Austin is a genetic counselor for Genetic Support Foundation, a non-profit genetic counseling group, where he provides telehealth genetic counseling from his home base in Vancouver, WA. He a first time blogger, long time reader of the DNA Exchange.
A study recently published in Science sought to answer the age-old question: Where’s the ‘gay gene’? As a member of both the genetics and LGBTQ+ community, this headline naturally piqued my interest. I’ve always thought that this question is inherently a double-edged sword: by ‘proving’ that non-same sex attraction is in some way genetic, the whole ‘it’s a choice’ argument can finally be put to rest. But finding a scientifically detectable ‘cause’ for non-heteronormative behavior naturally brings up an equal (if not greater) level of concern.
Even when we think we understand the genetics of a trait, the outcomes often aren’t as straightforward as we once believed. Particularly for a trait such as ‘nonheterosexual behavior’, where social, religious, family, and political influences also strongly affect one’s beliefs and how they may choose to reconcile those beliefs with their lifestyle. Genetics is leaping forward faster than the majority of us had probably anticipated, and we’re getting a real lesson about putting the cart before the horse.
There are some issues with how the study was conducted, as sexual identity is very complex and some of the questions have been viewed as being too binary and focused on behavior rather than sexual orientation. The researchers categorized people into two buckets: those who have EVER had ONE or more same-sex sexual experience are categorized as ‘nonheterosexual’ while those who have never had a same-sex sexual experience are categorized as ‘heterosexual’. They do make an attempt later in the study to outline that sexuality is a spectrum, but that assertion is buried amongst other extrapolations.
The data sets for this study were collected from the UK Biobank, as well as direct-to-consumer testing company 23andMe. Companies such as these encourage their customers to consent to having their DNA used for research, promising that their selfless contribution will further the field of genetics and healthcare. In all actuality, it appears that this data is being sold to entities that are using it for less medically noble endeavors. Aside from individuals not fully understanding that their data could be used for such ‘research’, they may actually unknowingly be participating in research that could potentially lead to discrimination and other harms against them in the future.
The authors of the ‘gay gene’ study determined that ‘like other behavioral traits, nonheterosexual behavior is polygenic’. There you have it folks: it’s not ONE gene. It’s LOTS of genes! Is that better? Worse? Depends on what you do with that information…
Enter GenePlaza, a company that boasts that it can take the DNA information that you’ve received from companies like 23andMe and Ancestry.com and use its internal apps to tell you things like how smart you are or how good you are at math (in case your grades in school didn’t tell you already). With data taken from this new study, GenePlaza proposed that for $5.50 they could tell you exactly how gay you are.
Backlash to the announcement of the app was swift, and a petition was quickly announced in an effort to get the app shut down. Although at the time of this publication it not yet reached its goal of 2,500 signatures, it appears to have been effective as there is no sign of the app now on GenePlaza’s app site.
As the authors of the study said, we should resist ‘simplistic conclusions because the behavioral phenotypes are complex, because our genetic insights are rudimentary, and because there is a long history of misusing genetic results for social purposes.’
Some have raised concerns about the motivation of such research studies. But once something like this is out of the bag, it’s very difficult to put back in. No matter the motivation, this is another shining example that when it comes to genetic technology, we regularly need to be asking ourselves not only ‘Can we?’, but ‘Should we?’.
As recently discussed on the DNA Exchange, general population screening for any health condition has both risks and benefits, and sound health policy should weigh all of these factors to ensure that we are doing more good than harm. But the debate about what, who, and how we should be screening for hereditary cancer risk seems to be mainly an academic exercise practiced by some in the clinical genetics and public health communities. While we continue to debate the merits of population screening, the commercial laboratories keep pushing forward, making these tests readily available to the general population through direct to consumer (DTC) testing products.
Often the cancer genetic test isn’t the main product that the customer is seeking, but rather may be a bonus of sorts provided along with ancestry and other DTC tests. Such is the case for the new health reports for MUTYH variants that 23andMe began releasing this past summer. Individuals who inherit one MUTYH pathogenic variant may have a slightly increased risk for colon cancer. Individuals who inherit biallelic pathogenic variants have a very high risk for colon polyps, colon cancer and other cancers and are said to have MUTYH-Associated Polyposis syndrome, or MAP.
So who should be screened for MUTYH variants? If you ask 23andMe the answer would be everyone. How should we screen? According to 23andMe, screening should be done by a two variant genotype panel. And who decides who is screened? From what I gather, this new health report was not driven by customer demand, nor were healthcare providers calling for more access to MUTYH testing. Generally ourguidelines recommend MUTYH testing only in very specific circumstances, such as when a patient has multiple adenomatous polyps, or if they have a sibling who has been diagnosed with MAP. But it is not the healthcare providers or guidelines directing who is screened. Presently it would seem that 23andMe decides who gets screened for MUTYH variants, and with the blessing of the FDA. I am curious to know how my genetic counselor colleagues are handling or are likely to handle such cases. What would you most likely offer to a patient that comes for genetic counseling with a heterozygous positive DTC MUTYH variant report, and no family history concerning for MUTYH polyposis or other hereditary cancer syndrome?
