From the Emergence of Genetic Testing to Cascade Screening

Considering the history of genetic testing more generally is useful for understanding cascade screening’s potential for improving individual and public health outcomes as well as the legal and ethical frameworks that surround it. The utility of cascade screening relies not only on targeted genetic testing of populations with a known risk for a pathogenic variant, but on the ability to offer some sort of reasonable intervention once a variant is found. Some of the earliest genetic health screenings that offered an intervention were those in prenatal medicine, designed to provide parents with the choice to abort a fetus with significant genetic health issues.Reference Susan Lindee¹⁰ The development of a test for phenylketonuria (PKU) made it the first genetic disease for which screening (through the heel prick) appeared to offer a life-saving clinical intervention in the form of a low-phenylalanine diet.¹¹ The potential impact of detecting the disease at birth led to the implementation of widespread public screening programs across the US. However, follow-up data began to highlight that this largescale screening approach also caused new problems, like overdiagnosis and false positives. It turned out that not all the children who tested positive in the screening actually required the special diet.¹²

The discovery of a genetic screening test for pathogenic variants linked to cystic fibrosis in the late 1980s is another important moment in this story.¹³ The CF test, however, also gave rise to a whole host of new ethical and practical questions for researchers, clinicians, and bioethicists to consider even as public expectations and enthusiasm for the medical technology grew.Reference Lench, Stanier and Williamson¹⁴ Excitement about CF screening waned, however, as feasibility studies showed that the costs and ethical complexity of another widespread genetic screening program might outweigh the benefits.Reference Holloway and Brock¹⁵ Researchers, for example, noted the increase in unnecessary anxiety that widespread carrier testing for CF caused, as well as the high financial cost and logistical complexity of such a mass screening program.Reference McCabe and McCabe¹⁶

Given these concerns with mass genetic screening programs, geneticists began to experiment with the idea of cascade testing — “starting with individuals with a family history and their spouses, then offering to test the relatives of all those who are positive.”Reference Super, Schwarz and Malone¹⁷ By targeting specific populations with a known risk for carrying a pathogenic variant, cascade screening offered the chance to more fully integrate genetic testing into healthcare, while lowering the costs as well as the risks of overdiagnosis and false-positives that broader screening programs generated.Reference Srivastava, Koay, Borowsky, De Marzo, Ghosh, Wagner and Kramer¹⁸ By the end of the twentieth century, cascade screening for familial hypercholesterolemia (FH), a genetic condition that leads to high cholesterol and the potential for heart attacks, even at a relatively young age, emerged as the next big hope in genetic medicine.Reference Tonstad, Vollebaek and Ose¹⁹

Understanding the Ethical Landscape of Cascade Screening

Years of studying public responses to screening programs, by the early 2000s, helped illuminate key ethical issues that arose in tandem with the development of these cascade screening efforts. Studies into the psychological, economic, public health, and social impacts and limits of cascade screening sought to understand both what the utility of cascade screening was as well as how patients and their families viewed genetic health information and the processes surrounding it.Reference Lerman, Hughes, Lemon, Main, Synder, Durham, Narod and Lynch²⁰ Researchers and ethicists initially asked many practical questions like: Should cascade screening be adopted as a public health tool? Reference Krawczak, Cooper and Schmidtke²¹ Under what circumstances and for what goals?Reference Van Maarle, Stouthard, Marang-v.d, Klazinga and Bonsel²² Would knowing one’s genetic status for diseases like Huntington’s disease, CF, hereditary breast and ovarian cancer, and FH, change individual behavior and lead to better health outcomes?Reference Umans-Eckenhausen, Defesche, Sijbrands, Scheerder and Kastelein²³ With the meteoric expansion of genetic research and the emergence of precision medicine during this era, more refined questions about how to collect and use genetic health information in the clinic also emerged. Researchers began to ask: What kind of genetic information should be considered clinically useful for individuals? What information is actually welcomed by individuals?Reference Swartling, Eriksson, Ludvigsson and Helgesson²⁴ How should family members be contacted and confronted with the opportunity to undergo genetic testing?Reference Hull, Glanz, Steffen and Wilfond²⁵ And how might the results of this increased testing shape lives and health outcomes individually and at the population level?Reference Lynch, Snyder, Lynch, Karatoprakli, Trowonou, Metcalfe, Narod and Gong²⁶ These considerations only became more relevant as the scale and depth of genetic information available expanded. Other questions surfaced, too, about the rights of individuals “not to know”Reference De Wert²⁷ their genetic status. These discussions about unwelcome knowledge cited examples in which patients who underwent genetic testing learned information that challenged their identity or kinship ties,Reference Ross²⁸ as well as situations in which people became overwhelmed with anxiety, failed to act on the information altogether, or regretted or resisted learning their status.Reference Phillips²⁹

