Hello, everyone, and welcome. I am Tanya Epley, and I want to thank you all for joining today's Geneticist Academy session entitled, Ethical Principles Every Geneticist Needs to Know. I am especially excited to share with you that this is the first contribution of the ACMG-ELSI committee to the Genetics Academy. With that in mind, we welcome suggestions for any other topics of interest from the audience and the genetics community for the future. For today, though, we welcome two additional speakers. They are Bimal Choudhury and Malia Fullerton. Dr. Bimal Choudhury received his MD and an MPH in bioethics from Boston University. After pediatrics residency and neonatal perinatal medicine fellowships, he completed his medical genetics residency at the University of Pittsburgh Medical Center and Nationwide Children's Hospital. He is an assistant professor of pediatrics at the Ohio State University College of Medicine and Nationwide Children's Hospital, and he is co-chair of the Hospital Ethics Committee. Dr. Malia Fullerton is professor of bioethics and humanities at the University of Washington School of Medicine. She received a doctorate in human population genetics from the University of Oxford, and later retrained in ethical, legal, and social implications research with a fellowship from the NIH, National Human Genome Research Institute. Dr. Fullerton contributes to a range of clinical translational genomics research projects, including eMERGE, the Electronic Medical Records and Genomic Network, and PRIMED, the Polygenic Risk Methods in Diverse Populations Consortium. And finally, I am an associate professor in the Department of Molecular and Human Genetics at Baylor College of Medicine. I received my master's degree in genetic counseling from the University of Pittsburgh, and have worked as a genetic counselor in prenatal and later in adult and cancer genetics clinics at Baylor College of Medicine. In addition, I am an affiliated member of the BCM Center for Medical Ethics and Health Policy. All right, moving on to some housekeeping details. This is the ACMG disclaimer. This activity is intended for educational purposes only. In terms of financial disclosures, Dr. Chaudhuri has disclosed that he is the site PI of Inozyme, and neither Dr. Fullerton nor I have any financial disclosures. This session is approved for one hour of accredited continuing education. ACMG is accredited by a CCME to provide CME. A recording of this webinar will be available in two weeks in the ACMG Genetics Academy. We encourage questions to be asked throughout the presentation. However, as a courtesy to all presenters, all attendees have been muted. Please use the Zoom Q&A box for any questions you may have as the presentation progresses. Those questions will be read aloud during the last 10 minutes of our webinar. Now, moving on to today's learning objectives, they are as follows. First of all, to define the ethical concerns that might commonly be found in the context of clinical and laboratory genetics. Next, to identify select ethical principles in the context of clinical and laboratory genetics through exploration of case examples. And finally, to identify resources for expanding knowledge of ethics in the clinical genetic setting. As we move through the presentation today, we will be presenting several case vignettes as a platform for thinking through ethical issues the genetics professionals may encounter. If you're familiar with medical ethics, you may already know that often this field does not provide clear answers. That is, seldom is any answer barely or entirely right or wrong. As we work through the scenarios presented, we will be focusing on exploring the ethical considerations involved and how one might think through the ethical implications of a case. I'll now turn it over to Dr. Chaudhary for presentation of our first case. Thank you for the introduction, Tanya. And our first case deals with assent, consent, and the best interests of the child standard. And this is a format that we'll use throughout the cases. In this case, we have two vignettes, and you'll see that they are very, very similar. And so, imagine a six-year-old boy who is referred for genetic evaluation due to clinical diagnosis of autism and a history of seizures, and you're seeing him in an outpatient setting. And there is a discussion about whether or not the child should be referred for genetic evaluation. There is a discussion about the risks, benefits, alternatives of genetic testing for these indications. And the child, who has been to many medical appointments in his life and has behavioral concerns that you might associate that testing may include a blood sample and or other ways to collect this information, and he doesn't want testing because there is an emotional outburst in the office that is perhaps distressing to some. And ultimately, one of the parents takes the child out for a walk, and you complete a discussion with the other parent, and then maybe have a reciprocal conversation with the parent who took the child out before. But ultimately, the decision is that the parents think that genetic testing is important, and certainly other healthcare providers perhaps do as well, and by hook or by crook a panel is obtained. Contrast that now to a 14-year-old boy with similar indications for testing. He also doesn't want testing when it's discussed in the office during your visit. But he's actually able to articulate a specific reason, and that he, by working with his therapist, has recognized in himself that there's a high amount of anxiety that he has about knowing the future. And ultimately, after a discussion that does include the child, there's a decision that is made, for example, that might lead to trioexome sequencing, but specifically without return of secondary findings for the proband. And so I'm going to walk through now a series of considerations where we will consider how these things differ between the 6-year-old and the 14-year-old. And ultimately, in both cases, the conflict is that the adult, the parents, as well as the healthcare providers, want what they think is best for the child. And the child also has their own distinct preferences, and they may not always align with each other. And anybody who is a parent, I think, recognizes