My hunch is that most genetic counselors would offer follow-up clinical testing, and that this will usually be at a minimum a full analysis of MUTYH. I certainly can see the benefit of identifying patients who have biallelic MUTYH variants to allow for earlier and more frequent colonoscopy screening and prevention of some cases of early onset colon cancer for those who may not otherwise have known that they were at increased risk. Since the announcement of the new health reports by 23andMe I have been curious about how many individuals with MAP could be identified through this stepwise screening, first with 23andMe and then follow-up clinical testing of the entire MUTYH gene for all of those who first have one or two variants detected through 23andMe.
Staying with the estimated 4 million 23andMe customers of European descent who opted for the health reports, I estimate that there are about 390 total people out of the 4 million who have MAP, and of these about 250 would be identified through testing the two common variants alone (homozygous or compound heterozygous for Y179C/G396D. (My calculations and assumptions are all available here.) Through this stepwise screening of sequence analysis only for those who are first found to have at least one common variant, we would identify approximately 374 of the total 390 people with MAP, while missing about 16 people who carry two less common MUTYH variants. The cost per MAP case identified depends on the cost of follow-up genetic testing.Publicly available pricing suggests that single gene analysis of the MUTYH gene through a clinical lab is typically between $500-$1,500 per test for complete single gene analysis, although clinical testing may be priced as low as $250 to more than $2,000 per test. Thus, through this stepwise process (full gene analysis for those with one or more common variants first identified) the cost for clinical genetic testing would be somewhere on the order of $42,000 – $378,00 per MAP case identified. Given that general population guidelines recommend colon cancer screening should begin at age 50 and becauseapproximately 75% of colon cancer in individuals with MAP occurs in patients under the age of 50, this genetic screening approach, and initiation of colonoscopy screening at an earlier age than typically recommended, could prevent as many as 94 cases of early onset colon cancer in this 23ndMe screened group, with cost per case prevented in the range of $168,000 to 1.5 million. It is important to note that this only considers genetic testing. A more complete economic analysis may include genetic counseling costs, additional cancer screening costs, as well as the estimated cost for genetic testing in other family members.
23andMe isn’t the only company that has an interest in MUTYH screening. Several labs offer DTC, or the close relative of DTC testing, the so called “patient-initiated, physician-mediated” testing in which an individual may request testing themselves, and a physician contracted by the lab signs off on the test order to bypass the need for FDA scrutiny (a discussion for another post).MyHeritage, who previously offered only ancestry testing recently began offering a “health” component which includes four variants in the MUTYH gene (including the two common European variants). Color Genomics and Invitae both consumer-initiated, physician-mediated tests as well as clinician ordered tests that provide a more complete analysis of MUTYH and other cancer susceptibility genes.
Is more comprehensive testing such as full gene sequencing better when it comes to MUTYH testing in the general population? It depends on how better is defined. I can certainly appreciate that detecting those additional 16 individuals with MAP (and being able to prevent about 4 cases of early onset colon cancers) that would have been missed in our 23andMe population of 4 million people would be one benefit to more comprehensive testing. But what’s the trade off?
At the recent American Society of Human Genetics meeting in Houston,Invitae presented data reviewing MUTYH variants found in analysis of a cohort of 270,806 patient samples that were submitted for multigene hereditary cancer risk panels. They reported that through a more complete analysis of MUTYH they discovered 5,929 patients with pathogenic or likely pathogenic variants in MUTYH, of which 1,377 (23%) of these patients carried one or more variants other than G396D and Y179C. That’s no surprise – in fact it fits well with our current understanding of the population frequencies for these genetic variants as well as our appreciation that about 80% of variants detected through MUTYH testing in a population of mostly individuals of European Caucasian ancestry are the G396D and Y179C variants.
The presented statistic that is getting the most attention in the news since the meeting is Invitae’s assertion that 40% of individuals in the cohort with biallelic mutations would have been missed by the targeted variant testing. But the necessary context that is missing here is that about 90% of those that would be “missed” in that 40% would have one of the two common variants paired with a second other, undetected variant. Through a stepwise approach in which only individuals with one or more of the common variants on first screening through 23andMe had follow-up clinical sequence analysis, approximately 96% of the total MAP cases would be identified. That means there would be only about 4% of individuals who would have biallelic variants that both would have gone undetected by a stepwise approach that begins with a two-variant screen.
If we were to ask Invitae who should be screened, I believe they would likely agree with 23andMe that everyone should be tested. Where they differ is in how the screening should be done, with Invitae advocating for more complete next generation sequence analysis for all people rather than targeted SNP panels. I can appreciate the logic in this argument that this strategy would detect more cases of MAP, especially in people who are not of European ancestry. But how would the cost of testing compare for the number of cases detected? The devil is in the details of how this testing is done and who pays for it. Invitae currently offers a patient-initiated, physician-mediated cancer gene panel for $250. If people elected this test and paid for it on their own instead of having 23andMe, given that it is considered a clinical test and no follow-up studies would be needed, then we would not see the additional cost in follow-up clinical testing (although we may see more downstream costs with follow-up for variants, including variants of unknown significance in other genes on the panel). My sense though is that people seek out tests like 23ndMe for reasons other than to know there MUTYH or other cancer gene status. So if we are considering the total cost of clinical testing for all people rather than just for those who present with at least one of the common mutations on a screening DTC test we would see quite a dramatic increase in the cost to identify a case of MAP as well as the cost to potentially prevent a case of colon cancer before the age of 50 (61-fold increase over the stepwise approach).