Critical work also pointed out that data produced through genetic testing could not always adequately capture the true risk of disease based solely on a genetic test since not all pathogenic variants are known and others, while present, may not always be expressed. The overuse of testing for conditions that are either very common or exceedingly rare also have limited utility. Individuals may be found to carry variants that have no direct clinical utility, like those in the MTHFR gene which impacts the production of an enzyme. Such variants are extremely common but carry only vague implications for a person’s health. In extremely rare disorders, risk information from genetic screening is difficult to parse. Furthermore, identifying pathogenic variants through genetic testing does not directly dictate an individual’s access to healthcare, choices, or health outcomes. Reference Rose³⁰ The recognition that there could be substantial negative impacts on individuals from exposure to genetic health information has led to the creation of guidelines and standards for offering genetic tests and screening. Organizations like the American College of Obstetrics and Gynecology and the American College of Medical Genetics and Genomics, for example, have supplemented an imperfect net of Federal regulations that have been governing genetic tests since the passage of the 1988 Clinical Laboratory Improvement Amendments.³¹ These patchwork efforts recognize that genetic health information, while often beneficial, can also have negative consequences.

The protection of genetic privacy and the uses of patient information, then, have also surfaced in these discussions about the potential harms of genetic testing, more generally.Reference Hanna³² Scholars have raised concerns about the possibility of discrimination in the workplace and by insurance companies who might use genetic health information to deny or terminate insurance coverage and benefits, declare pre-existing conditions, and reject claims. These anxieties have helped to drive calls for the protection of genetic privacy. Eventually, these discussions helped inform the creation and passage of specific legislation in the form of the Genetic Information Nondiscrimination Act (GINA, 2009), meant to prohibit this genetic discrimination, particularly in employment and health insurance. This sensitivity to genetic privacy also influenced the 2013 revision of HIPAA.Reference McGuire and Majumder³³

Cascade screening as a health tool has not emerged de novo. It has instead grown up within a broad and complex legal and ethical landscape that has been evolving since the 1970s, contextualized by a history steeped in the debates surrounding reproductive and prenatal medicine, health insurance, employment discrimination, and privacy. The majority of the legal and ethical discussions that have shaped this landscape for cascade screening over the past two decades have thus been heavily shaped by the weight of arguments rooted in concern for privacy and individual autonomy.Reference Rapp³⁴ Yet, in the case of cascade screening, the entire process is designed to look beyond the immediate interests of the individual, to include those of a “cascade” of biological relatives. Empirical studies on participant and family attitudes towards various aspects of the cascade testing process conducted over the past decade help illuminate the need for an ethical framework that gives greater weight to the rights of biological relatives when it comes to genetic health information.

