Clinical genetic testing: State law, cost, and myth-based biology

Dr. Robert Nussbaum: We need to dispel some myths. Myths such as your genes determine your health and there's nothing you can do about it if you have a certain genetic background. And this is not true in the vast majority of cases. We also have to eliminate some of the stigma. There are many cultures where having a genetic disorder in your family stigmatizes that family. Dr. Daniel Kraft: Welcome to Healthy Conversations. I'm Dr. Daniel Kraft, and today we're fortunate to be in healthy conversation with Dr. Robert Nussbaum, who is the Chief Medical Officer at Invitae. Welcome, Robert. Dr. Robert Nussbaum: Pleasure to be here. Thanks for having me. Dr. Daniel Kraft: Before we sort of dive into Invitae, you're still a practicing clinician, volunteer clinical faculty, a professor of medicine at UCSF. Maybe give us a taste of your clinical training and your experience as an academic now transitioning to industry. Dr. Robert Nussbaum: I trained in internal medicine at Barnes Hospital, Washington University, and then fellowship specialty training in medical genetics at Baylor in Houston. And then after that I'd been a assistant professor through to full professor at University of Pennsylvania, as well as an investigator in the Howard Hughes Medical Institute. And from there I went to NIH in the newly formed intramural program of the National Human Genome Research Institute and spent 13 years there. And then after that went to UCSF where I'd been on the faculty as a professor and Head of Division of Genomic Medicine for about nine years and then left to go to Invitae. Dr. Daniel Kraft: So you've had an incredible breadth of your career and seen, especially, the field of genetics change dramatically. It sounds like you might've been at the NIH at the time the first sequence and battle to do the first human sequence was en route. Dr. Robert Nussbaum: Yes, I was there the entire time that the Human Genome Project was being launched and run. And then I was there when it was sort of officially closed, not really, since it's still not quite over yet, in 2003. Dr. Daniel Kraft: Small story, I grew up in Silver Spring. I got my start in science at the NIH and later worked there in Building 36 when I was a [inaudible 00:02:19] undergrad. And the lab down the hall was Craig Venter. Dr. Robert Nussbaum: Oh yeah. Dr. Daniel Kraft: And so I met him there in the late eighties before he left to do other things. You've now been catalyzing a lot of the work in bringing genetics to the bedside, to the clinic, to research. Can you help us summarize what Invitae's work is in the genetic health space? Dr. Robert Nussbaum: Sure. Invitae's mission is to bring genetic information to everybody on the planet who could use it for reproductive planning, for having a healthy family, for identifying their own risks for disease, for learning how to manage disorders, for determining susceptibility or sensitivity to certain medications through pharmacogenetics. So it's really runs the gamut, all stages of life broken down, I'd say, into three main areas. Reproductive genetics, the second is diagnosis from infancy through to adulthood of genetic disorders, and then the third is screening, identification of people who are at risk because of their genetic makeup. Dr. Daniel Kraft: How do you differentiate what Invitae does compared to let's say a 23andme or DNA direct? Dr. Robert Nussbaum: It's very, very different. So the direct-to-consumer testing companies, generally you're focusing on non-disease traits. Things like can you curl your tongue or smell asparagus? And also ancestry. In the few areas where the direct-to-consumer companies really are asking questions of medical significance, they're doing so in a very narrow way. So, for example, if you're looking at hereditary breast and ovarian cancer risk, or familial hypercholesterolemia risk, the direct-to-consumer companies are missing between 60 and 95% of all the variants that can occur and can be disease-causing. So it's sort of the difference between proofreading, looking for whether three words are misspelled or actually proofreading an entire chapter, word for word, line by line. That's what we do. Dr. Daniel Kraft: Is that because these other companies are primarily doing SNPs, single nuclide polymorphisms, or is it because Invitae's doing full sequencing of the entire genome? Dr. Robert Nussbaum: It's because we're doing full sequencing of the coding regions of genes, the parts of genes that actually get translated into proteins, plus the flanking regions around them, in depth, with a very sophisticated method for being able to interpret variants. A lot of the changes that one sees in a person's genome, we don't know what they mean. And so you have to have a really powerful system in place to do the best you can using all available information to be able to interpret those variants. That's not something the direct-to-consumer groups do. They basically just look at a few variants where we already know that they are disease-causing and just report on those. Dr. Daniel Kraft: And you're now actually partnering with folks like CVS Health to integrate that into sort of guided genetic health products? Dr. Robert Nussbaum: Yeah. They're