What is difficult to tease out in these analyses is that most tests that include MUTYH are not ordered with a high suspicion or concern for MAP. In most cases, it is included as part of a bigger panel, and MUTYH is not the primary reason for testing. In the case of 23andMe it comes along as part of a bigger ancestry, traits and health screen. In the case of Invitae it usually comes along as part of a multigene cancer panel for which the primary indication is usually for evaluation of genes other than MUTYH. So should we consider that extra information provided by the MUTYH analysis in patients a bonus or a burden? As DTC and consumer-initiated testing becomes more common, and as clinical testing panels more often include MUTYH, are we spending more time counseling patients about MUTYH results that are unlikely to significantly affect health outcomes or screening recommendations for the patient or their family members? I worry that patients may put too much value on these results as a possible explanation for their cancer, when it may unlikely be the case. And I feel conflicted about how much we should be advocating for family member testing when there is such a small chance that their care and outcomes will change as a result.
The focus right now seems to be on the question of how we should be screening for MUTYH. I think we are engaging in the wrong discussion here – I think we should go back to the heart of this and really take a close look at why we are doing this testing? What is driving adoption of expanding genetic testing to include analysis of genes such as MUTYH? And how should we integrate these technologies into practice in a way that will help the most people and cause the least harm. We need to critically consider the statistics that are presented and carefully weigh the costs versus the benefits of expanding testing.
Given that we are just a week away from the annual NSGC conference, I’d like to make a plug for the 3rd annual ‘GC’s Got Talent’ hosted by Genetic Support Foundation on November 6th from 7-10 pm. The event will be Emceed by the ever engaging and talented DNA Exchange blogger, Bob Resta. In addition to storytelling, dancing, singing and comedic acts, a silent auction will showcase the artistic and creative talents of GCs. It’s not too late to sign up to share your talent and we are seeking storytellers for the themes: “Confessions of a Genetic Counselor” or “Most Awkward Moment in my Career”…Contact email@example.com for additional info.
Should all women undergo BRCA testing? This question has been an item for discussion once it was given the authoritative weight of Mary-Claire King, the widely respected genetics researcher who has made invaluable contributions to the discovery and elucidation of the BRCA genes. The appeal is clear. Under current protocols, many women at increased risk of carrying a pathogenic variant are not undergoing BRCA testing. It breaks my heart each time I meet with a 40 year old mother of young children who was just diagnosed with a preventible serous epithelial ovarian cancer or a triple negative breast cancer. Furthermore, a significant number of pathogenic variant carriers are missed by just about every set of testing guidelines. Not only that, guidelines are so complex, evolving, and variable that no one can keep track of them any more, except maybe the unsung heroes among the support staff at commercial laboratories who are tasked with verifying insurance coverage for genetic testing all day every day. I half-jokingly tell my oncology colleagues at tumor boards that my new criteria for genetic testing are are simple: 1) Does the patient have cancer? 2) Does the patient have genes?
I understand the appeal of population BRCA screening. Risk mitigation strategies and enhanced screening have the potential to reduce morbidity and mortality, or, more simply put, it could reduce suffering and saves lives. This benefit looms particularly large in the face of that sly and nasty devil, fallopian tube/ovarian cancer. But the benefits – and I don’t mean to diminish them – can lead us to subconsciously overstate upsides and downplay downsides. As Guido Calabresi and Philip Bobbitt pointed out more than 40 years ago, allocating medical care is full of tragic choices, i.e., no matter what course of action we choose, some people will suffer and some people will benefit. The hard part is deciding who should benefit and who should suffer. Let me be clear, though, that if BRCA population screening were to be implemented, I hope that my concerns prove to be unfounded or are addressed up front.
In comparison, my back of the napkin calculations suggest that of the approximately 42,000 breast cancer deaths and 14,000 ovarian cancer deaths in the US each year, roughly 5% of breast cancer patients and 15-20% of ovarian cancer patients carry a BRCA mutation (I am not including other high risk breast cancer related genes such as PALB2 and TP53, but their inclusion would not substantively change the calculations). This would amount to theoretically saving about 5000 lives annually. This rough estimate is based on the very unlikely assumptions of full population participation in both genetic testing and follow up cancer screening and risk reducing strategies, and that these strategies save lives. While the evidence is pretty good that risk-reducing saplingo-oophorectomy reduces ovarian cancer mortality in unaffected BRCA mutation carriers, the mortality/morbidity reduction benefit of combined mammography and breast MRI is less well established. Risk-reducing mastectomy significantly reduces breast cancer risk and disease and treatment morbidity but the mortality reduction is not as great as one would hope, especially as a woman gets older. And many healthy BRCA pathogenic variant carriers delay or decline mastectomy. At most, about half of unaffected BRCA pathogenic variant carriers undergo risk-reducing mastectomy.
