholarship that has produced frameworks that incorporate aspects of principlism, relational ethics, human rights, communitarian values, and political philosophy. For this reason, it is not useful to refer to public health ethics as one school of thought. Rather, public health ethics builds on several theoretical tools that share a focus on maximizing the well-being of populations. The aim of public health ethics is to balance this goal against potential infringements on individual or smaller group interests (particularly autonomy interests) while attending to relational values and concerns about social and distributive justice.

Three frameworks of public health ethics are particularly useful to the question of whether and when system-led contact is ever an appropriate approach to initiating cascade screening. Childress et al. [84] argued that public health interventions need to be evaluated according to their potential effectiveness, their proportionality to the problem they are trying to solve, the necessity of the intervention compared to alternatives, the extent to which they minimize the infringement of other rights and interests, and the extent to which the program is publicly justifiable to the parties who will be affected by it. Roberts and Reich [85] proposed a complementary framework that draws upon relational ethics and explicitly acknowledges the importance of supporting relationships and caregiving as an essential component of collective health. Kenny et al. [86] contributed a more equity- and procedural-justice-focused framework by highlighting the central importance of transparency, fairness, inclusivity, and attention to systemic inequalities to any program that affects collective interests.

If cascade screening using direct contact to relatives is viewed as a program, rather than as an element of 1:1 patient-provider communication, then these theories of public health ethics offer valuable guidance about the details of program design. This is because these frameworks weigh considerations about the allocation of benefits, burdens, and scarce resources while recognizing that institutional or role-based responsibilities exist in the context of interpersonal relationships that matter deeply to communities [83]. If direct contact for cascade testing is implemented as an institutional program rather than as a practice of individual providers, then public health ethics offers useful tools for evaluating the effectiveness, proportionality, necessity, burdens, and public acceptability of such programs in specific contexts [83]. While relational frameworks are less useful for distinguishing which conditions it is acceptable to use system-led contact for, they do emphasize that individuals’ interests are intertwined with those of their relatives, which is one of the central rationales for implementing a system-led approach. With respect to equity, relational ethics also highlights that relatives’ opportunities to access screening should not be dependent on the cohesion of their family relationships, the quality of their family communication, or the number of competing stressors in their lives. This matters because evidence shows that barriers to family communication about genetic risk disproportionately affect minoritized and historically underserved people [22, 87].

With the exception of newborn screening, public health ethics frameworks have not often been considered in genomic medicine because genomics, until recently, has not universally been thought of as a tool of public health. Particularly in matters concerning reproductive planning, the dominant ethical preoccupation in the field of genomics is the protection of patient autonomy, which is often cited as a reason to privilege patient confidentiality at the expense of other values. Historically, since most genetic conditions have been viewed as untreatable and preventable only by avoiding so-called vertical disease transmission by interfering with or manipulating childbearing, many practitioners of genomic medicine have stopped short of treating the prevention or mitigation of genetic conditions as a matter of public health for fear of regressing into eugenic practices [88]. What is often overlooked is that public health practitioners typically distinguish between primary prevention (prevention of disease occurrence) and secondary prevention (measures that lead to early diagnosis and disease treatment) [89]. Most secondary prevention measures for genetic conditions do not involve interference with reproductive decision-making or childbearing; they merely provide an at-risk person with a window of opportunity to delay disease onset or mitigate disease severity.

In the U.S., state-mandated newborn screening is the most successful example of using public health ethics to justify routine genetic screening, without informed consent by default, to carry out secondary prevention of serious heritable illnesses for conditions that meet specific criteria. The original Wilson and Jungner criteria for disease screening are as follows [90]:

  • 1.

    The condition sought should be an important health problem.

  • 2.

    There should be an accepted treatment for patients with recognized disease.

  • 3.

    Facilities for diagnosis and treatment should be available.

  • 4.

    There should be a recognizable latent or early symptomatic stage.

  • 5.

    There should be a suitable test or examination.

  • 6.

    The test should be acceptable to the population.

  • 7.

    The natural history of the condition, including development from latent to declared disease, should be adequately understood.

  • 8.

    There should be an agreed policy on whom to treat as patients.

  • 9.

    The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care.

  • 10.

    Case-finding should be a continuing process and not a “once and for all” project.