focused on identifying people who are personally at risk, or if having a pregnancy, might be at risk for having a child affected with a genetic disorder. Looking for cancer risk, risk for cardiovascular disease, or problems with children inheriting from both parents changes, which in the parents themselves don't really cause any disease, but in a child, if the child gets two copies of an abnormal gene, one from each parent, they can end up with a very serious illness. And unfortunately, most children who are born with these types of disorders, the parents are unaware that they were even at risk. But by doing a carrier screen, they can be warned in advance and therefore can manage the pregnancy in different ways. Dr. Daniel Kraft: So what percentage of the, even the at-risk population, whether it's sickle cells, Tay-Sachs, is getting preconception screening at this point? Dr. Robert Nussbaum: Unfortunately, the vast majority of carrier testing is being done once the mother and the couple has already become pregnant. Because she then goes in to see the obstetrician for a first prenatal visit. We really think that carrier testing should be part of every person's medical care prior to getting pregnant, when they're considering starting a family. You have so many more options to avoid having a child with a serious illness if you get your testing done in advance. Dr. Daniel Kraft: Do you think we'll be at an age pretty soon where everyone's sequenced pre-birth, at birth? Or those of us who are a bit older are going to sort of have our standard one time genome done? And when and how might that integrate into our medical records so it's actionable. Dr. Robert Nussbaum: The obstacles to full genetic data incorporation into medical care is not just the expense. Yes, the cost is there, but it's come down quite far and it's going to continue to come down. I think the obstacles are much more in the area of, first of all, people feeling comfortable with getting that information and wanting it. There's a certain fraction of the population that are early adopters. They love this sort of stuff and will go out and do it. The vast majority of people have some concerns. They're worried about is the information going to be used against them by insurance companies? Increasingly, I can see it year by year that genetic information is being adopted and used at two major stages of life. One is we already have newborn screening for a couple of dozen well-known disorders where there are interventions possible and it's possible to prevent really serious illness. Things like phenylketonuria, where we know with dietary therapy you can prevent irreversible intellectual disability. That is going to expand. And then the second is when people get ill they want to know if there's a genetic basis for the disorder. Are there other members of their family who are at risk? Are their children at risk? And third, increasingly, knowing the genetic basis for the disorder affects management in powerful ways, allows certain medications to be used, and suggests that other medications should not be used. And that is a rapidly growing area. Dr. Daniel Kraft: Has the ethics or the speed of, let's say, sequencing technology and the ability to do that while you're in utero or shortly thereafter exceeding where we are with the sort of the policy and the ethics to help keep that sort of information secure and useful in the medical sense, but not abused? Dr. Robert Nussbaum: People may not be aware of this, but when the Human Genome Project was first launched, 5% of its budget was committed by congressional mandate to ethical, legal, and social issues. And they have been discussed and evaluated very extensively. For example at Invitae, we are a healthcare organization that is covered by the strict HIPAA regulations that every healthcare organization is. Every hospital is affected. So to the extent that any set of data is secure, I mean my IT colleagues keep telling me there is nothing that can't be hacked. Even the NSA can be hacked. But if you put that aside, it is as secure as it possibly can be. Dr. Daniel Kraft: Maybe just summarize some of the safeguards that are out there now and might be needed next. Dr. Robert Nussbaum: The public policy issue around people having to give consent for their information to be used is very solidly grounded and it is a major principle at Invitae that people control their own data. So whatever gets generated, it doesn't get sold or given away to anybody unless the patient understands what it's being used for and agrees to it explicitly. There's a federal law called GINA, or Genetic Information Non-Discrimination Act, which forbids the use of genetic information in employment decisions and in health insurance decisions including setting premiums and that sort of thing. It doesn't cover everybody. For example, it doesn't apply to people in the armed services. It doesn't cover life insurance or disability insurance or long-term care insurance. Now there are state laws that have broadened GINA protections. Florida's passed a state law now that is much more progressive than the federal GINA law. I'm in awe of what they've done. It's fantastic. Dr. Daniel Kraft: Let's stay dystopian for a second now. The fact that sequencing is