this. This is not unique to healthcare and certainly not unique to genetics. I'm going to refer to three ethical principles. These are, you know, classic ones that have previously been outlined by Beecham and Childress and are repeatedly referenced throughout the principles bioethics literature. And so we think about autonomy or respect for person's decision making. And oftentimes, we respect the autonomy, particularly of adults, by allowing them to consent or decline to consent for healthcare procedures. Beneficence is doing good, nonmaleficence is not doing harm. And these are priorities that do not always all indicate the same decision is preferable. So, when I introduced autonomy, I did discuss consent, right? So, again, respect for persons includes respect for their decision making, and true respect for decisions includes respect for disagreement, right? You know, one of my bioethics professors always used to laugh, the only time that anybody ever comes to the Hospital Ethics Committee is when the patient won't do what the doctors want, right? But really, if you're willing to respect their decision to agree with you, you ought to respect their decision to disagree with you. But, again, that comes with some caveats. Consent, and by analogy refusal, ought to be informed. So, whoever is doing the agreeing or the disagreeing needs to be adequately informed needs to be adequately informed to make that decision. They've got to be able to, at least to some degree, weigh the risks, benefits, and alternatives of the choices they're making. And that weighing can certainly, and frankly should be done with guidance and input from experts, whether that's genetic counselors or medical geneticists, depending on the setting. But, again, the goal of the consent process is to facilitate the autonomy of the individual. Minors, in general, are incapable of such judgments and are unable to consent, and if you can't consent, you can't refuse to consent for your care. You know, and vignette A sort of classically demonstrates this. A six-year-old cannot meaningfully consent to almost anything, and certainly within a legalistic healthcare framework, they can't consent to anything. This is why you have a parent or guardian show up to your doctor's appointment. But the boy in vignette B is actually a lot more thoughtful about his preferences, and so while he still certainly legally can't consent, and many moral philosophers would say that even from an ethical perspective, what he's doing or not doing isn't consent or refusal of consent, clearly there is a difference in the thoughtfulness of the refusal that is expressed by the two individuals. And before I get into that distinction from the child's perspective, which I think is really important, I'll just point out that the parents, what they're really doing is providing permission for the plan of care to occur to the child, because they're acting as representatives of their minor child's best interests. And in practice, the courts, at least in the U.S., will seldom overrule parental refusal of care except to avoid imminent and significant harm. I think the sort of prototypical American example is blood transfusion perioperatively or in life-saving circumstances for Jehovah's Witnesses, right? And I think that we would all be hard-pressed to liken the benefits of genetic testing in the scenarios I've presented as preventing harm in any analogous way to that scenario. What the minor is doing, or what the clinician is trying to elicit from the minor, is asset and the American Academy of Pediatrics, because assent is largely a pediatric concept, has a lot to say about this. But the goals of assent are to help the patient to achieve a developmentally appropriate awareness of their diagnosis or problem. And developmentally appropriate, yes, age correlates with development, but for many pediatric genetics providers in particular, a suspected underlying genetic diagnosis may also impact their developmental level. We ought to be telling the patients what they can expect with tests or treatments. We should assess the patient's understanding of the situations and factors that influence the response. And this is a key distinction between the Boyne vignette A and vignette B again. And then finally, solicit an expression of willingness to accept the plan. And this is detailed much more in the AP statement here that was recently reaffirmed. But anybody who's actually been in the room for these conversations knows that this is a lot more complex. And this is unsettled in the literature. And I think there's a spectrum of perspectives. Is assent mere acquiescence? Is it consent without legal weight as an opposite extreme? I think an important way for bedside clinicians to think about this is that the role of consent is actually to secure well-being of the child, or permission will secure the well-being of the child. The role of assent is to respect the child's expressed preferences to the extent that is appropriate or possible. So should you always seek assent when developmentally appropriate, especially if you don't plan to honor their refusal? Delisting a preference that you fail to honor is morally injurious to anybody. And if you're going to do that, then you ought to also be prepared to apologize, express your regret, and explain in developmentally appropriate languages why you can't do what the child wants to do. Alternatively, should you only seek assent if you will honor the no? Well, then you fail to elicit developmentally appropriate preferences, which is itself is also morally injurious. And it is not clear which of these approaches is superior, despite the AAP's endorsement of the former strategy. And then finally, there are practical questions. And then finally, there are pragmatic considerations. The boy in vignette B is 14 years old. If he really wants to fight testing, so not just what he does and doesn't want from the secondary findings, for example, but even going to the lab, how far are the adults in this child's life really willing to go to coerce the testing? Physical or pharmacologic restraint is harmful. And you got to ask yourself if the juice is worth the squeeze, as it were. And similarly, if the child can physically get there, lying to get the child there is also probably