The “Right to Know”

Cascade screening can be a cost-effective and helpful tool in treating gene-linked diseases, but its implementation in the US has remained limited.³⁵ Stakeholder studies conducted in European countries, however, have shown that family members conceptualize access to genetic risk information as a right.Reference Whyte, Green, McAllister and Shipman³⁶ In the Netherlands a survey of patients (n=379) and healthcare professionals (n=1000) found that the majority of all respondents named a “right to know” for family members, and considered it to be a “dominant issue,” in determining the extent to which healthcare providers should be involved in contacting relatives about their genetic risk.Reference van den Heuvel, Stemkens, van Zelst-Stams, Willeboordse and Christiaans³⁷ The right to know is related to concerns about the “right not to know,” which has long played a role in conversations about screening of all sorts. The right not to know is often accompanied by discussions about avoiding psychological harm and respecting individual choice, autonomy, and privacy. It asks: Is it ethical, fair, or just to burden someone with information they did not seek out on their own? As preventive treatments for genetic diseases become more available, however, the ethics of this equation appear to be shifting³⁸

Born out of the literature on incidental and secondary findings from genetic tests, the discussion of the “right to know,” has become increasingly salient in light of the possibilities of expanded genetic testing abilities.Reference Shaefer and Savulescu³⁹ In the case of genetic health information, it asks: Is it fair to deprive a person of access to genetic risk information that they would not otherwise know about? The right to know has received less attention in the US, although today the American College of Medical Genetics recommends the return of results from genetic research for conditions they have deemed actionable.Reference Green, Berg, Grody, Kalia, Korf, Martin and McGuire⁴⁰ Perhaps the idea has been slow to gain traction in the U.S. because the right to know can conflict with longstanding cultural concerns for the protection of individual autonomy and privacy. The right to know, however, can be strengthened when seen in terms of equity and justice. We know, for example, that in the U.S., Black ovarian cancer patients are less likely to obtain genetic testing than white patients.⁴¹ Although the issue of underrepresentation in genetic research more generally remains a significant barrier, giving greater weight to the right to know may help reach populations that are disproportionately under-screened.

When it comes to sharing genetic risk information with individuals and family members, the right to know is also supported by the “duty to warn,” or the “duty of easy rescue,” two additional and related ethical considerations that have wound their way into genetic testing discussions. The duty to warn focuses on the ethical obligations faced by a clinician or researcher to warn “third parties about the threats of a dangerous patient”⁴² but also extends to informing “family or third parties of their patients’ infectious disease status or genetic risks when an actionable intervention against the threat exists.”⁴³ Although there are a handful of court cases in which the duty to warn has withstood medical breeches of individual privacy for the benefit of family or others in harm’s way, these have been limited to extreme scenarios in which an individual or their health information poses an immediate threat to the welfare of others. These instances are limited because embracing the duty to warn can often mean breaking HIPAA’s Privacy Rule.Reference Rulli and Millum⁴⁴ Bioethics scholars have argued persuasively that the duty to warn must be balanced carefully against privacy concerns and an individual’s right not to know. They point out that it alone cannot be used to justify the return of genetic results to family members without the patient’s consent.Reference Boers, van Delden, Knoers and Bredenoord⁴⁵

The “duty of easy rescue” may also support the “right to know.” Generally, it suggests “if someone can prevent a serious harm to another person at minimal cost to herself, then she has a moral duty to do so.”⁴⁶ Some have argued that this duty extends beyond clinicians and researchers to impact all participants in a health/research system. If we acknowledged the duty to easy rescue in the context of genetic health information, then genetic risk information might be more easily shared with the biological relatives of individuals who test positive for certain pathogenic variants. Some have even claimed that the duty to easy rescue supports the use of genetic health data from stored tissue specimens “for the benefit of society,” even without prior consent.Reference Mann, Savulescu and Sahakian⁴⁷ Consensus seems to have emerged, however, around the argument that broad consent is required for the use of biospecimens, and so the application of the duty to rescue as a justification for sharing individuals’ genetic health information remains weak and is not particularly useful for the case of our traceback study.Reference Tomlinson and DeVries⁴⁸

In the case of cascade screening in traceback testing, the family members’ right to know remains in tension with the privacy and autonomy rights of the patient. For this reason, the patient’s consent has remained essential for ethically and legally sharing genetic risk information with family members. This conflict between the rights of the patient vs. the family is most visible in the discussion about how genetic health information should be disseminated to biological relatives, and by whom, particularly in cases when the patient has died without leaving a clear statement of consent.

