MIRA KEDDIS: Good afternoon. Welcome to our Grand Rounds. My name is Mira Keddis, and I'm the Center for Individualized Medicine Education Director. Really excited to join you here on the Florida campus and to introduce our speaker today. As a reminder, our lecture series is designed to highlight two main objectives, showcase the latest in scientific discovery and innovation and demonstrate how individualized medicine can be translated into practice to meet current and future patient needs.

It's my absolute pleasure to introduce today's presenter, Dr. Megan Allyse. Dr. Allyse is an Associate Professor of Biomedical Ethics in the Biomedical Ethics Research Program, and she's also an Associate Consultant in Quantitative Health Science with a joint appointment in obstetrics and gynecology. Her research focuses on the translation of emerging medical technology from research endeavors into clinical practice, particular interest around reproductive health, ethics, and women's health and health disparities and access to care.

Her previous research work examined the intersection of assisted reproductive care with embryonic stem cell and human cloning research and management of oocyte exchanges. And more recently, she's developed a portfolio around the clinical translation of innovative, non-invasive prenatal genetic screening, including informed consent, patient education, stigma in the disability community, and understanding the impact of prenatal, genomic information on patient care and the experience of pregnancy.

She's also interested and has great work in the area of providing high-level care regardless of socioeconomic status. And in fact, today's talk will highlight to us how traditional models of clinical translation of genetic therapies have focused on metrics of safety, efficacy, and cost. However, there's wide disparity in the use and benefits of genetic medicine using these metrics. And she'll be proposing to us a fourth metric and showcase how it can be operationalized to increase accessibility to all individuals.

So without further ado, please join me in welcoming Dr. Allyse as she presents on the Translational Justice and Health Disparities Research in Genomics.

MEGAN ALLYSE: Thank you all for coming today. I'm happy to be sharing this new concept that we've been working on developing. I am going to apologize in advance. Whatever respiratory disaster is going around has found me, so I will try not to cough during this presentation, but I make no guarantees. Just to start off, I have no disclosures.

So I want to start off by outlining what we mean by translation. So I think that for some of us, translational medicine is sort of a given thing that we all do, but not necessarily everybody.

So when we say translation, we generally mean the process by which we get from something that's been discovered in a bench lab or a wet lab. And that is moved through a series of validation procedures until it becomes clinical medicine, and then it ends up in the patient. So when I say translation during this talk, that's what I'm referring to, is, how do we go from biological or chemical discoveries into things that actually touch patients in the clinic?

So as we all know, especially in this day and age, clinical translation is governed by three principles. Safety, efficacy, and cost-effectiveness. And historically, if you met all of these three criteria through very rigorous clinical trials or other forms of validation measures, you were considered to have the gold standard.

However, if you look at what things look like out in the world, it's not clear that these three principles are doing the work that they say-- we say they're doing, right? So this is a quote from a woman who gave birth during COVID. And she's talking about the fact that because the COVID-19 vaccines, the clinical trials that validated them specifically excluded pregnant and lactating individuals, which is not uncommon from clinical trials.

The result was that a wide variety of pregnant women that we spoke to during the COVID-19 pandemic were unwilling to become vaccinated because they said there was no safety data available for them. So they didn't know the impact of the vaccine on their pregnancy. Ergo, they declined to get vaccinated.

Now as we later found out, COVID-19 is very dangerous for pregnancy. It has significant impacts on the possibility of preterm birth. And so we should have been vaccinating pregnant women. We should have been making a concerted effort, in fact, to vaccinate pregnant women. But because they were excluded from the trial, we didn't have safety data.

If you look at efficacy, it's not entirely clear what efficacy has come to mean. So if you look on the CDC website, they will say very clearly that many of the therapies that we have available today were not researched in the population that they're actually designed to be used in.

So the vast majority of clinical trials include almost exclusively-- not almost exclusively-- predominantly individuals of European background, and many of them are largely skewed towards a male gender because of the exclusion of reproductive-age women. It should be pointed out that not only are currently pregnant individuals excluded from most trials, most trials will also require some form of birth control for any participant who wants to participate and multiple pregnancy tests. And so that's a disincentive for people-- women of reproductive age to participate in clinical research.

So we have a large body of research that is based in European descent males, but is therefore unknown about its efficacy in other populations. And so this is a woman that spoke with us as one of our trials. And she's a Black woman, and she has had breast cancer.