Would the resources devoted to saving lives through population BRCA screening justify a reduction in allocation of resources to other far more common health problems or disparities within cancer care itself, such as racial and economic differences in access to care, morbidity, and mortality? Of course, numbers are not the only deciding factor for resource allocation, which is ultimately an ethical decision that society arrives at in a somewhat unpredictable and disorganized fashion. On the other hand, those numbers cannot be ignored. Population BRCA screening may prove to be cost-effective but that does not necessarily mean it would be the best use of limited health care dollars and resources. It is not exactly a zero sum game, but no matter how you slice and dice it, all health care problems cannot be covered with even the most generous allocation of resources. Eliminating the hundreds of billions of wasted health care dollars in the US might start to address resource limitations, but, realistically, drastic reductions in unnecessary spending are not likely to happen any time in the near future nor is it guaranteed that the saved dollars would be reapportioned to other areas of health care. Which lives “deserve” to be saved and which diseases “deserve” to be prevented? Tragic choices, indeed.
Then too there is the problem of health insurance, or, more precisely, the lack of it. BRCA testing on a population scale would presumably lower the cost of genetic analysis to affordable levels and labs would likely absorb the costs of those who can’t pay (or at least would figure it into their pricing). However, it is in the follow up of mutation carriers where the annual costs start to pile up. Annual mammography and breast MRI, mastectomy, reconstructive surgery, and salpingo-oophorectomy would not likely be available to the ~14% of the US population who lack health insurance, with even higher rates of non-insurance among young women, the very population who theoretically would benefit the most from BRCA testing. Yes, the cost of treating those women for cancer is much greater than the cost of screening and risk-reducing surgery, but if the women do not have the financial wherewithal to pay for surgery and screening then those interventions just aren’t going to happen. Before we even think too hard about implementing population BRCA screening, the national health insurance crisis must first be addressed. BRCA screening could unintentionally result in further health disparities for low income women.
Even among women identified at high risk of developing breast cancer and who have health insurance, uptake of MRI screening is low even in facilities where MRI screening is available, with some demographic variability in uptake. Thus, innovative efforts are needed to improve outreach, education, and motivation to participate in semi-annual screening that would likely last for decades. In addition, if population BRCA screening becomes a reality, more MRI machines will need to be purchased, more radiologists will need training if they don’t routinely read breast MRI images, and more surgeons will be needed to perform mastectomy and reconstruction. A commitment to BRCA screening requires a lot more resources than just increasing the availability of genetic testing.
I admit that I am a professional worrier, and maybe all of my concerns are just another expression of my character flaws. No doubt many of the Good Readers of The DNA Exchange will have strong differences of opinion with me. I want to save lives and avoid cancer treatments just as much as the next person, and maybe even more so than many others after having spent two plus decades watching women and their families go through the nasty physical and existentially threatening experience of chemotherapy, disfiguring surgery, radiation therapy, and dying all too young. On the other hand, there are many more people suffering from other serious and potentially preventible health problems. Are they less worthy? Tragic choices are so…..tragic.
Our word choices in speech and writing are often reflexive rather than reflective. Some words become so engrained into our vocabulary that we use them out of habit rather than after careful consideration. We think we are communicating clearly because everybody “knows” what a particular word means so we don’t pause to consider what the word might really mean or suggest. This can be particularly true of professional vocabulary, wherein we are inculcated with a set of specialized terms and word choices early in our training that are later reinforced throughout our careers by journal articles, books, and at educational meetings.
Even the rhythm and meter of spoken language can silently work their way into professional oral presentations. The next time you attend a multi-day conference pay attention to how the speakers at the end of the conference may unconsciously repeat the speech patterns of the speakers from the previous days. I first noticed this phenomenon about 10 years ago at an annual genetic counseling education conference during which a few speakers at the beginning of the conference frequently used a high-rising terminal (i.e., a rise in pitch at the end of a sentence). By the last day of the meeting it seemed like every speaker was raising their pitch at the end of too many sentences and it was starting to drive me crazy (I’ve since adapted). The “right” way to speak or write is the one that we encounter most often and most recently by respected members of our professional and social circles.
Reflexive vocabulary usage can sometimes mislead or confuse. Let me offer two examples of vocabulary used by – but not unique to – the medical genetics community that in my view need some reconsidering and revision: whole exome/genome sequencing and gender neutral pronouns (for related discussions, see my prior postings about the words “psychosocial.” and “mutation“).