not an appropriate technique here. Because technically, if there's a consent form, um, you could falsify it and have the child sign the assent line if your lab has one, and then have the parents separately sign for secondary findings against the child's will. But that seems like a really, really bad idea. Um, I just made the solution to the problem easy in vignette B, right? Honoring the child's concerns by not requesting secondary findings seems like an easy compromise with the child. But you can make things more complicated should his parents take his concerns into account when deciding if they want to know their secondary findings. Because if they know and they have something, even if the child didn't look, child can probably, may be able to rub two brain cells together and do the math on what 50-50 means, right? Um, and also conversely, if the child wants to know the secondary findings, but the parents don't, they may or may not choose to honor his wish. But know that if he's 14, when he's 18, presumably assuming he has the capacity to consent for himself, he can go back and find this out anyway in four years. And you sort of have to work out again, is the conflict worth it? Again, as introduced, more questions than answers, per se. But these are the considerations when the wishes of parents and children conflict in many pediatric settings. So we'll keep that in mind and hand over to our next speaker to preserve time for questions at the end. Sorry, while controlling the slide, I did not have the ability to unmute. Let me get control back. There we go. My case focuses on privacy and confidentiality in a genetics evaluation. In this case, we have a woman who comes to clinic. She's a 48-year-old mother seen in the genetics clinic due to her recent diagnosis of breast cancer. She is found to have a pathogenic variant in the BRCA1 gene and counseled accordingly. Later, her 25-year-old daughter comes to the genetics clinic. She's being seen for her concerns related to the possibility that she may have hypermobility type EDS. During that visit, the daughter remarks to that she and her mother are estranged, but that she saw on a Facebook post that her mother had been seen in this genetics clinic, had a great experience, and the patient has made comments that let you know she's assuming mom was also seen for evaluation due to HEDS. When you're taking the family history, the patient reports a history of gynecologic cancer in her maternal grandmother. She doesn't know if it was ovarian cancer versus some other gynecologic cancer. She also thinks that there are other cancers in the family, but she lacks details, and at no point does she mention mom's history of breast cancer that you're aware of from mom's visit. You discuss with the patient the option of doing a broad cancer panel. Given she does have this cancer risk, has some limited details, but the patient declines. She explains that right now her priority is dealing with getting her EDS symptoms under control before she decides to explore what she sees as a really distant cancer risk. So here's what we know. We know that mom has a BRCA1 pathogenic variant. We understand that if mom has this pathogenic variant, then the daughter has a 50% chance to have the variant as well, and we know about the cancer risk that would go along with her having that pathogenic variant. We also know that guidelines tell us that individuals with a BRCA1 pathogenic variant should begin breast MRI screening at 25 to 29 years of age, so that the daughter's at the early end of this, and that we should consider risk-reducing salpingo-oophorectomy in individuals with a BRCA1 pathogenic variant between about 35 to 40 years of age. This might not impact the patient today, but knowledge of the result could influence her family planning for the future. On the other hand, we know that the U.S. Preventative Services Task Force recommends that all women, so we're talking about general population, average risk individuals, get screened for breast cancer every other year starting at age 40. And so a couple of things to consider. We know that the recommendations for surveillance differ for those individuals at average risk as compared to those with a BRCA1 pathogenic variant. When we're thinking about whether a course of action is ethical, one of the things we consider are the possible consequences. So if we think about the consequences of not doing testing for the daughter or her not knowing her risk, well, if she actually doesn't have the BRCA1 pathogenic variant and we just don't know it, course of action wouldn't have been different. The general population surveillance would have been appropriate for her, so presumably no harm. Now, if she carries the BRCA1 variant, but we don't test her, we don't know it, maybe she goes on to develop cancer that we could have detected earlier with increased surveillance, then we have some risk for harm. Another thing to consider is the expectation of confidentiality in patient privacy. When patients come to their healthcare provider, there is some expectation that their information will be held private. Patients could potentially become reluctant to proceed with genetic testing if they don't have the confidence that healthcare providers will keep their information private and secure. There can also be some legal ramifications for sharing your patient's information. I went to the Department of Health and Human Services website and on that website, it says, a person who knowingly obtains and discloses individually identifiable health information in violation of the privacy rule may face criminal penalty of up to $50,000 and up to one year of imprisonment. Now, I'm sitting in the state of Texas, so I also looked at the Texas website regarding HIPAA privacy training and found that similarly, there are civil and criminal penalties that can apply if one violates health privacy rules. Similarly, depending upon your institution, most institutions, if not all, are going to have rules regarding violation of patient privacy and confidentiality. So what information is actually protected under HIPAA? HIPAA protects information related to an individual's medical conditions, treatment, and payment. And when I refer to protected health information and identifiers, I'm talking