And one of the things she expressed frustration was that the genetic testing that her family was offered was not specific to Black women, and that there are different mutations in Black women. We know that they have a higher incidence of triple negative breast cancer, for instance. And so if we don't do the research in the population we're trying to help, can we really say that we've met this threshold of efficacy?

And finally, cost-effectiveness. I think cost-effectiveness is measured as willingness to pay per quality adjusted life year or some other standard that you've used. But it's not really clear that this applies, especially in the US system, in which we don't have a centralized payer who's invested in, for instance, preventative health because of future cost savings later down the line. And so the question of cost-effectiveness is actually very contingent on the socio and political setting in which you are trying to implement this standard of care.

So this is a woman. Again, pregnant during COVID. Different cohort. This is a low-income Black and Latina cohort. And the interviewer's asking her how much she would be willing to pay for cell-free DNA testing of the fetus, which tests for Down syndrome, trisomy 13, 18, XY variations.

And she said the most she could pay is $50, and that's only because she gets a Child Tax Credit. That credit, by the way, was COVID-specific, I believe, and so may no longer be available. But it's worth noting that the minimal billable reimbursement for this cfDNA test is $250. So when we say cost-effective, I think we have to ask ourselves, cost-effective in what context, and for whom?

So all of this leads us to question, or at least leads me to question whether safety, efficacy, and cost-effectiveness really add up to the gold standard of translational success that we think they do. And the answer in the US is pretty clearly no, because it becomes pretty clear that safety, efficacy, and cost-effectiveness as a standard are insufficient to help medicine meet its moral obligations.

And in saying that, I am asserting that justice is a moral obligation of medicine. We can have that conversation. But we can see that because our healthcare system demonstrates so many disparities and such wide differences in health status, healthcare access, and morbidity and mortality between different groups, it is clear that the standard of justice is not being met.

So we would like to suggest that rather than only-- and not incentive-- but rather than only safety, efficacy, and cost-effectiveness, we need to attend to some principle of justice when translating genetic technologies or any technology from scientific knowledge into medical care. And so we define translational justice as procedural and outcomes-based attention to how clinical technologies move from bench to bedside in a manner that equitably addresses the values and practical needs of affected stakeholders with attention to the needs of the most morally impacted.

So what we mean by that basically is that when we are conceiving of a translational pathway, starting as early as possible, as far back as when we are making that hypothesis in the lab, all the way through the process to the end of dissemination and evaluation, we need to be thinking about, who is this for? Where is it going to be used? How can it be used best for the most people in that setting?

Rather than getting to the end of the translational pathway, realizing that there are going to be inequalities, and then trying to retroactively address them. Because as we have seen, based on the level of disparities in this country, that's not working.

So I'm going to give you a couple examples of how our group has been operationalizing these kinds of concepts. So the first is in hereditary breast and ovarian cancer. As I've mentioned, there are differences between white and Black populations with hereditary breast and ovarian cancer.

So if you're not familiar with hereditary breast and ovarian cancer, it is a heritable form of several mutations. The one that most people are aware of is BRCA1 and BRCA2. And it relies on what we call cascade screening.

So basically, if we have an affected individual, we test them. It is shown to be a germline mutation. We would then recommend testing all of their first-order relatives because it's possible that they have also inherited the mutation.

If we can do that, if we can catch people before we know that they become symptomatic, we have seen in the literature that pre-diagnostic awareness allows us to begin screening earlier via MRI rather than just mammogram. The earlier we diagnose any form of breast and ovarian cancer, the obviously better our outcomes are. The more likely we are to be able to clear it surgically.

And so HBOC, when we're looking at cost-effectiveness, is estimated to generate 75 fewer mortality cases and 288 adjusted life years per 100,000 women. So from a health systems perspective, from a health perspective, this kind of screening can be highly effective in reducing overall morbidity.

And that is why the NCCN, the National Cancer Collective Network, recommends that we should be testing susceptibility genes in any individual with a blood relative with a known or likely pathogenic variant in a cancer susceptibility gene. And that is why most of us, if not all of us, have been asked to fill out a form like this on the left at some point in our medical journey-- generally, when you're coming to your primary care physician-- of all of the relatives that you have that have ever experienced cancer, and what kind of cancer.