Whole Genome/Whole Exome Sequencing – These are inaccurate and misleading terms. The descriptor “whole” suggests that the entire genome or the entire exome is being sequenced. In fact, the analysis usually includes a lot of the genome or a lot of the exome – but not the entirety of either. They don’t quite go the whole nine yards. The limits of some “whole” techniques and platforms become even more salient when you understand that they may not reliably detect some of the most common DNA-based disorders such as Down syndrome, fragile X syndrome, and alpha-thalassemia. I suggest that we drop the word “whole” and simply call it genome sequencing or exome sequencing, a practice I’ve already seen in some journal articles. But it should include a descriptor that indicates which technology was used to sequence the genome – short read, long read, optical mapping, etc. Each has its strengths and limitations and knowing which technique was used informs us as to which conditions are reliably or unreliably detected.
Incidentally, genome was coined (as genom) in 1920 by the German botanist Hans Winkler. Until the discovery that most DNA was non-coding, the word genome implied the sum of an organism’s genes. Now that we know that only a smidgen of an organism’s DNA are genes as we understand them today, the 20th century sense of genome does not align with the current sense of genome that refers to the entirety of an organism’s coding and non-coding DNA. Exome, on the other hand, arose out of 21st century technology. The earliest article I could find in PubMed that used exome in it’s title or abstract was a 2008 publication about J. Craig Venter’s exome (Venter was the senior author).
Gender Neutral Pronouns and Verb Agreement – I wholeheartedly support the use of gender neutral or third gender pronouns in English, even if I think a few of them like zie, zir, and ver will not likely catch on. The vagaries of language evolution could ultimately prove me wrong but no matter how conscientious and respectful you try to be, these neologisms entail learning new words that have no clear etymology to guide the user or listener as to their meaning. However, pronouns such as “they” or “them” as a singular subjective or objective pronoun or “their” as a singular possessive pronoun have gained more linguistic traction. These pronouns have historical usage as a a singular form. Take the sentence I wonder who left their mobile phone on their seat in the auditorium? Whoever it is, they are not going to be happy when they realize it. “They” is a pronoun substitute for the singular “that person.” This sentence would have been perfectly clear and acceptable in just about all English dialects well before gender neutral pronouns became a subject of debate and discussion. Further, “they” and “them” do not have a linguistic history of denoting a specific gender.
My question, though, is not about which pronouns will survive the test of time but rather which verb form to use with that pronoun. Does it call for the plural or the singular verb form, as in “They are” or “They is?” I vote for “They is.”
I confess to being a bit of a fanatic about the arcana of grammar and syntax, but I am not a language tyrant. Language evolves so quickly that the “rules” desperately try to keep up with usage. Good writers instinctively know the rules and then go about flaunting and manipulating them. I am not trying to be snobbishly picky when I raise the question of pronoun/verb agreement. There are two important issues raised by verb choice in this situation, one of meaning and one of value judgment. “They is” clearly communicates the meaning of one, and only one, person rather than a group of people. The value judgment implied by using the singular verb is implicit acceptance and acknowledgment of the person’s choice to not identify as being of male, female, or any gender. The slightly jarring effect of hearing a singular verb follow a typically plural pronoun makes “they” stand out in the sentence. It’s not just any old use of “they.” It’s a special case that reflects and honors the desires of that person.
Yeah, I know. “They is” just sounds plain wrong. But it only sounds wrong because we are used to having heard it another way for our entire lives. If the singular verb is used more frequently and consistently, the dissonance will fade. I remember the endless discussions about whether one should use a singular or plural verb with the word “data.” Now, it’s like Who Cares? “Date are” and “Data is” both now sound equally fine and either form is considered acceptable by most authoritative usage guides. Rule-obsessed grammarians can argue all they want; the rest of us just get on with our linguistic lives.
No doubt some of you will disagree with my suggestions. So I open up the discussion to the Good Readers. What do you think? And is there other vocabulary that needs reconsidering and discussion?
As is the case with many topics in genetics, I learn the most in my time away from the office, researching questions for friends and family. And the genetics questions du jour are almost all related to pharmacogenomics (PGx) testing. More specifically, PGx testing for psychiatric medications. Maybe you are getting these questions too? For me, they usually go something like this:
Are these genetic tests that promise to tell you what
antidepressant medication will work best for you a real thing?
And if they are, why isn’t everybody taking them?
I have witnessed friends and family members struggle with medication management for depression, anxiety and mood disorders. People in these situations are often desperate for help and quite vulnerable. I can fully appreciate the hope that a simple genetic test could provide the answers to ease the journey. But as we find with many things in genetics, the reality is much more complicated than the hopeful answer we wish we could give. Ultimately, I know my position on this will disappoint many who are looking for that silver bullet. While there are a handful of applications for pharmacogenomics in specific situations related to psychiatric medications that have evidence to support their use, there is little evidence that multigene panels in this area lead to better outcomes. There is concern that harm may come because of the use of this unproven information to guide important decisions with prescribing and dosing of psychiatric meds.