about any information that could be used to identify the patient. There are some exceptions though to HIPAA and one that's relevant in this case is that we're told that when necessary to prevent or lessen a serious and imminent threat to the health or safety of a person or the public, a disclosure can be made. So one question that comes up, which I'll come back to later, is does a person's genetic test result indicate a serious and imminent threat to their family members? All right. So one part of that is that we do know that identifiable genetic information is considered to be part of the information that's protected by the privacy rule. Now switching gears just a little bit, there's another exception that we can think about in terms of disclosure of health information. And that is that we, as healthcare professionals, can have information be disclosed when it's being shared for treatment purposes. So for example, you might imagine when you are sending a referral for your patient to a specialist, you're disclosing some information with that. But usually that disclosure is specific to the care of your patient. The question becomes, what about when you're disclosing information or considering disclosing information for the care of a family member? So I found this article that speaks directly to that question. What guidance does HIPAA give us regarding disclosure for the purpose of familial risk notification or cascade genetic testing? And quoting from this article, the authors say, in final rules regarding HIPAA regulations and an accompanying FAQ, the U.S. Department of Health and Human Services and its Office of Civil Rights has interpreted this to apply also to the treatment of another individual, such as family members, and that the rule permits, but does not require such disclosure. Permits, but does not require. I think that this really leads to even more questions. So if it permits, but doesn't require, then what obligation do we as healthcare professionals have to warn family members? And do we still have a risk if we do disclose genetic PHI? So I decided to go directly to the source. I went to that FAQ document from Health and Human Services to see what do they say about disclosing information for the treatment of a family member. Again, they reiterate pretty clearly that the rule does permit a doctor to disclose protected health information about a patient for the care of a family member, and that we can do so without the first individual's written authorization with the exception of disclosure of psychotherapy notes that we cannot do. And again, that it permits, but doesn't require. There's also one exception, and that's that individuals do have the right to request additional restrictions on their information. So someone could say on their record, I specifically do not want you to share this information with my daughter, son, spouse, whomever. All right. So that's what Health and Human Services had to say about the topic. I also found this article in Cold Spring Harbor Perspectives in Medicine, and they offer what these authors see as the ethical consensus about this topic. They say because genetic information can have significant value to family members, healthcare professionals should inform patients about the ethical relevance to their genetic information to family members, and encourage the patient to disclose such information to their relatives. They also share with us two cases that are relevant to this question. The first is the case of Safer versus Estate of Pack. In this case, back in the 1950s, Dr. Pack treats a patient for retroperitoneal cancer. Unfortunately, this patient passes away, and then 30 years later, his daughter is diagnosed with colorectal cancer. She then goes on to sue Dr. Pack's estate for failing to warn her that her father's condition was heritable. The court rules that a duty was owed to the patient's immediate family to warn them of what they see as an invertible risk from genetic causes. Unlike the next case that I'm gonna talk about, the court did not limit the scope of duty to informing the patient of the familial risk. They were actually saying that we did have a duty, or the provider did have a duty to warn the family members. Now, in the next case, we have a mother with medullary thyroid cancer. Back in 1987, her physician failed to inform her that the condition was an autosomal dominant condition. Her daughter is later diagnosed with medullary thyroid cancer, and in 1995, the Florida Supreme Court ruled that the physicians owed a duty of care to identify third parties in the zone of foreseeable risk, essentially that physicians should warn patients about the heritability of conditions, but they say that the duty to warn relatives is satisfied by warning the patient, and they go on to explain that requiring a physician to seek out and warn the patient's family would often be difficult or impractical, would place too heavy of a burden on the physician, and would conflict with obligations to protect privacy. So, all of this raises a lot of questions. Is the duty to warn fulfilled by informing the patient about the risks to their family members, as the Pate case suggests, or must a healthcare professional sometimes warn a relative directly, despite the potential confidentiality conflict as suggested by the Safer case? If the latter is true, then how could the genetics profession the genetics professional, who's already stretched thin, allow for this? How would the logistics or practicalities work when maybe we don't have contact information or even know who all of those relatives may be that are at risk? And how could this ultimately impact our field or limit our workforce? So, as we think through what we might do in a similar situation, there are some questions that a genetics professional can ask themselves. One group of questions really has to do with the risk. So, do we believe that the patient's genetic test result is a serious and imminent threat to their relatives? Do we think that if it is, that disclosure of that information would be necessary to prevent or limit that threat? And if it does, then would the relative reasonably be able to lessen that threat? Could they take steps to lower their risk? So, how can we be sure the threat is imminent? Well, if