So again, this is-- the sort of principle of cascade screening is that you have an affected individual. You test all of the family members, and all of the family members you find mutations in them that might be suggestive of an increased risk of cancer.

However, we do see that there are, again, significant disparities. Black women with breast and ovarian cancer have lower survival rates. They tend to be diagnosed later in the diagnostic-- or in the disease progress. They experience more delays in treatment.

And they are significantly underrepresented in clinical trials of novel therapies for hereditary breast and ovarian cancer. They are also less likely to receive genetic testing to understand their personal increased or decreased risk of hereditary cancer.

So we were asked by a group called the Coalition of Blacks Against Breast Cancer, which is founded by Dr. Michelle Halyard and Marion Kelly out of the Mayo Arizona site. And we put together, with some funding from the Breast Cancer SPORE at Mayo Clinic Cancer Center, to put together the ADVANCE Study. And basically, the goal of the ADVANCE Study was to understand if there are barriers to genetic testing among Black women with personal history or family history of breast and ovarian cancer, and how those barriers might be overcome.

So I'm just going to give you some stats from it. This is the cohort that was eventually recruited. We did have a first cohort, which was recruited largely through the Divine 9 and traditionally Black sororities. The second cohort was recruited in a general population Medicaid clinic, so a much lower socioeconomic status and income level.

So here are some of the things that we learned. We learned that in these communities, there is a significant taboo about discussing health information, and especially cancer. So this is an individual who was eventually diagnosed with cancer at 55. So obviously was at significant increased risk.

She's talking about the fact that she didn't even know that she had a family history of breast cancer until she got cancer and disclosed that to her family. And then they responded to say, oh, yes, your relatives have also had cancer.

So this obviously raises a problem because if you're not discussing family history, then that form that you filled out in the doctor's office is not very helpful to anybody because you don't know that you do actually have a first-degree relative who has had cancer. And this is another quote from an individual in the second cohort, just talking about how her family never shared medical history, and that the attitude was very much one of don't ask, don't tell.

When we asked about perceptions of genetic testing, this is a woman who has a daughter, an aunt, and a mother with breast cancer at age 42. She thought-- when you say genetic testing, she thought about Angelina Jolie, which is a very high-profile case, obviously.

And then she said, I thought about it as a celebrity thing, not something that somebody like me would get. I never hear about Black women who've had genetic testing. And she said, I'm the only Black person I know who has had genetic testing.

And then finally, we had asked them about their knowledge of genetic testing for HBOC and whether they would be willing to do it. And in fact, we heard that most of the participants we spoke with, once it was introduced as a blood test, not as a particularly invasive test, said that they actually would be very likely to accept genetic testing if it was offered to them, and that they didn't see any significant barrier to doing that.

And so what we learned from all of this was I think there was this qualitative research, which is not hypothesis-driven. But if you looked at the general zeitgeist in the literature, there was a lot of literature about trust. Black people don't trust genetics. They don't want genetic testing because they don't trust.

And what we found was actually not that. What we found that the reason-- the most likely reason that we were seeing a lack of uptake of genetic testing was a lack of knowledge of family history, which meant that they didn't know they were eligible for genetic testing. And also, just not being offered it. We had several women say, nobody's ever asked me if I wanted genetic testing.

So this is really when we think about, how do we focus on the translational justice of hereditary breast and ovarian cancer, we are seeing a disparity. It's not the cause by what we thought it was caused by. It's caused by something else. And so when we look at intervening, we are trying to target what our qualitative research tells us is the actual, appropriate target here, which is knowledge of family history, and not necessarily comfort with genetic testing or awareness of genetic testing or heredity.

So this is a trial that we submitted to NCI. It has not been funded at the moment. But it's basically a two-part intervention, one which is an awareness campaign to help families understand that the more conversations they have about history, the more conversations they have about the possibility of somebody inheriting cancer, that there are concrete health benefits to that.

And one of the things we did hear from a lot of women, especially older women, was that they do experience that taboo, that reluctance to talk about cancer. And they don't want to be a burden on their family members. We heard that a lot.

There's a paper that just came out this week talking about the paradox of the strong Black woman, which is something that came up a lot in this cohort where they felt like they had to be the strong Black woman and not place their burdens and their problems on family members, unless it was introduced to them that by telling their family members, they might actually help family members, especially younger daughters and granddaughters, that there would be a concrete benefit to them, and that there would be a health benefit to them.

