Expanded Carrier Sequencing: Would You Rather?

On summer road trips, my kids loves to play a game Would you rather?  For instance, would you rather eat a bowl of spaghetti noodles without sauce or a bowl of spaghetti sauce without noodles?  Would you rather have a unicorn horn or a squirrel tail?

In the spirit of summer road trips and the holiday weekend, I’d like to play a game of Would you rather? that only genetic counselors can appreciate.

This is a trade off we have to make with carrier screening.

Carrier screening programs intended for the general population as supported by the practice guidelines put forth by our professional societies tend to favor Option B. The reason being that more harm than good may result when providing information that is uncertain or ambiguous, especially in the context of reproductive decision making.

These days however, Option A is becoming increasingly common. Although at odds with society recommendations, which generally recommend a more targeted approach, the use of expanded carrier screening (ECS) panels that utilize sequencing are being more commonly accepted into practice with labs often claiming that more prenatal testing is better.

But is more really better?  

In theory, it makes sense to offer screening that provides as much information as possible. However, we know that what makes sense in theory does not necessarily lead to good medical practice. And there are warning tales of screening programs that were initiated with good intention but led to unfortunate, unintended consequences.

Consider the early days of carrier screening for cystic fibrosis (CF) as an example. After years of careful study and deliberation, in 2002 experts from the American College of Medical Genetics together with American College of Obstetricians and Gynecologists published recommendations for use a panel of 25 mutations in the CFTR gene. However this initial panel was revised in 2004  when it became evident that one of the originally defined mutations,  p.I148T (c.443TC) was in fact a benign polymorphism.

On a panel of just 25 mutations, in a well known gene, for a well defined condition, after years of critical expert evaluation, a mutation that  was initially included on a panel as causative of disease was eventually determined not not be, only after being put into practice. It is likely that Option A was a reality for some families in the early days of CF carrier screening.

Now consider that with expanded carrier screening panels that increasingly perform whole exon sequencing, often of >100 genes, one can imagine that many of the mutations being called with carrier screening are not disease causing. I believe that Option A will become much more frequent with greater utilization of carrier screening panels that use sequencing.  

And in addition to the possibility of incorrect variant classification, there is also a concern for increased false positive results as carrier screening expands. A reality with any screening test is that the rarer the condition, the more likely a positive result is a false positive result.

 

When questions arise regarding interpretation of variants on ECS panels, the labs often respond that they follow the ACMG Standards and Guidelines for Interpretation of Sequence Variants.

But here’s the thing, these guidelines were not developed for carrier screening in a healthy population. To quote the ACMG document: “The following approach to evaluating evidence for a variant is intended for interpretation of variants observed in patients with suspected inherited (primarily Mendelian) disorders in a clinical diagnostic laboratory setting.”

 

The authors of the ACMG Standards also warn: “Caution must be exercised when using these guidelines to evaluate variants in healthy or asymptomatic individuals or to interpret incidental findings unrelated to the primary indication for testing. In these cases the likelihood of any identified variant being pathogenic may be far less than when performing disease-targeted testing. As such, the required evidence to call a variant pathogenic should be higher, and extra caution should be exercised. In addition, the predicted penetrance of pathogenic variants found in the absence of a phenotype or family history may be far less than predicted based on historical data from patients ascertained as having disease.”

 

As genetic counselors we are trusted to advise patients of this information, and knowing that such information is used to make life changing reproductive decisions (i.e utilizing prenatal diagnosis, pregnancy termination, undergoing assisted reproductive technologies and preimplantation genetic diagnosis, or deciding not to have biological children) we know how important it is that the information we provide patients is unambiguous, accurate, and evidenced based.

However, we seem to be accepting the move to expanded carrier screening panels using sequencing rather than more targeted genotyping panels with little question about whether this is the right thing to do.

While many have accepted that expanded carrier screening with sequence analysis is the new normal, we should note that despite the marketing spin by the companies that this method of testing is superior, there are still no prospective studies that demonstrate clinical validity and utility of expanded carrier screening panels with sequencing. And guidance from our professional societies recommends a more limited approach to carrier screening.

While labs promote certain conditions included on their carrier screens as “recommended” by the ACMG and ACOG, they fail to acknowledge that those professional societies specifically advise against whole exon sequencing, and instead recommend a more targeted approach that evaluates, and reports on only well characterized mutations.

From the ACMG Position Statement on Prenatal/Preconception Carrier Screening (2013):  “There must be validated clinical association between the mutation(s) detected and the severity of the disorder.”  And more recently, from the ACOG Committee Opinion 691 on Carrier Screening for Genetic Conditions (2017):  “Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening.”

Who should decide which test is best?  The testing laboratories? The professional medical organizations?  Patients?

It seems that for now, that the laboratories are steering this ship. Despite the lack of evidence proving benefit and many cautions against it, several labs have sunsetted genotyping panels and have moved exclusively to sequencing, for what seems to be an ever growing number of rare conditions. It is becoming increasingly difficult for clinicians to follow the guideline recommendations when ordering tests for patients and we seem to be quickly entering a time where Option B is not an option at all.