the risk to inherit a condition is 50%, is that risk really imminent? If the condition isn't 100% penetrant, would we consider the risk to be imminent? And is it imminent if the threat may occur sometime in the future, but we really don't know when? Another question that a genetics professional can ask themselves is, is this disclosure something that would be consistent with applicable law and standards of ethical context? So, for example, what the genetics professional societies have to say on the matter. Well, in terms of law, one thing to consider is that HIPAA's regulatory language doesn't preempt state laws. So, HIPAA may tell us that we're permitted, but not required, but state laws might actually be more stringent and might have more protection against disclosure. So, you should know your state's laws before making any disclosure. Also, with regards to applicable standards, the importance of protection of patient confidentiality is reinforced by many professional societies. Two that I have here, the National Society of Genetic Counselors Code of Ethic does not support disclosure of genetic information to at-risk biological relatives. The American Society of Human Genetics does say that genetics professionals may disclose, but are not required to. And they also give us some very specific situations in which the genetics providers may disclose information. Those are when attempts to encourage the patient to disclose have already failed, when the harm is likely, serious, and foreseeable, and when the at-risk relatives are identifiable, and when we believe that there is some method of prevention or lowering of risk that can be done by monitoring or by treatment. With this particular case, another thing to consider is the individual's right not to know. Our patient, the 25-year-old, has already clearly expressed to the provider that her priority is managing her symptoms related to EDS, that she wants to put the cancer risk on the back burner. Now, we may feel that we have more information than she does in making that decision, but when we think about the right not to know, we're talking about the idea that an adult should be permitted to control whether they receive genetic information and that their preference should be respected. Two different ethical principles really feed into this, and that's the respect for patient autonomy, which you heard about with the last case, as well as that idea of protection from harm, in this case, the harm of receiving unwanted and potentially distressing information. So, some ways that we could deal with the ethical conflict in this case would be thorough and possibly repeated counseling of the mother regarding the risk to her family members and potential implications, maybe even offering some tools like family letters so that it can enable her to share this information with her daughter, even if they don't have reestablishment of some connection. Another option can be counseling the daughter regarding risk related to her unknown cancer history and what is known about her cancer history about the grandma, and the availability of genetic testing to help address that risk. You can kind of develop a management plan for her current EDS concerns so that she can then move on to secondary concerns for her, like the family history of cancer. You can also identify other sources of support to help the patient with her current priorities. And then another thing to consider as a possible step for conflict mitigation in this case would be increased population genetic testing. Would that have lessened the chance that this would have been an ethical consideration in the first place? Like the last case, I think I've left with more questions than answers. That's often the case in ethical dilemmas, but I will now turn you over to Dr. Fullerton. All right, thank you so much, Tanya. And yes, I am here to present our third and final case as part of this session, a case that is going to focus on beneficence and how we should think about ethical considerations when we are working with the management of unexpected or uncertain genetic information. Just make sure that I'm getting this right. Just make sure I can, there we go. So let's return to the case example that Professor Eble just presented to us. And now, rather than having that 25-year-old daughter who's interested in managing her symptoms of HEDS, basically say no to a more comprehensive cancer panel, let's say she's an information seeker and she does agree to undergo a broad cancer panel, which will give her information related to her current symptoms, but also about possible other unknown risks. Of course, I think as we are aware and given the specifics of the case that we just heard, the results come back and suddenly she finds, well, first off, she hears that she has no findings that are directly related to any of her current symptoms. And so therefore, none of the genetic test information is helpful to her in the context of her symptom management. But also of course, the comprehensive cancer panel does uncover the pathogenic variant in the BRCA1 gene, suggesting that she is at really rather enhanced risk for developing hereditary breast cancer over the course of her life. She, and I imagine many patients, but she in this case example is actually super unhappy that the genetic testing is not giving her any help where she needs it the most with her current symptoms. And actually, because she was someone who wanted to preserve her right not to know and because she did not understand that her mother had a hereditary predisposition to breast cancer that she possibly inherited, she possibly inherited really distressed at receiving this unanticipated secondary information about her very high risk for breast cancer. So just as in the two previous conversations, two previous presentations, there's a number of salient issues that we can stop to consider. Whoops. All right. So I think it's probably many people who are joining the educational session today are aware multi-gene test panels are now commonly ordered in many specialty settings to inform diagnosis and our treatment decisions. So this is not an unusual example. This is probably what's the case in many practices and also increasingly more common that whole genome and whole exome sequencing