Indirect vs. Direct Contact

By the early 2000s, the practical and ethical validity of cascade screening had been firmly articulated. Many felt strongly that cascade screening could be more widely implemented across a broader spectrum of diseases and disease risks, within certain contested ethical parameters, and that doing so could save lives.Reference Krawczak, Cooper and Schmidtke⁴⁹ One of the details that researchers and ethicists continued to explore during this era was how best to get the family members of impacted patients to participate in cascade screening. Afterall, cascade screening can only be effective if biological relatives act on the information they receive about their risk by getting tested, themselves. These conversations focused almost exclusively on a scenario in which a patient was living, but today they provide an important ethical scaffolding for thinking about how to approach a traceback process in which the patient is deceased.

In “indirect contact,” a living patient is left to discuss information about their genetic health status and cascade screening options with their family on their own terms. Indirect contact is often seen as a good way to balance respect for the patient’s right to autonomy and privacy with beneficence and respect for the right to know of their relatives.⁵⁰ Clinicians and researchers may discuss contacting family with the patient, but ultimately must leave it in their patient’s hands to decide how to proceed. In a “direct contact” approach, clinicians reach out to family members directly.⁵¹ There are significant benefits to direct contact, including the mounting evidence that the uptake of testing is higher when clinicians contact family members directly. Furthermore, empirical work has suggested that patients may actually prefer direct contact, especially when it is preceded by the patient obtaining verbal consent from their family members prior to the outreach. Reference Henrikson, Blasi, Fullerton, Grafton, Leppig, Jarvik and Larson⁵² This kind of approach highlights a middle-ground for recruitment into cascade screening that again aims to both respect the autonomy of the patient and the family members’ right to know.

Advocates of direct contact have generally focused on whether testing for a particular genetic variant will make a significant difference in reducing mortality or increasing wellbeing. In the case of familial hypercholesterolemia, for example, direct-contact advocates have often argued that the principle of beneficence and the obligation to respect family members’ wellbeing and autonomous decision-making ought to outweigh the patient’s right to privacy.Reference Newson and Humphries⁵³ Studies in the disclosure of pathogenic variants in BRCA1/2 have suggested, furthermore, that despite the increased burdens of guilt and worry over their health and the health of their relatives, that positive test results do prompt family members to engage in more active management and mitigation of their cancer risk — suggesting that the direct disclosure of genetic risk information may yield significant benefits for hereditary cancers, as well.⁵⁴ Additionally, some have highlighted that the sense of duty and obligation that a patient may feel to discuss their genetic results with family can cause psychological harm, harm that could be mitigated through a direct-contact approach.⁵⁵

Over the past two decades, researchers have produced a substantial body of empirical work to put different versions of these contact methods to the test. In the case of cascade screening in hereditary breast and ovarian cancer, a consensus has emerged around the direct approach because it yields a higher response from relatives. Still, the literature has continued to maintain the importance of securing the patient’s participation in the process of contact in some form whenever possible, acknowledging that familial relationships, privacy, and individual autonomy are best respected when the patient plays a role in communicating with their family.Reference Douglas, Hamilton and Grubs⁵⁶ This hybrid, or “two-step” approach to direct contact has garnered significant support among clinicians and ethicists alike, many of whom approve of the balance that it strikes between the autonomy and privacy rights of the patient and the rights of their family members to know, and not know, as well as its higher success rate for enrollment.Reference Suthers, Armstrong, McCormack and Trott⁵⁷