getting relatively less expensive and the data interpretation is getting better, even if your employer or insurance company, health insurance company, may not be able to leverage that information for premiums, what's the stop, let's say, those of us who are genetic eights or nines from banding together and getting a- self-insuring compared to those who might have a whole set of other risks for dementia or cancer? Is there a potential future where the power of the crowd will drive certain elements based on their genetic underlying entity? Dr. Robert Nussbaum: That's a really fascinating question. I think there's a couple things to keep in mind. So we all have certain risks. Genetics is not your destiny. We need to think about this as being kind of a social contract that some people are dealt a somewhat worse hand genetically than other people. But then those same people who maybe have been dealt a somewhat better hand are going to be dealt a worse hand in other areas of their health. And so we should think about this as that we're all in it together and we're supporting each other. If you adopt an every man for himself kind of attitude, which I'm afraid is somewhat of what's going on in society today now just with regards to COVID vaccinations, that is a formula for a severe dissolution of our society contract. I worry a lot about it. Dr. Daniel Kraft: A hundred percent. How do you think about the workflow, how to make it understandable and actionable? Dr. Robert Nussbaum: There is no question that a certain amount of decision support, clinical decision support is necessary. You do not want a situation where a physician is thinking about prescribing a medication and at that point decides to run a pharmacogenomic test. You want that information obtained in advance and placed in the electronic medical record and available with clinical decision support. I mean, pharmacogenetic variants are given these terms called star alleles, star ones, star two, star three, with star one as generally the common "normal" version of a gene. To tell a practicing physician, oh, your patient has star two, star 23 for CYP2C19 doesn't tell that doctor anything. You have to be able to interpret it to say this person is going to be an intermediate metabolizer of clopidogrel activation and therefore clopidogrel is not going to be a very effective drug for them. But more than that, you need patient education and the opportunity of patients to ask questions. And that's why at Invitae we have a very substantial genetic counseling group that allows tele-counseling with licensure in every state in the United States. It's at no additional charge. That's badly needed. It's only going to get even more acute as the level of information, the sophistication of that information, expands. Dr. Daniel Kraft: Right. We're have an exponential increase in the number of sequences, whether it's your genome, your proteome, your microbiome. But maybe a slightly linear rise in genetic counselors. Dr. Robert Nussbaum: Yes. Dr. Daniel Kraft: Another thing that sort of seems to be coming, some work, is poly genetic risk scores. The idea that we can start to risk stratify folks based on multiple genes, the risk for cancer, diabetes, dementia, and potentially vastly alter, just like you mentioned on certain genetic diseases, the diet early on. That's a little more complex, but seems to be really part of the promise of the future. Dr. Robert Nussbaum: Polygenic risk scores are kind of right on the cusp. What makes polygenic risk scores so interesting and valuable is, first of all, it provides information on the genetic basis for some common disorders, coronary artery disease, type two diabetes, breast cancer. We can't point to a change in a single gene as being responsible for why someone has developed a higher risk for that disorder. The second is that people who are not of Northern European ancestry are grossly underrepresented in our research, in our databases, and also in the polygenic risk score. And there's growing information that some of the polygenic risk score information is transferrable, but some of it is not. And so you then end up with this, what for me is a very uncomfortable and inappropriate situation, where you might offer a polygenic risk score, but it's actually only valid for people of a certain ancestral background. And you're telling people of other ancestral background, we can't do this test for you. It doesn't apply to you. But there's a lot of work being done now on expanding polygenic risk scores into non-European ancestral groups. And I'm confident that we're going to have it nailed down and available in short order. Dr. Daniel Kraft: Along those lines, what can we do to encourage populations that were underrepresented to help build the next data sets? There's the NIH All of Us trial, for example, of which I'm a data donor. I'm European Caucasian derived. And also now we have many individuals, especially in the United States, who are mixed of Asian, European, African heritage. That creates a whole 'nother conundrum, I imagine. Dr. Robert Nussbaum: The NIH fully recognizes this bias in genetic information. So for example, there's a consortium called the Emerge Consortium, which works on the use of electronic medical records for providing health