That was very helpful in helping them get over that unwillingness and say, yes, I will talk about my family history of cancer. I will encourage my family member to get genetic testing because it could actually benefit them.

So this is a very complicated tree about the study flow. But really, the point of it is that what the focus is actually on at every step is what we call pathways to care. So genetic information independently cannot do anything, really. It's just data in a computer.

So first, you need genetic information. Then you need interpretation of that genetic information. And then you have something called knowledge. But knowledge is dependent on actionability, right? So you don't get to power until you can actually do something about something.

And this was a problem with a lot of the earlier genetic testing studies that were done where they got to information plus interpretation equals knowledge. So they were testing people, telling them they had, you know, for instance, a gene for hypercholesterolemia, but not taking that extra step to actionability. What can they do about it? How are you actually improving their health? And so that's the important thing about this trial is taking from increasing information, trying to get more people tested, but also having a very concrete pathway to care.

And so you'll see that we wanted to make sure at every stage that if we found somebody who was at increased risk, we did test them. There would always be access to genetic counseling and then into an enhanced breast clinic monitoring so that we weren't giving people information, but not providing them with a way to use that information and concretely benefit their health.

The second example I'm going to talk about is human gene editing. This has been in the news a lot recently with the FDA approval of the latest trial for gene editing in sickle cell disease. We have a current study, which is running now-- it started recruiting at the beginning of the year-- looking at the possibility of gene editing prenatally.

But this is founded on some studies that we've done previously in trisomy 21, which I think everybody is fairly familiar with. There was a trial a few years ago of a pharmaceutical that had shown some early promise in treating or reducing certain signs and symptoms of trisomy 21 in children. And it did go to a clinical trial, and there were a number of children that were enrolled.

And the trial was actually shut down early due to what the researchers said was a lack of efficacy data, that they didn't think that they were finding any improvements. And a lot of parents of children enrolled in the trial were pretty upset by that because they felt that they did actually see signs of efficacy, that they did feel that there were behavioral changes in their children. And furthermore, that they would be more qualified to identify those improvements than whatever proxy measures the study had set up.

So in response to that trial, we made the GIFTD study. And this was a study with caretakers of individuals with Down syndrome. And we offered them five interventions. So one was a prenatal surgery, prenatal gene editing, neonatal surgery, pharmaceutical, or a vaccine for Alzheimer's. If you're not aware, individuals with Down syndrome have a 90-plus percent risk of getting Alzheimer's generally fairly early on in their 50s. And so we'd offered these five interventions. Would you be willing to accept each of these intervention?

So this is just a table of who was in the trial. This was a survey. It was disseminated online. So we had-- more than 500 people responded. And what you can see in this chart is that the blue lines are people who said, yes, I would accept this intervention on behalf of my child.

So pediatric physical intervention. Those are usually cardiac surgeries, neonatal cardiac surgeries. Very, very common. Pretty much everybody said they would do that. You can see strong support for the pediatric cognitive intervention, which would be similar to the pharmaceutical we discussed before. But even fetal surgery, which I think most people see as more invasive and problematic, pretty strong support.

What we were interested in was the fact that when we offered that prenatal gene therapy, not specifically gene editing, but some form of prenatal gene therapy, we got a lot more ambivalence. And we thought that was interesting.

So some of the contents that we talked about is that parents really felt that changing their kids on a genetic level rather than a physical level was especially problematic. It was an extra layer of problematic because it seemed to suggest that their children had a pathology in Down syndrome that they didn't really see as a pathology.

So it was easy to see a cardiac malformation as a pathology. It was easy to see certain facial features. Cleft lip, all of those. But they had struggled to find genetic changes that made their child, quote, unquote, "who they were," that they didn't really feel like they would be comfortable changing that.

So we did another study with parents of individuals of trisomy 13 and 18. And you know, these parents said it would be OK if that was available. I wouldn't object to it. But I wouldn't-- I wouldn't have done it. I wouldn't have chosen it. And in fact, the mother of a living child with trisomy 18, again, says she seems to be happy. I'm not going to change her and change her genetics just because I feel like it or just because I can.