Importantly, these criteria were proposed as a starting point to use in designing a screening program. In recognition of changing evidence, these criteria have been expanded and updated over time, and there has been tailoring and variation of their application to different contexts [91, 92]. To address this, a different but analogous framework should be used to identify a list of genetic conditions for which it is ethically appropriate to initiate cascade screening using direct contact. Such a framework would be similarly amenable to adaptation over time in response to changing evidence about the population incidence and burden of a condition, the availability of prevention and treatment measures, and the public acceptability and cost-benefit profile of the proposed program.

To date, such a programmatic approach to evaluating and justifying system-led contact has not been common. Over the last 20 years, public health genomics has arisen as a multidisciplinary field to study “the responsible and effective translation of genome-based knowledge and technologies for the benefit of population health” [93]. Experts have modified the Wilson and Jungner criteria to assess the appropriateness of the application of genetic testing for screening [92] and the development of guidelines, such as the CDC’s 3-tier class system of genomic applications, to assess hereditary conditions most appropriate for population screening [94]. These efforts showed an agreement that an evidentiary threshold should be met demonstrating the analytic validity, clinical validity, clinical utility of a genetic test with sufficient evidence-based recommendations before implementation. However, these programs have largely focused on evaluating individuals rather than looking to the family as the unit of significance. Statewide programs have been adopted but have not traditionally applied public health ethics models to develop a rationale for system-led cascade screening. A close analog is the American College of Genetics and Genomics’ recommendations for the reporting secondary findings from clinical exome and genome sequencing, which recommends disclosure of unanticipated disease-associated findings to patients if they are well characterized and have effective prevention or treatment measures (assuming the affected patient has not opted out of receiving such information). However, these recommendations have functioned as opportunistic screening rather than an intentional population screening approach to genomics [95].

Systems that use direct contact to notify relatives about their increased risk of a genetic condition must account for the obvious fact that not all genetic conditions are equally common or amenable to prevention and treatment. Like others before us, we argue that the more common, well characterized, and medically actionable a genetic condition is, the higher the benefits of disclosing a patient’s risk are to both them and public health. Accordingly, for common, well-understood, and preventable or treatable conditions, it is justifiable for healthcare providers and systems to be proactive about notifying at-risk relatives of their elevated risks. For conditions where the magnitude of the potential benefit of disclosure is less clear, we do not find the practice of direct contact to be appropriate.

Critics of this mentality often point to the risk of breaching patient-provider confidentiality and invading the privacy of relatives without paying close attention to elements of program design that can mitigate these risks. Regarding patient confidentiality, system-led contact programs can and should require patients to opt in or opt out of having relatives contacted via informed consent. The notification of relatives can also be delayed so that patients have an opportunity to introduce the topic of a familial disease risk to their relatives (if they so choose) without being weighed down by the burden of providing all the relevant information and follow-up resources. To minimize the privacy risk to relatives, direct contact programs can be designed so that relatives are made aware that it could be beneficial for them to seek genetic risk assessment without specifying their risk of a particular condition, leaving the option of following up on the notification entirely in the hands of the relative. While we acknowledge that this does not eliminate the risk of infringing a relative’s privacy, the relative’s privacy interest is protected by the fact that they can still choose whether and when to follow up on the limited information provided. In addition, the residual privacy risk to relatives is outweighed by the potential individual, familial, and public health benefits of disclosing the information. Moreover, the notion that individuals have a strong “right not to know” clinically actionable information about their health risks has been criticized as being philosophically weak, legally suspect, and insufficiently cognizant of beneficence considerations [96].

System-led contact programs must also be designed with resource constraints in mind. Historically, direct contact has been criticized as an undue burden to clinicians because of the time-consuming nature of tracking down, contacting, and counseling additional patients as part of the cascade screening process. To counter this concern, we point to the many advancements in controlled access health data sharing as well as a growing range of digital tools that can and have been successfully employed to minimize the health system burdens of this process [16, 97]. While technology is not an all-encompassing solution, it has the potential to significantly reduce the time and extra work that health system-led contact involves, as being demonstrated by the pilot project described earlier in this paper [24, 98] and other novel digital communication tools like ConnectMyVariant [99]. In addition, partnership with patient advocacy groups and public health institutions may provide opportunities to outsource undue burden on clinicians and provide innovative solutions to direct contact methods. Taking these considerations into account, and drawing upon theories of public health ethics from Childress et al. [84], Roberts and Reich [85], and Kenney et al. [86], we propose the following criteria as a starting point for determining whether it is appropriate to use health system-led contact for a particular genetic condition (Fig. 1).