My conclusions regarding these tests are in part based on critiques from reputable sources on the current state of commercially available PGx psychiatric panels, including the American Psychiatry Association Workgroup for Novel Biomarkers and Treatments. This workgroup performed a detailed review of several commercially available tests and concluded that there is a lack of sufficient evidence to support the widespread clinical use of the proprietary combinatorial pharmacogenomic models used by these labs. There are many publications that highlight issues with existing studies about these tests including concerns related to conflict of interest and problematic study design. The financial sector is also following this topic closely given much has been invested based on the promise of these testing products being adopted broadly. Recognizing the strong commercial drivers at play here also causes me to view laboratory claims with a dose of skepticism.
But when it comes to the general public, I think the commercial push to see these tests more broadly adopted is drowning out the voices of the experts who are urging caution. It seems that since many in the field of psychiatry aren’t convinced that these tests are ready for prime time, the labs have decided to bypass the most relevant specialty, and go straight for patients and primary care providers. Additionally healthcare payers are banking on the promise that these PGx tests will more than pay for themselves by allowing for better precision in prescribing of expensive medications. Payer support is helping to move psychiatric PGx testing to the mainstream.
New pharmacy-laboratory partnerships are emerging to promote these tests. Last year, PGx lab Genomind® announced a partnership with Albertsons Sav-On, Jewel-Osco and Acme Sav-On pharmacies: pharmacists can discuss PGx testing with patients and, if the patient consents, the pharmacists will directly contact the prescribing provider to “suggest the Genecept® Assay. ” The sample can be collected right in the pharmacy. Last month, Myriad Genetics, Inc. announced a similar program with Kroger Prescription Plans to promote GeneSight® genetic tests in Kroger pharmacies. From the GeneSite® press release: “pharmacists at more than 2,300 Kroger stores will provide counselling about GeneSight® to eligible employer group members and facilitate testing with their prescribing healthcare professionals.”
Pharmacists are now direct marketing genetic testing to patients. And while members of the pathology and clinical laboratory space are taking some issue with this, there hasn’t been much public concern raised by the broader medical genetics community about this proposal to have pharmacists providing “genetic counseling” and facilitation of genetic testing.
It will be interesting to see how these programs evolve with greater attention from regulators. With several years of push and pull between labs marketing these tests and clinicians raising concerns about their clinical utility and safety, the FDA has recently started to flex their regulatory muscles in this space. In Oct 2018, the agency published a Safety Communication, warning patients not to change management based on PGx results without first discussing with their healthcare provider and to be aware that claims made by genetic testing laboratories about PGx tests are not supported by sufficient clinical evidence. The FDA cautions healthcare providers in the use of these tests and directs providers to FDA-approved drug and genetic test labels. Lastly, the communication advised test manufacturers not to include specific drug information that is inconsistent with FDA-approved drug labeling. In April, the FDA sent a letter to Inova Health System with concern that the clinical validity of their PGx tests had not been established for the reported intended uses. Shortly after this letter was issued, Inova elected to cease offering their MediMap® tests. The FDA has been in communication with several other laboratories and stated that “most firms addressed the FDA’s concerns by removing specific medication names from their labeling, including promotional material and patient test reports.”
Some of the critiques I have heard about the FDA’s engagement in regulating these tests is centered around whether or not the FDA should be the authority on the evidence required to support the relationship between certain variants and drug metabolism. A frequently referenced pain point is the difference between the PGx genes/variants that make the cut per FDA drug labeling and the evidence grade rating per the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network (CPIC). In looking at most of the commercially available PGx tests on the market today though, it is clear that many of the variant-drug connections included on lab reports are not consistent either with the FDA-approved list or with CPIC guidelines.
For example, the sample GeneSight® report available online as of the day of this posting, under the category of “Mood Stabilizers” shows three drugs in the red bucket, “Significant Gene-Drug Interaction” and no drugs in the green, “Use As Directed” bucket. Top of the red list is lamotrigine (Lamictal®), which has a footnote that reads “Use of this drug may increase the risk of side effects.” The justification given in the Gene-Drug Interactions table is a variant in the UGT1A4 gene. Search of the CPIC database gives the UGT1A4 – lamotrigine pair a “D” level rating. According to the website, the CPIC D Level is defined as follows: “There are few published studies, clinical actions are unclear, little mechanistic basis, mostly weak evidence, or substantial conflicting data. No prescribing actions are recommended.” How might this report affect a person with bipolar who is struggling to find the right medication? One can imagine that it may be difficult for both the patient and the prescribing provider to feel comfortable with a treatment plan when not supported by this genetic test report.
For the same GeneSite® sample report, under the “Antidepressants” heading, there are a total of 22 antidepressents for which analysis is available, with only three in the “Use as Directed” green bucket. Top of that long list of 22 drugs in the red, “Significant Gene-Drug Interaction” bucket is bupropion (Wellbutrin®). Bupropion is a medication commonly used to treat depression and has been approved by the FDA for use since 1985 with a generic version of this drug readily available. There is no data in the CPIC database to support the assertion made my GeneSight® of a “Significant Gene-Drug Interaction” with bupropion. And interestingly, the only three antidepressant medications that made it to the green “Use as Directed” category are expensive drugs for which no generic version is available: levomilnacipran (Fetzima®), desvenlafaxine (Pristiq®), and vilazodone (Viibryd®). If I received this report and didn’t know better, I might assume that these drugs would be worth the high price tag if they are genetically the most likely to treat depression without the potential for side effects. There is no gene-drug information in CPIC about any of these three preferred medications, and I didn’t have to look very far beyond the GeneSight® report to see the long list of side effects and contraindications associated with each of these medications. But imagine the difficulty a prescribing provider might have in convincing a patient to consider forgoing the expensive new drugs in the green bucket to consider a more affordable medication with a longer history of success in treatment from the red bucket. Lab reports are not often looked at as one piece of the puzzle, but rather as the *truth* by patients. And as I have previously written on a different topic, it is incredibly difficult to convince a patient that an expert assessment may be more trustworthy than what is printed on a test report.