is being pursued. These tests have the advantage that they can allow for comprehensive screening of many high-sufficient genes at the same time in a cost-efficient and time-efficient manner. And they can get information to clinicians, practicing clinicians quickly and often more quickly than sequential testing. But these kinds of tests alongside other kinds of whole genome approaches also bring along the complication, as we see in this case example, of identifying more potentially disease-linked variants than those related, including the identification of secondary findings, which now many clinical laboratories look for as a matter of course, the identification of other kinds of unanticipated or uncertain information that can be identified during testing. And also, of course, particularly with large gene panels, variants of uncertain significance, which can be reclassified after initial test report and therefore need to be taken account of, managed, and as they become reclassified, information shared with providers and patients. So there's a number of salient concerns. Sorry. All right. And patients who do not understand the potential for receiving such findings or unaware of this possibility of reclassification may be caught unawares and end up harmed or certainly, if not directly harmed, very unhappy with the outcome. So what I'd like to do in the rest of my presentation today is to take a few minutes to explore the ethical dimensions of these considerations in a little bit more detail and with reference to some literature. So first, with regard to reporting findings unrelated to the primary referral, I think as many of us are aware, routine identification of select pathogenic and likely pathogenic secondary findings, which encompass expert-agreed gene-phenotype pairs, have been actively encouraged by the ACMG and is now pursued in the course of much clinical exome and genome-scale sequencing under a primary ethical rationale of beneficence. In other words, we believe that it is important for people who may not be aware of their family history, who might be estranged from family members, who are receiving pathogenic results, and for other reasons, for people to become aware of this information, particularly when there is some way to act on it to reduce their lifetime disease risk. However, to maximize autonomy, ideally, and this has been acknowledged alongside the recommendation to look for these secondary findings, to maximize autonomy, patients ideally would be explicitly asked about their willingness to receive such results during the informed consent process. And we heard examples about this in both of the other case vignettes had been discussed. These are not, of course, the only kind of unexpected findings that can result from genetic testing, which can include results such as evidence of misattributed or non-paternity, as well as unreported or unacknowledged consanguinity. And in these cases, here the ethical principle of avoiding harm or non-maleficence often leads to these kinds of results being selectively or actively withheld, or certainly downplayed in the course of the clinical encounter. And different providers and health care systems approach these concerns in different ways. Similarly, uncertain test results, which we often refer to as variants of uncertain clinical significance, or VUS, are a ubiquitous feature of most genome scale genetic tests, largely owing to the fact that our ability to interrogate and identify genetic variation has outpaced our ability to predict the clinical consequences of such variants, particularly in less well-investigated candidate genes. So while most clinicians, and the conundrum here is that while most clinicians trained in medical genetics and genetic counseling understand that VUS is such variants where we do not understand exactly what the relationship to disease is, they're inherently uncertain, and therefore that they should not be acted on until they are confirmed as either pathogenic or benign, many non-genetics providers' understandings, as well as patients' understandings, are more limited. And so it's partly for this reason that our recent points to consider, article led by Ream and colleagues, have recommended that clinical labs limit the return of such information. And there has been a number of considerations, including this review, which came out several years ago by Burke and colleagues, which demonstrate, so there's beginning to be empirical evidence, that VUSs, even where we understand they should not be acted on, still ring a bell that it's very hard to unring and complicate clinical decision making, and can result in patients wanting to be more proactive, even when the evidence of disease risk is uncertain, and can so directly and indirectly lead to patient harms. So we have to be very, very careful with conveying such information in the context of a clinical encounter. Finally, the potential for variant reclassification, which I think we're very familiar with, is genomic knowledge accrues, either by downgrading a pathogenic or likely pathogenic variant, downgrading a pathogenic or likely pathogenic variant of VUS or benign status, or vice versa, is a very real concern, and one that poses a variety of ethical and legal conundrums for many practitioners. While the ACMG regard patient recontact in the wake of a reclassified test finding as a shared responsibility, in other words, that the patient provider and clinical lab all bear some shared responsibility for revisiting test findings on a regular basis, in practice, these responsibilities can often become confused or neglected. For this reason, policymakers have put weight on the informed consent process, and authors such as Kilbride, reference shown here, have advocated for direct, personalized communication in the face of reclassification, rather than sort of automated messaging that might be overlooked by both providers and patients. And what happens in all of this, many of these recommendations, there is an emphasis on patient autonomy. There is an emphasis on informed consent. And addressing these concerns in the context of the informed consent process makes fundamental. And nevertheless, it sits uneasily alongside practice trends in which many more non-genetic trained specialists are