We did another study with congenital and progressive sight loss. And this is an individual who has not had sight. He's not had sight for their entire life. And they're saying, you know, I actually wouldn't make blindness a target of gene editing. I'd be much more excited about breast cancer.

And so I think that it was interesting to us because, in fact, Leber congenital amaurosis is, in fact, one of the interventions that is currently undergoing gene editing trials. But this individual really didn't think that not having sight was a legitimate target, or at least the most important target of gene editing technology, even though it's possible that they themselves might benefit, might receive a therapy that would make them able to see.

So those were the preliminary studies that led to the PASAGE study. So this is an R1 from NHGRI. As I said, currently began recruitment this week.

And basically, we were interested, in much the same way that the GIFTD study is interested, in how communities would react to the prospect of prenatal gene therapies across the family system genetic illness framework. So you can see on the left side, these characteristics. Lethal, penetrant, and early onset. And then over to the right side, not lethal, only a risk factor, and early onset.

I am going to say for our geneticists here, we understand that both autism and deafness are very complex genetically. Our gene editor. We have a CO-I who is an actual scientist who does gene editing.

But he agreed to let us leave that because there is a lot of discussion in the autism community about the possibility of gene editing in much the same way that there have been discussions about previous neurological research, really problematizing the idea of whether autism should be a target of those sort of normalizing influences. And in fact, before we even began formally recruiting for this study, the first people to reach out to us were self-advocates in the autism community, volunteering to participate in this study because they really felt that they had strong things to say.

So this spectrum, basically what we're trying to understand is, where on this spectrum do various communities place themselves in terms of the appropriateness of prenatal gene editing based on the fact that trisomy 21, those families struggled with whether that was acceptable or not? And so we're interested in seeing what everybody else thinks as well.

So sickle cell obviously is now in gene editing trials. SMA is in gene editing trials. There's ongoing research on the rest of these, which is why they were chosen.

And in fact, our colleague who is doing gene editing research, their target is a gene editing technique that targets the liver, and they've just received a very large grant to do preclinical studies of PKU with the goal of entering clinical trials in humans in the next five years. So we added PKU. And then I was in a conversation yesterday about gene editing for osteogenesis imperfecta prenatally, so we may be adding that as well.

So the reason we chose prenatal gene editing is because it's a technology that's on its way. There's definitely a fair amount of, as we say, animal research, bench research that's starting to show that this may be something that's going to work prenatally in humans, but it's not there yet. So like PKU is probably-- and PKU is starting in children. Nobody's really suggesting prenatal yet, but there's a lot of movement around if we can do it pediatrically, would it then not reduce morbidity to do it prenatally?

So this gives us the opportunity to see this translational justice question from more or less the beginning. To say, what if we trace prenatal gene therapies all the way from the beginning of their translation and stayed with them all the way through? And that's the goal, is that we're now writing additional translational justice questions into these additional grants.

So the next grant is about regulatory approval of clinical trials. What are the translational justice questions there? Then we'll do the clinical trials, and hopefully we'll have translational justice elements there.

And so some of the questions that we've started asking all the way back to the beginning about when you're choosing your hypothesis, what about legitimacy? So there's been a controversy recently in achondroplasia where there was a company that developed a pharmaceutical that basically, if children take it fairly early on, it undoes some of the effects of achondroplasia in making people short. So it basically allows them to grow taller.

But there was a lot of actually pushback from the achondroplasia community because they said, look, there are lots of things that we would like you to study in achondroplasia, but being tall wasn't one of them. That's not our problem.

You know, most of the disability that attains to achondroplasia is social because we have a society that is built for people of a certain stature, and that excludes little people. And we can address that socially. We don't need a drug to address that.

So conversations about where the legitimacy of the target is. And again, that's why autism and deafness are on this scale, because there's been a lot of pushback from those communities about pathologizing the lack of hearing or pathologizing different ways of thinking and reasoning in the world. And you know, people saying those are not legitimate targets of gene therapy, and we don't want to see that.

Obviously, any time we talk about these sorts of studies, commercialization comes up. We've had a lot of ups and downs in the commercialization of genetic technologies, going back to BRCA1 and 2, Myriad, the sort of arms race with cystic fibrosis. And so we really want to see if can we conceptualize a different pathway?