  • 1.

    The condition must have effective prevention or treatment that is reasonably accessible (Effectiveness).

  • 2.

    The condition must be relatively prevalent in the population, to justify the use of scarce resources to achieve societal benefits (Proportionality).

  • 3.

    The benefits of the direct contact program should be empirically established and should be proportional to the burdens it places on the healthcare system as well as providers and families (Proportionality).

  • 4.

    There should be no obvious and more effective way of identifying and notifying at-risk relatives within the relevant time window for disease prevention or treatment (Necessity, Least Infringement).

  • 5.

    There should be an informed consent requirement that allows patients to opt in or opt out of having their relatives contacted (Least Infringement, Transparency).

  • 6.

    There should be research demonstrating that there is broad support of the program from the parties who will be affected by it (Public Justification, Transparency).

  • 7.

    It should be clear that direct contact will achieve more equitable access to cascade screening than alternatives (Responsive to Systemic Inequalities).

Fig. 1.

Proposed criteria for system-led direct contact. When considering the implementation of system-led direct contact programs, the following should be considered: effectiveness, proportionality, necessity, least infringement, transparency, public justification, and responsiveness to systemic inequalities.

Fig. 1.

Proposed criteria for system-led direct contact. When considering the implementation of system-led direct contact programs, the following should be considered: effectiveness, proportionality, necessity, least infringement, transparency, public justification, and responsiveness to systemic inequalities.

Close modal

While evaluations of some of these dimensions may be subjective and require the engagement of multiple viewpoints, this can be addressed by prespecifying concrete methods and thresholds for measuring benefits and burdens with input from representatives of all potentially affected groups. Even without such prespecified methods and thresholds, we find that the criteria can sensitively distinguish conditions which system-led contact is appropriate for from conditions it is not appropriate for. In Table 2, we demonstrate the use of these criteria to evaluate the comparative appropriateness of system-led contact for two conditions: FH and cystic fibrosis (CF). As the table illustrates, these criteria are sensitive enough to distinguish the value of the direct contact approach in the case of FH and not CF. We view these criteria as a practical and meaningful way to embrace the fact that system-led contact can be an ethically appropriate way to initiate cascade screening without arguing that it is always an ethically appropriate way to do so. Our goal in presenting these criteria is to break the argumentative gridlock that portrays the ethical debate about cascade screening in absolutist terms by acknowledging normatively meaningful differences between different genetic conditions that may shift as the genomic evidence base changes.

Table 2.