using genetic testing in their clinical care, and may be unfamiliar with or uncomfortable with common aspects of pretest counseling, and so give it short shrift. And partly as a consequence, pretest genetic counseling is, in many sectors, going away. It might be skipped or given short shrift with implications for patient autonomy. And in those cases, it becomes increasingly important to ensure that if a genetic test is ordered, that referral to genetic counseling is also the need for that. So that when results come back, post-test counseling can occur in a timely fashion, rather than having potentially disruptive or extremely clinically salient results that were unanticipated kind of land on the patient without adequate post-test counseling. So there are various ways in which we could begin to address the potential ethical concerns that I've just scratched the surface of here in my brief presentation. Certainly ensuring the adequacy of pretest counseling and access to medical geneticists and genetic counseling, irrespective of who is wanting to have the test ordered, is super important, including allowing patients the opportunity to proactively decline the receipt of secondary findings or other kinds of unexpected information that they might not wish to receive. And then if patients still want to receive that kind of information, carefully managing return of unexpected findings to minimize or avoid potential adverse impacts on the family, and particularly not withholding information that has explicitly been requested. A second set of things that we can do, and already we're beginning to see recommendations in this regard, is minimizing wherever possible the return of uncertain information, and being very, very explicit and clearly specifying who will be responsible for monitoring for reclassification updates and on what timeline. If it's the patient's responsibility, the patient needs to know that. If they're going to hear back on a regular time interval, helping them to understand that that's going to be the case and be aware and looking for potential reclassified variants can be an important conversation to have with one's patients. And then finally, prioritizing. As I suggested in that last slide, post-test counseling for patients who did not adequately receive pre-test counseling in advance of testing, perhaps on account of clinical urgency, would be a very good way to proceed. So all of these ethical considerations are weighty but potentially manageable, both by changes in practice standards, many of which have already begun to be discussed widely in the field, as well as a bit of good sort of communication between clinical teams and upfront planning. And that concludes my presentation for today. So I will hand us back to Tanya, who I believe will be moderating the rest of our panel. And just to acknowledge other members of the ACMG ELSI Committee, formerly the CELI Committee, as well as Jamie Lopez and Mahmoud Arabi, who were very, very helpful with us as we designed the content of this session. Thank you so much, Dr. Fullerton. All right, we do have a few questions in the chat, and I encourage you all to continue adding your questions if you have any. We have a few moments here. Our first question is regarding newborn screening. So we're asked, in newborn screening, benign hemoglobinopathy carrier status is sometimes reported on neonates. They give the example of hemoglobin D trait. They say, should the newborn screening lab report this? And they ask that we consider that pre-test counseling for newborn screening might not be very sophisticated compared to other genetic testing, and that some families do not know what the primary conditions are, let alone the incidental findings. So great question. I don't know, Mimol, if you have any thoughts on this issue. I mean, I could say a few things. I'm very much hoping that my esteemed colleague from Seattle would bail me out here. You know, as luck would have it, I just heard a wonderful presentation on newborn screening policy just yesterday by my colleague from Case Western, Aaron Goldenberg. And so it's just, it's in fact reporting relatively benign information in the context of newborn screening is generally discouraged. What we support in newborn screening are the identification of congenital biochemical anomalies that we can actually, that are important to intervene on in the newborn period. So that would not be good information. And then in terms of pre-test counseling, generally that does not happen at all. Parents are lucky to be notified that newborn screening is happening at all, and newborn screening is generally happening as a compulsory manner. Although, of course, policies vary from state to state with the ability of some parents to opt out for religious or philosophical reasons. So yeah, this definitely would not be the common class of information to return. And I think that a lot of our kind of conventional wisdom at newborn screening would argue against returning that kind of information. All right, another attendee asks us, as a remote employee who provides direct patient care, would the applicable state law regarding disclosure be for the state that she resides in, the state where the patient is located, or the state where their company is headquartered? I haven't seen this question specifically before, but I do know that a person can only provide care in the state where they're licensed. So obviously you're licensed in that state where your patient is located, and you're following the laws of that state, wherever it may be. And so my sense, and please, if my colleagues here want to jump in to contradict me, my sense is that it would be the state where your patient is located. However, I want to add very strongly that your company likely has a risk management department or a legal department. When in doubt, always go to them. Always go to them. They can be huge assets and resources for you. If there's a question of whether this is legal, I would just rather be safe than sorry and ask that question of them. Any other comments on that one before we move on? I agree with the suggestion to go to risk management, yeah. All right. Another question, and I'm not sure if I 100% understand the context of this one. It came to us during our last case. Are