Regulation of genetic testing is a big and thorny issue, and I don’t claim to have easy solutions for improving these challenges. But what I do hope to do is to begin a conversation with my fellow genetic counselors on what role we should have in the dissemination of information regarding PGx testing. I feel it is our professional obligation to understand, to the best of our abilities, the evidence or lack thereof when counseling our patients, consulting with other healthcare providers and discussing these tests with friends and family. When people first started asking me about these tests, my initial feeling was one of hope and optimism. Of course it would be wonderful if a simple genetic test could provide a clear path towards the best medication for those who are suffering. Now, after having spent hours down the rabbit hole to try to better understand the current state of this field, I remain hopeful that these tools may someday provide real benefit for the masses. Unfortunately, it seems to me that at the present time, this wild west of the competitive genetic testing marketplace has resulted in bigger but not necessarily better panels, including information that is often not evidenced-based. I worry that these reports could lead people down a wrong, and potentially dangerous path.
So for now when my loved ones ask me, “are these genetic tests that promise to tell you what antidepressant medication will work best for you a real thing?” I will give the more cautious and complicated answer. While this technology holds promise for the future, the evidence we have at this point does not support that these tests will help guide better care and lead to better outcomes for most people. And I will continue to do my best to support them on the journey forward, wherever the bumpy and winding road may lead.
The recent stories about Medicare fraud and genetic testing have been pretty awful. Taking advantage of older people in order to scam the government…. well, what can you say? There’s a cheater born every minute and they are doing their best, or, really, their worst, to turn honest people into feeling like suckers.
Moral outrage aside, the stories got me to thinking about how unsure I am about the costs of genetic testing and how it gets billed to patients and insurers. Important point – I am not suggesting that reputable labs are flimflammers or hucksters. I am forever grateful to labs for their efforts in working with patients’ health insurers to determine coverage. I understand that pricing structure and billing are complicated even for professionals who spend their whole life doing it. Labs should make as much legitimate profit as they can. Sometimes the eligibility and testing guidelines are not so clear. I was born – but not yesterday.* I just don’t know how it gets done and how the rules and regulations are navigated, at least in my narrow world of cancer genetics, though I suspect it is a problem in other specialties too. I’ve tried to become an informed user but it is a dense subject. I feel as clueless as Buzz Lightyear (or, as Woody sometimes calls him, Buzz Light Beer). Genetics is easy in comparison. So I have questions.
I understand that each lab negotiates prices with each private health insurer and that the specifics are sort of Top Secret. But why are the negotiated prices for essentially the same test so different for each lab and insurer? Surely insurers are not so incompetent that they don’t realize this. They too are looking to be as profitable as they can be. All else being equal, shouldn’t insurers negotiate about the same price with Labs A, B, and C? And if Lab D doesn’t like the price, well tough on them and they can be relegated to the dreaded status of “nonpreferred lab.”
Then there’s Medicare. Medicare rules vary a bit by region and are potentially negotiable in particular instances. But Medicare guidelines make it clear that usually patients must have a diagnosis such as breast or ovarian cancers (and in some situations also need to meet family history criteria) for testing to be covered. Some labs will not bill Medicare for patients who do not meet criteria and charge patients an out of pocket amount consistent with what they would have charged Medicare if it was a covered service. Other labs will bill Medicare and appear to eat whatever Medicare does not cover. Is it all a matter of different interpretations of ambiguous bureaucratic wording? And is it an illegal inducement if a lab offers free genetic counseling along with testing?
When insurance is bypassed and a patient pays out of pocket how is it that the charge to the patient for more or less the same gene panel across labs can range from $250 to ~$2,000? Depending on which lab you use, patients can even get a panel for fifty bucks if they are “fortunate” enough to have a pathogenic variant segregating in their family. Or the patient at risk for a specific familial pathogenic variant could get the gene in question sequenced, but not a panel, for free, if testing is ordered within 90 days of the relative’s test. Or that same patient could just be tested for the specific variant and pay around $400-$500 out of pocket. If you have prostate cancer, or certain other genetic conditions, you can get a panel test at no charge because the testing is “sponsored” by a separate lab, usually from Pharma, with whom de-identified data may be shared (is it still possible to deidentify DNA anymore?).