The success of this approach is exemplified by the practices of the South Australian Familial Cancer Service. In 2006, the authors’ published on their experiences with indirect vs. direct contact and helped to empirically demonstrate the benefits associated with disclosure of cancer risk information to relatives. Before undergoing genetic screening, participants were asked if they would assist the clinic in contacting their relatives if a pathogenic variant was found. If a participant tested positive for one of the variants in question, they were asked to provide contact information for their relatives and the clinic sent them a letter. On average, they saw almost twice as much uptake of genetic testing among family members in the direct contact vs. indirect contact cohorts. They also reported that direct contact with family members about genetic risk could reduce the stress and burden upon the patient to talk to their relatives. Finally, they found that direct contact minimized the undue pressure relatives might feel to pursue testing when confronted by a family member compared to the clinic team.⁵⁸

Understanding the evolution of the ethics surrounding cascade testing is critical for thinking about the ethics of traceback testing. Both the “the right to know” and the groundwork on direct contact that have been established in the cascade screening discussions are vitally important because together they establish a path towards providing genetic risk information to families, even in cases when the patient is deceased. This discussion, however, is no longer confined to clinical settings. Over the past decade, researchers, participants, and ethicists have begun to raise similar discussions about the ethics surrounding genetic health data produced in the context of scientific research.

Disclosure in Research to Participants and Their Families

In the 2010s, the conversation around the ethics of sharing genetic information and cascade screening shifted beyond the clinical realm and intersected with ongoing discussions about the return of results to participants in scientific research. Scholars began to point out that, unlike patients in the clinical setting, participants in genetic research may unwittingly expose themselves to the production of genetic information that they never intended to actively seek out, raising additional concerns about personal autonomy, the right not to know, and informed consent. As the line between clinical medicine and research blurred in genomics, however, researchers and ethicists sought to establish guidelines for how to return important health results to living research participants in an ethical way.Reference Fabsitz, McGuire, Sharp, Puggal, Beskow, Biesecker and Bookman⁵⁹ Just as with cascade testing, many have argued that these concerns naturally extend to the family members of affected research participants, as well. In 2010, for example, Boddington wrote:

“Research in genomics creates challenges for the historically dominant approach to medical research ethics on at least 2 fronts. First, it generates data that has potential implications not just for the individual participant but also for biological relatives…Second, it tends to raise questions that concern harms that relate to information generated rather than physical harms. Concerns raised focus on issues such as privacy, confidentiality and rights to information. These concerns can then extend to relatives.”Reference Boddington⁶⁰

The ethical obligation of researchers towards participants has historically been framed as an exclusive relationship, in which obligations from researchers to participants generally cover respect for a participant’s autonomy, the minimization of harm, and the maximization of benefit.⁶¹ Within this framework, consensus eventually began to emerge around the argument that researchers do have an obligation to make clinically-relevant information generated by their work available to individual research participants,Reference Wolf, Paradise and Caga-anan⁶² despite concerns that it might fuel therapeutic misconception — or the misinterpretation of research as clinical care.Reference Clayton and McGuire⁶³ However, there has been far less consensus on whether or not the researchers’ obligation to a participant also extends to their family members, an issue that is particularly relevant if the participant dies. As Black and McClellan noted in 2011, “At stake here is a balance between the privacy rights of the research participant and the ‘right to know,’ not quite an established right of the participant’s family.”Reference Black and McClellan⁶⁴

Discussion: Seeking Practical Solutions

More recently, scholars who favor familial disclosure of genetic results have begun to seek alternatives that attempt to resolve the legal impossibility in the U.S. of direct disclosure of a deceased’s genetic information to living relatives, while still taking a more active approach than passive disclosure allows. So far, these possibilities include: (1) Disclosure to the deceased’s legally appointed representative (LAR;);Reference Wolf, Branum, Koenig, Petersen, Berry, Beskow and Daly⁸² (2) Disclosure to a relative through the relative’s physician for the purposes of their own treatment;Reference Henrikson, Wagner, Hampel, DeVore, Shridhar, Williams, Donahue, Kullo and Prince⁸³ and, as suggested by Henrikson et al., (3) Disclosure to a public health authority.⁸⁴ Of these three options, however, little empirical evidence has been gathered as to how these would work in practice, what it would take to implement these efforts, and what the ethical implications are of these possibilities.