information. There have been four rounds of Emerge. Invitae is a member of the fourth round. And in this round, a certain fraction of the people that they recruit have to be of underrepresented minorities in the United States. Some of the groups have to have more than half, others are something like 30%. What that means then is that these people who are doing research have to develop methods for reaching out to populations that have historically not wanted to participate. Some of them are socioeconomic, some are cultural. Some have to do with suspicion. The government has done bad things to us over many years. We don't want to be victimized again. With Mendelian disorders, there's a lot of variants that are changes only 'cause they're different from the Northern European version of a gene. That doesn't mean that it's disease-causing. And until we get more information from non-European groups, we cannot interpret what we see as well as we can. We call those variants of uncertain significance, or in the vernacular we call them VUS's. The VUS rate is higher in our patients that we test at Invitae when they come from non-Northern European backgrounds. And that's unacceptable. We have to do better. Dr. Daniel Kraft: And this has significant clinical applications. We're prescribing sometimes the wrong inhalers to Hispanic kids or African Americans. Can you kind of summarize some of the low hanging fruit about how clinicians need to be aware of genetic ancestry and how that might affect very common prescriptions and outcomes? Dr. Robert Nussbaum: Ancestry is really important when you're looking at the social determinants of health because society is treating people differently based on their ancestry. So I am not denying that ancestry is important in medicine. But as a surrogate for genetic background, I'd rather know what the genetic variants are and not their ancestry. Because, for example, so many people in the United States are of mixed ancestral background. Suppose I want to know whether somebody is a carrier for cystic fibrosis. The cystic fibrosis variant frequency is quite different in African Americans than it is in northern Europeans. So if you have a random person from Puerto Rico, if you don't know whether the region around their cystic fibrosis gene is originally of African ancestry or originally of European ancestry, it's not going to help you figure out what to do about their cystic fibrosis. You'd rather just test the DNA and ask the question. Is there a disease causing variant there or not? Dr. Daniel Kraft: Yeah, it's not the color of your skin, it's the genetics underneath it that are- Dr. Robert Nussbaum: Yeah, exactly. Dr. Daniel Kraft: ... going to be critical. Dr. Robert Nussbaum: But of course the color of your skin is going to impact profoundly the injuries that you receive at the hands of society. Dr. Daniel Kraft: Given different socioeconomic groups, how do you think about communicating differently about someone's genetics? And has Invitae already sort of started to integrate that design thinking around communication? Dr. Robert Nussbaum: We've done a lot. I mean, for example, we have developed conversation assistant, sort of known like as a chat bot, which allows people in the privacy of their own home to get simple questions answered, to provide information that then would be passed on to this patient's provider. So much of any counseling is really based on the way things were done 20 or 30 years ago with talking to somebody, writing them a letter. But are there graphical or visual or video methods that can help people understand information better where they're at? And we need to dispel some myths. Myths such as your genes determine your health and there's nothing you can do about it if you have a certain genetic background. And this is not true in the vast majority of cases. We also have to eliminate some of the stigma. There are many cultures where having a genetic disorder in your family stigmatizes that family. That kind of thing we need to get rid of. And then we are working hard at trying to make sure that even some of these sophisticated concepts can be communicated and can be delivered to people and they understand it. And they can report back to us that they understand it. That's an important part that really has not been done in almost all of medicine, which is to sit down with your patient and say, okay, I've just been talking to you about X, Y, and Z. What did you hear? And furthermore, if I just gave you some pretty serious news, you probably didn't hear a thing that I said after I gave you that serious news. I mean, what's in your mind is, oh my God, what is this going to mean for me and for my kids? We need to do a better job at figuring out how to get back to people when they're ready to hear more, not just sort of do these one-offs. Dr. Daniel Kraft: Speaking of hearing something and then maybe losing the ability to maintain that knowledge or share it, as when people get a cancer diagnosis, can you touch upon, since it looks like Invitae's quite involved on the cancer side, where you see the cutting edge and what's next? Dr. Robert Nussbaum: Yeah. There's been an absolute revolution in the ability to treat cancers at this point. The fact that we now have the ability