Application of proposed criteria for system-led contact

Familial Hypercholesterolemia (FH)Cystic Fibrosis (CF)
Effectiveness Effective disease prevention available (statins, diet, exercise) No effective prevention (disease management only) 
Proportionality Benefits proportional to burdens Benefits not proportional to burdens 
Prevalence: 1 in 220 people (condition is common) Prevalence: 1 in 3,400 people (condition is rare) 
Heritability: autosomal dominant (50% chance that first-degree relatives of proband are affected) Heritability: autosomal recessive (carrier frequency varies from 1/25 to 1/90 based on ethnicity) 
Necessity No better method of identifying patients at risk during the prevention window. Despite cholesterol screening and a clinical scoring system, less than 10% of FH patients are diagnosed [23Diagnosis made more easily in other ways (prenatal testing, newborn screening, clinical diagnostics) 
Least infringement Informed consent with opt-out provision minimizes potential autonomy infringement Contacting relatives remains proband-led, so minimal risk of autonomy infringement 
Transparency Informed consent provision offers transparency Informed consent provision offers transparency 
Public justification Preliminary data show that public attitudes support system-led contact at-risk relatives Data show that public attitudes support screening in prenatal or newborn period. Scant data on attitudes for system-led contact of at-risk relatives 
Responsive to systemic inequalities Opportunity for relatives to opt into risk assessment does not vary by family structure or quality of relationships/communication, which are inconsistent based on an individual’s specific family dynamics Optimal route for ascertaining cases is not via cascade screening, so not using health system contact in this instance does not address inequalities 
Overall assessment Condition suitable for system-led contact Condition unsuitable for system-led contact 
Familial Hypercholesterolemia (FH)Cystic Fibrosis (CF)
Effectiveness Effective disease prevention available (statins, diet, exercise) No effective prevention (disease management only) 
Proportionality Benefits proportional to burdens Benefits not proportional to burdens 
Prevalence: 1 in 220 people (condition is common) Prevalence: 1 in 3,400 people (condition is rare) 
Heritability: autosomal dominant (50% chance that first-degree relatives of proband are affected) Heritability: autosomal recessive (carrier frequency varies from 1/25 to 1/90 based on ethnicity) 
Necessity No better method of identifying patients at risk during the prevention window. Despite cholesterol screening and a clinical scoring system, less than 10% of FH patients are diagnosed [23Diagnosis made more easily in other ways (prenatal testing, newborn screening, clinical diagnostics) 
Least infringement Informed consent with opt-out provision minimizes potential autonomy infringement Contacting relatives remains proband-led, so minimal risk of autonomy infringement 
Transparency Informed consent provision offers transparency Informed consent provision offers transparency 
Public justification Preliminary data show that public attitudes support system-led contact at-risk relatives Data show that public attitudes support screening in prenatal or newborn period. Scant data on attitudes for system-led contact of at-risk relatives 
Responsive to systemic inequalities Opportunity for relatives to opt into risk assessment does not vary by family structure or quality of relationships/communication, which are inconsistent based on an individual’s specific family dynamics Optimal route for ascertaining cases is not via cascade screening, so not using health system contact in this instance does not address inequalities 
Overall assessment Condition suitable for system-led contact Condition unsuitable for system-led contact 

All system-led interventions must identify and address implementation challenges. We recognize that programs must be designed with nuance and should allow for multiple contact approaches. While the literature overwhelmingly has described patient support for system-led contact, some patients may prefer to relay risk information to their relatives themselves. Recent work by Pedrazzani et al. [100] showed that while proband-led contact is difficult and has its limitations, interviewed patients still desire to be involved in the familial notification process in some way. All system-led models therefore should include an informed consent process (transparency), allowing for probands to opt out of direct contact of relatives if preferred. Furthermore, we appreciate that different approaches to informing relatives about their potentially elevated disease risk are not mutually exclusive, and that optimal population health outcomes may rely on a mixture of both proband-directed contact and system-led contact.

As the evidence of the utility of system-led programs grows, the argument for system-led models in the U.S. becomes more compelling. We argue that the implementation of system-led contact represents a shift from treating cascade screening as an individual responsibility to viewing it as a programmatic responsibility of institutions. This invites a recalibration of the conceptual tools we use to evaluate the benefits and risks of contacting relatives to notify them about their potentially increased risk, so that providers, patients, and health system leaders can recognize the full range of relevant considerations in program design.

Some aspects of the U.S. healthcare system are not currently amenable to system-led contact. For instance, it will be necessary to clarify perceived or actual regulatory obstacles related to the HIPAA if such programs are to move forward successfully. HIPAA is a federal privacy statute that permits limited sharing of personal health information to “carry out treatment, payment, or healthcare operations” without any specific prior patient authorization [101]. This clause has been interpreted as permissive of some system-led contact programs, though for individual treatment and not public health reasons. One such interpretation reads the HIPAA privacy law as permitting disclosure of genetic risk information to relatives with proband consent and disclosure of genetic risk information to another healthcare provider without proband consent [57]. This interpretation has not been tested in the courts as of yet.