The drug for SMA famously costs in excess of $2 to $3 million per child. And while that may make sense if you look at it from a life course model, it's not sustainable. And so are there different translational pathways we can envision that can make these technologies more accessible? I hesitate to just say cost because if you say more expensive, then really, that's just a call for insurance companies or some other payer to step forward and pay for them.

But if you look at the current gene editing trial for sickle cell, it requires basically the equivalent of a bone marrow transplant. So you've got weeks of hospital stays breaking down the immune system. It's a very, very intensive trial to participate in. And there's many, many people with sickle cell who are not going to be able to, A, enroll in the trial, take that much time off work, take their child and stay with them for seven weeks in a hospital. And so we have to look beyond considerations just of cost to, what does access look like?

So again, there was a story recently of a family where they had two children affected by a very rare genetic disease. One is too far developed for therapy, but the younger child is eligible for therapy. There is a genetic therapy. Company is willing to give them the genetic therapy for free, but Medicaid won't pay for the hospital stay. So they can afford it technically, because it's free, but they also don't have access. And so I think when we talk about these kinds of models, we have to look beyond just cost.

There's also questions about scientific approach. So if you look, again, at the example of cystic fibrosis where there were more and more and more mutations identified as being causative of cystic fibrosis, and those were integrated into testing, and then we were basically able to capture a lot of young people with cystic fibrosis, the treatment has improved astronomically. So we now see people living later into life, except for what's called the last 10%.

And these are mutations that we can't find in individuals that we know are affected. And to go back to our earlier question about efficacy, the mutations-- the individuals in that 10% are very largely not European, right? So it surprises not very many people who are in this space that those last 10% of those people who are being left behind by all of the translation that we've already done are from populations that have historically been marginalized.

And so what does it look like to begin this process by saying, we want to find the rare variants? We want to find the variants that are more likely to be found in populations that have been marginalized historically.

And then regulatory uncertainty. So again, the reason, to go back to that question of safety and research in pregnant people, the FDA has made very clear that they will not allow for the inclusion of reproductive-age women in gene editing trials without the standards of extreme double precautions on contraception. And that-- you know, the same question all over again. And how are we ever going to understand prenatal gene therapy if we are excluding gene therapy-- pregnant and lactating individuals from gene therapy trials?

There's also a lot of uncertainty given the legal landscape surrounding the Supreme Court decision in Dobbs versus Texas that, again, enrolling pregnant people in any kind of research is going to become increasingly hard due to things called heartbeat laws.

And so is this translational pathway really kind of blocked from the beginning to address questions in pregnancy? We don't know. That's something that's being developed as we speak. But it's certainly a question of how we're going to end up translating these technologies.

So I just want to take a moment to thank the many, many, many excellent colleagues that we work with on all of the research presented here today, and I'm happy to take questions.

My question is, what can we do about it? What are your strategies to overcome this issue of less communication among family members for cancer, family history, and for gaining trust among Black people for genetic testing?

Well, we have a strategy. It's in a protocol that is currently at the NCI. And that strategy is to really do culturally tailored communication. So there is actually-- Invitae has a little app that they bought from Clear Communication that is an interactive, sort of AI-informed family history mapping app, and that you can get on your phone. And it allows people to get and document family history in this app in the privacy of their own home at leisure where they can talk to their mom or their aunt or their grandmother and be like, oh, did anybody in our family have cancer?

So our strategy was to pair a sort of culturally appropriate communication campaign that features Black women talking to other Black women, that features breast cancer survivors who are Black women talking about the importance of telling your family-- telling your family about your experience. And then everybody in the gynecology practice would also get a link to this little interactive app where they could-- before they come in for their annual exam, they would be able to fill out their family history. And the app actually compares that family history to the NCCN guidelines for sufficient family history to be screened high risk for hereditary cancer.

And then when they-- and that app then sends a message back to the clinic that says, this individual has screened as high risk. When they come in for their gynecology exam, you need to also ask them if they would like genetic testing. And the provider can actually-- the gynecological provider can actually order genetic testing straight from the clinic. And then if the individual tests high risk, they are reflexed to genetic counseling at a high-risk breast clinic.

So that was the plan. It's in partnership with the University of Florida in Jacksonville, which is a very high-volume gynecology practice and sees a very diverse population. And we just need somebody to fund us to see if it works. Thank you for your question.