to target therapies based on what the genetic architecture is of the particular tumor. Brilliant insights like tumors that lack the BRCA one or two function have an Achilles heel specifically, which is that another DNA repair pathway called PARP has to function in order for those cells to survive. So if you can inhibit PARP with a drug in someone who already is missing BRCA one or two in their tumor cells, you have tremendous advantage in being able to essentially cause those tumor cells to die. We're seeing something similar now, of course, with being able to overcome the immune resistance. Tumors have been able to escape our own immune system. And so the drugs that overcome a tumor's ability to escape immune surveillance are now becoming very important. And the more unusual materials a cancer cell makes, the more susceptible it's going to be to being recognized as being foreign. So now we know that certain tumors that have what's called mismatch repair, which is the basis of Lynch Syndrome, hereditary colon cancer disorder, if the mismatch repair is high, that tumor is a better target for your own immune system. This is just the beginning. I'm really excited about it. So what that means is that now every cancer will ultimately need to be profiled so that we'll know how to treat it. The same way that if you have a pneumonia, you need to get that bug out, take a look at the bacteria, and see what are its antibiotic sensitivities. Well, cancer, now we have to do the same thing. We have to characterize it at a genetic level. Dr. Daniel Kraft: In the same realm, what do you think more clinicians, physicians, to nurse practitioners, to pharmacists, should really start to be aware of in terms of genetic health and their care continuum? Dr. Robert Nussbaum: The standard practice has not caught up to what's even possible now. It's a goal post that keeps retreating because we're being able to do more and more and more. The primary thing is that the ability of genetics to really help one manage patients, manage their medications, manage their treatment, is underappreciated. I mean, I'm very sensitive to the fact that the typical primary care physician has, what, an average of 15 minutes or 12 minutes with every patient? It takes you three times that to get a decent family history, who believe and have evidence that genetics is valuable to provide people with the tools to really make that happen. For pharmacists, I mean, there are really good decision support tools now. Pharmacists can say, oh, this patient has now been prescribed this new drug. In goes the name of the dose of the drug, and up comes what that patient's genetic background is that might affect the way that drug acts. Those are available. And it's got to be done right at the point of care. It's got to be easy. It's got to be built in. Dr. Daniel Kraft: Just few minutes left. There's that famous quote from Bill Gates. We tend to overestimate what will happen in a year and underestimate what might happen in a decade. What would be the clinic of 2030, 2031, 2032? Dr. Robert Nussbaum: The first is that there's going to be much more widespread whole genome sequencing of individuals as part of their routine health care. And that that information will not only be stored, but it'll be mined and upgraded as we learn more and as more information comes on in a continual basis. And in particular, if something happens in their life, some change in their health status, and the question will be asked, could we have predicted that? And the second is that a lot of rare disorders, we'll know exactly which gene and what variant it is. And for many of them, there either will be or will be developing highly specific molecular tools to treat those rare disorders. It's a virtual cycle where the more you know about a rare genetic disorder and what its cause is, the more impetus there is to develop specific therapy for it. And the more specific therapies there are, the more people then get tested. We've done a study with the UnitedHealthcare looking at the fraction of patients who are getting appropriate genetic testing in colon cancer, in breast cancer. It's way under what even current guidelines are recommending, let alone what I think where the guidelines should be. So we're not even using the tools we have now. Dr. Daniel Kraft: So we always close with asking if there's anything we might have missed, anything we discussed but didn't cover completely. Dr. Robert Nussbaum: I mean, the economic aspects of this we have not talked about. We need to drive the cost down so far that people will stop arguing about whether this test should or should not be done. For example, we're talking about molecular therapies for rare disorders. They are extremely expensive. I don't have answers to these problems or questions. I just know that as a doctor, I want to do the best I can for patients who are suffering. That's what I want to see happen. Dr. Daniel Kraft: Well, first of all, thank you for the amazing work you've done from the NIH to UCSF to now in Invitae. [inaudible 00:26:42] the rubber hit the road and tremendous opportunity. So Dr. Robert Nussbaum, Chief Medical Officer for Invitae, thanks so much for joining us today on Healthy Conversations. Dr. Robert Nussbaum: My pleasure. Thank you.