who are the stakeholders of genetic testing who will request, who sees the results, and who talks to the patients and their families? Yes. I mean, this is some of what is making things so complicated now. It used to be that this was all very neat and tidily in the purview of medical genetics, who were the ones doing the pretest counseling, ordering the test, ensuring the patient received the test information in a timely manner, and providing post-test counseling. Increasingly, that is not the case. Many, many specialties are using genetic testing, ordering genetic testing to inform care, and treating, you know, and we in the genetics community have argued against treating genetic information as exceptional. So treating genetic testing as just another form of a kind of diagnostic information to inform treatment decision-making, not fully engaging with the disruptions that can result, particularly when information that is unexpected is returned. So I think there is a broad class of stakeholders and getting teams, having a healthcare system be aware of everyone who's ordering genetic testing, and I'm aware of some healthcare systems where they have laboratory-based genetic counselors who help to refine genetic test orders, would be the way to go in many cases. That's my two cents. I will say that even practicing in a center that is exceptionally well-resourced in this regard, I happen to be the on-service geneticist at my center this week, and I had a nurse practitioner stop me in the hall to describe a patient in one of our ICUs, and said, neurology's thought that we should get a microarray, and so I asked them if they were gonna provide the pretest counseling for that, because she had literally been to one of my talks for seeing me within our center, and she was like, yeah, the neurologist has said, oh no, the primary service takes care of that, and she was like, I don't think most of our neonatologists are routinely providing that service. I was like, I think you're right. Let's have a talk about this and figure out, one, if that's actually appropriate, test selection, and then once we come up with a plan, who's gonna provide the counseling, right? But this is, and it's a fine line, because you don't want medical geneticists to be the gatekeepers of all access to genomic medicine, because I think that way, then you run into beneficence problems. So there literally are not enough of medical geneticists or genetic counselors to be the only people who provide ethically sound pretest counseling if we're actually gonna deliver on the promise of genomic medicine. Thank you. All right, our next question just brings so many questions to my mind as I read it. It's, can you speak to the privacy concerns patients have when they do not want to have their genetic counseling or testing results in the electronic medical records and the requirements of the provider to document? This presents some real challenges, and I wonder, I mean, we think a lot about the patients. I also have to think about the legitimate self-interest of the providers. If you don't document, you know what they say, if you didn't document it, it didn't happen. I mean, that's not always the case, but how do you prove that you counseled your patient appropriately if there's no documentation of the same? If you want to make recommendations for a particular surveillance or management, how would you justify to an insurance company coverage of the same if there's no documented reason that the patient needs that screening or that management? I can see where a patient might be concerned, but we also have to think about, you know, what exactly is being limited? If we have to enter the order just to get the blood drawn, but then we're not entering other parts of the documentation, is it in there somewhere where whatever entity that they want to keep this from would still see something to let them know that there's a piece of the puzzle missing? Those are some of the initial thoughts that come to my mind reading this question. Yeah, I get this a lot actually in my regular practice and this is kind of weaselly, but in the overwhelming majority of these cases, understanding the motivation and the concern, because not all privacy concerns are equal, right? Or at least not identical. They are all, almost all of them are morally equal, but they are not factually equal. And in my experience, the vast majority of them, I am able to identify, either provide reassurance that their concern is legitimate, but that the outcome that they fear from the action that I would normally take, like that those two things are not actually causally connected in the way that they were. I would say I'm frequently able to provide that. And then in the small minority of cases where we end up in the situation that Tanya is describing, I think you have to have a frank discussion with the family that I also have professional obligations for these things. And that if I can't do the thing afterwards, then I also can, then I can't arrange the testing potentially. There are some things that are necessarily connected and that's what good counseling ought to be about is an understanding that doing the first thing necessitates the second thing, if they are in fact mandatory. Thank you. Just to say, I completely agree, yeah. And I guess at some point during that counseling, we would probably also talk about GINA and the protections that patients have. Potentially that might also lessen some of their concerns. Yeah, although I will sound a dissenting note here is that any legislation that is passed can be overturned. And I know I've begun to hear rumblings of concerns about GINA being possibly overturned. I mean, so I would be keen to have reassurance because there are no guarantees, of course. But I think the bigger issue, which is your clinical care will be impacted if this information does not travel with you in your electronic health record, I think is the important one to convey. Thank you. Well, on that note, we are at two o'clock, so I will turn this back over to our ASA team. Thank you everyone for attending today.

Ethical Principles

Geneticists

Medical Genetics

Bioethics

Informed Consent

Genetic Testing

Patient Confidentiality

Secondary Findings

Genetic Counseling

HIPAA Regulations