Uses of the public health exception (PHE) to HIPAA, which allows limited disclosure of personal health information to public health authorities for the purpose of preventing or controlling disease, injury, or disability, have thus far been restricted to public health emergency surveillance for fear of seeding public mistrust [102]. Neither the PHE nor any state laws make explicit reference to acceptable disclosures of genetic information [103]. Whether system-led contact constitutes a public health activity is also a matter of ambiguity under the PHE. Individual states and municipalities are responsible for deciding whether notifying relatives of a disease risk is permitted as a public health activity, leading to substantial variation in the legality of routinely disclosing risk information depending on which conditions a state considers “reportable.” While it is useful to use evidence-based criteria to determine which genetic conditions are common and preventable enough to warrant system-level contact for cascade screening, secondary disease prevention is not equivalent to the traditional public health scenario in which the goal is to prevent rapid horizontal disease transmission. The relatively less urgent nature of cascade screening may raise concern that it is not an appropriate use of public resources, even if available data suggest otherwise [32]. Even if these issues were resolved, individual hospital systems would need to reevaluate their institutional policies regarding data privacy and disclosure, and professional societies would need to issue statements that provide guidance and support for system-led approaches.

Apart from regulatory issues, there are also downstream implications of system-led contact for relatives. Following up on risk assessment can be logistically burdensome and costly for some, and access to risk assessment is not distributed evenly across the U.S. [104]. Moreover, there are varied levels of state protection against insurance uses of genetic information by life, disability, and long-term care insurers, which leave some asymptomatic patients with a disease-predisposing genetic test result more vulnerable to insurance discrimination than others, as these insurance types are not addressed at the federal level by the Genetic Information Non-Discrimination Act [105]. Close attention to these nuances will be essential in crafting the details of system-led programs. It will still be necessary for practitioners to evaluate the risks of using system-led contact for individual families on a case-by-case basis. Relatives’ degree of legal protection against insurance discrimination, based on where they live, should be taken into consideration when systems decide what kind of information to provide when contact is made.

Lastly, while system-led contact has been demonstrated as efficient and effective for certain conditions [32], implementing it will undoubtedly incur transition costs. System-led contact may also be more feasible for health systems that have already invested in digital communication tools or which have large workforces that can absorb the transition costs more easily. Transition costs should be viewed as an investment in long-term healthcare quality improvement and secondary preventive public health. The burdens of transition can be ameliorated by relying on novel digital information-sharing tools that allow for controlled information access and by partnering with patients, advocacy organizations, and companies that can make risk assessment more accessible via telehealth and consumer-led testing platforms [81, 106‒108]. The most successful cascade screening outcomes will likely arise from multimodal approaches that allow patients to opt into one or more methods of notifying relatives that works for them and their families. By embracing both system-led and direct contact as options, health systems will be flexible enough to address the communication needs of families who are comfortable with digital technologies and those who are not.

This work proposes a normative framework for assessing the ethical justifications for systems-led cascade screening and is not meant to serve as a formal literature review of all cascade screening methodology. Future meta-analyses of recent system-led approaches being implemented in the U.S. may be beneficial as evidence continues to grow. Continued research on the perspectives of diverse and underrepresented populations in healthcare service delivery and genomic medicine will also benefit assessments of cascade screening models and ensure principles of justice and equity are centered in future design and ethical analyses.

We have made the case that in carefully chosen circumstances, system-led contact is not only feasible and broadly acceptable, but also ethically desirable. One implication of our framework is that hospital administrators and clinicians should shoulder more of the responsibility for implementing cascade screening, compared to a status quo in which individual healthcare providers and patients attempt to uphold this responsibility. This raises the question of precisely which institutions should be held accountable for the outcomes of system-led contact programs. Most likely, there will be more than one answer, especially in the U.S., where there is modest centralized public health infrastructure and healthcare is provided and system-led contact is a promising approach to maximizing the utility of genomic information that has not yet reached its full potential. While there are barriers and potential risks to implementing system-led contact, ethics should not be used as a blanket rationale for dogmatic adherence to the status quo approach of relying on newly diagnosed probands to shoulder the sole burden of risk communication to their relatives.

The views expressed are the authors’ own. They do not represent the position or policy of their employers, including the National Institutes of Health or the Department of Health and Human Services. Leila Jamal and Benjamin Berkman are US Federal government employees. The views expressed in this manuscript do not reflect the views of the US Federal government. The authors declare no additional conflicts of interest.

Leila Jamal is funded by the Intramural Research Program of the National Cancer Institute.

Conceptualization, writing – original draft: Katherine Bonini and Leila Jamal. Writing – reviewing and editing: Katherine Bonini, Leila Jamal, Emily Bonkowski, Hadley Stevens Smith, and Benjamin Berkman.

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