I am all for removing financial and other barriers to genetic testing and counseling. I work hard at making sure my patients pay the lowest possible price for a quality test. I understand the need for research and cooperation between labs to develop new treatments. And it can be cut-throat competition out there where everyone’s trying to hack off a big chunk of market share. For sure, many of these issues are symptoms of the crazy health care system and spending in the US. At the same time, I wonder whether my pursuit of making sure that my patients get coverage for their genetic testing is blinding me to problems with billing and charging. I do not want to cross any ethical or legal lines and I don’t want put my patients in financial jeopardy.
Perhaps the Good Readers of this blog are willing to share their insights and stories. Please don’t name names or try to vilify a particular lab; keep it de-identified. We can air it out collegially and constructively.
– I admit that I stole this great line from Season 2 of the Showtime series The Chi.
Genetic counselors are proud of the psychosocial component that we claim to bring to patient care. Hey, we’re not just programmed human chat boxes, clever information-givers, or educators. We attend to the emotional and psychological needs of our patients and strive to transform our sessions into something closer to a psychoeducational experience, sometimes with psychotherapeutic effects. All that “psycho-” is what transforms genetic counseling from a cold clinical encounter into a humanistic endeavor.
Hence many readers may be upset when I suggest that we retire the sacred word “psychosocial” from our vocabulary. This bug was put in my ear by my esteemed colleagues Barb Biesecker, who has enough publications to fill 3 careers; Jehannine Austin, a world leader in psychiatric genetic counseling; and Laura Hercher, Renaissance woman and host of the genetics podcast The Beagle Has Landed. I am authoring a chapter for their soon-to-be-published book (Genetic Counseling: Clinical Practice and Ethical Considerations, in the Cold Spring Harbor Laboratory monograph series Topics in Medicine). When I submitted my chapter they asked me to remove the word psychosocial from the text. Similarly, Barb Biesecker, Kathy Peters, and I are co-authoring a genetic counseling textbook to be published this Fall by Oxford University Press (Advanced Genetic Counseling: Theory and Practice), and “psychosocial” was dropped from that text too, unless my Find and Replace function missed a few instances.
It’s not that I or they think that genetic counseling shouldn’t have a psychological component. On the contrary, I and they think it is a defining element of our profession, even if in practice genetic counseling may be “less psychosocial” than we say it is. The point of contention is that “psychosocial” is too imprecise a term to be meaningful in a research or outcomes kind of way in the context of modern genetic counseling.
Historically speaking, it was natural for the fledgling field of genetic counseling to borrow some of its vocabulary from social work. Sheldon Reed famously and vaguely defined genetic counseling as “a form of genetic social work.” Joan Marks who, along with Melissa Richter, established the first genetic counseling training program at Sarah Lawrence College in 1969, was a social worker and perhaps this is where the term reflexively entered into the genetic counseling lexicon. Particularly during the first two decades of the profession, not a few genetic counselors were social workers (In my younger years, when there were far fewer genetic counselors, I was professionally acquainted with at least five social workers, two of whom helped train me). The psychosocial approach helped give genetic counselors a raison d’être that set us apart from clinical geneticists and provided a focus to our training and the care that we provide. The psychosocial paradigm in genetic counseling is embodied in Jon Weil’s 2000 classic text Psychosocial Genetic Counseling (Jon, by the way, was a psychotherapist, not a social worker).
But those were the early days when we provided a limited service to a narrow segment of the patient population. The psychosocial component gave us a leg to stand on but now it seems like more 0f a crutch. At a half century old, genetic counseling can no longer be considered a new profession. The average age of its practitioners is much less than the age of the profession itself. Genetic counseling is now better characterized as a mature specialty. It’s about time we stood on our own two feet. I celebrate the outstanding work done by social workers but genetic counselor are not social workers, and vice versa.
Deep down, the fuzziness of the term has always made me uneasy. And let me tell you, Barb and Jehannine, two of the most passionate genetic counselors I have ever met, have far stronger criticisms of “psychosocial” than just its fuzzy qualities. Although a dictionary will provide a definition, in the setting of genetic counseling its unstated meaning is something like “those components of a genetic counseling session that are not strictly educational or technical.” It tells us nothing about assessing the effectiveness of the components or outcomes of genetic counseling; or how to improve them; or how to develop a scientific foundation for teaching, applying and researching genetic counseling; or how we can contribute to basic research into the human mind and behavior. For decades, genetic counselors were very poor at demonstrating their utility or effectiveness or at investigating those aspects of our service that were beneficial, harmful, or useless to patients (except in the Netherlands, which has consistently produced some of the best genetic counseling research, and a few other select researchers). This may have been in part due to the imprecision of the term “psychosocial.” That needs to change.
No doubt many of the good readers of The DNA Exchange will be angered, upset, and confused about the proposal to drop psychosocial from our vocabulary. And just plain disagree. Well, good. That’s one of the reasons I write this stuff. I want us to get worked up about genetic counseling, think hard about it, question its very core, and engage each other collegially. Those are the sorts of reactions we should have if we are as passionate about genetic counseling as Barb and Jehannine are and if we want to deliver the best possible patient care.