It should not come as a surprise that the labs are pushing this new expanded testing as there is an incentive for labs to use sequencing over genotyping from a business perspective.

Sequencing genes rather than using a defined mutation panel allows for labs to boast of a higher detection of carriers, thus provides bragging rights for their marketing materials. One lab highlights on their website that their test identifies “30% more pregnancies affected with cystic fibrosis or spinal muscular atrophy” when compared to the ACMG and ACOG  recommended panel. What is omitted on their website is that for some of the mutations identified, we do not yet have definitive information about disease causation or phenotype. And thus we are asking patients to make reproductive decisions based on uncertain information.

Another compelling reason for the labs to expand to sequencing is that detecting more mutations in the patient begets more testing of their partners. And more testing is the name of the game with laboratories that aim to increase test sales. Understandably that is their goal as it should be, we need labs to sell test in order to stay in business and provide a needed service for patients and providers. That said, lab sales and profits should not be driving best practices for patient care.

 

While more may seem better in some situations, this notion should be especially scrutinized in the area of reproductive carrier screening. As the professionals that are trusted to interpret these tests results and help patients understand this information in the context of their own lives, we need evidence beyond modeled hypothetical disease risk to demonstrate that these expanded tests will truly benefit pregnancy outcomes. As has been discussed on the DNA Exchange in a prior post by Bob Resta, positive change to do best for our patients in this area will require work from multiple parties. Labs should put the brakes on with regards to marketing new tests and step back while independently funded research assesses the relative harms and benefits of testing. Governments need to fund such research. And clinicians need to critically evaluate the testing that is offered to patients, especially when unproven testing strategies are being introduced and promoted that may create more harm than good.

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Press Secretaries and Prenatal Diagnosis

The prevailing psychological paradigm views the human mind as two different interacting agencies – the unconscious and the conscious. The influence of the unconscious on the conscious mind began receiving scientific attention in the 19th century, reaching a critical juncture with Sigmund Freud’s deep dive into the murky and lurid waters of the unconscious. While many of Freud’s theories have not stood the test of time, his core concept that our unconscious mind is driven by darker instincts that our conscious mind tries to cover over is still widely accepted. And, in a sort of cosmic joke, it is extraordinarily difficult for us to know our own minds because our brains were shaped by evolution to deceive us into thinking we are good people who are conscientious members of society. We are really good at lying to, and believing, ourselves. I like the imagery employed in Kevin Simler’s and Robin Hanson’s recently published book The Elephant in The Brain that compares the conscious mind to a press secretary that tries to positively portray the less saintly aspects of the unconscious mind. Think of a governmental press secretary who has to explain a leader’s questionable statements and decisions without always being aware of what the leader is saying or doing.

So what does the deep mind and its personal Press Secretary have to do with genetic counseling? Well, a lot actually. In previous posts, I have discussed how the unconscious mind can influence genetic counselors’ perceptions of their conflicts of interest, how the pauses in a conversation between speakers can subliminally communicate meaning, and how I sometimes struggle to not let my darker thoughts insinuate themselves into my interactions with patients. In this posting, I look at the role of the unconscious mind in patients’ decisions to accept an offer of prenatal screening for Down syndrome and in deciding whether to continue a pregnancy in which a fetus has been diagnosed with this condition.

There is a common and deep negative attitude toward people with disabilities, even among their care providers, that sometimes borders on fear. Pick your reasons for this – ego threat, announcing to the world your reproductive unfitness, an assault on your concept of an ideal child and family, selfishness to prevent the loss of how you want your life to play out, rejection of those different from us. Readers more astute than I at probing the unconscious can probably think of others. This negative attitude is the driving engine of the prenatal screening train – given a choice, many people do not want to raise a child who will have significant cognitive or physical impairments. Some of this stems from misunderstanding and misinformation about disability. But decisions are typically based on the darker motives of the unconscious mind, not on information.

Here is where the Press Secretary comes in to play. People prefer not to admit to these less socially acceptable thoughts. Instead, they manufacture very plausible explanations to justify their decisions. Mind you, I am not implying that people are liars, hypocrites, or morally derelict. Rather, the unconscious mind usually rules the roost and leaves it to the Press Secretary to put a positive spin on it. This is how the human mind works, and it is crucial to understanding how patients make difficult and morally ambiguous decisions. It is like a role reversal in the Wizard of Oz.* Professor Marvel, Acclaimed by the Crown Heads of Europe, isn’t behind the curtain. Instead, the flaming, smoking, blustering, self-important gigantic head of The Great and Terrible Oz is back there. Oz doesn’t have the heart or courage to fight the Wicked Witch of the West and manipulates Professor Marvel to impart the task to Dorothy the Small and Meek (and, yes, Toto too). Professor Marvel is a bad wizard trying to pass himself off as a good man.

 

For example, what I often heard from patients as an underlying reason for a decision to proceed with testing or terminations shifted the focus from darker to more personally and socially acceptable reasons:

  • “We wouldn’t want our other children to bear the burden of caring for a disabled sibling after we are gone.”
  • “It would be unfair to our other children if we had to devote so much attention to a disabled sibling.”
  • “My doctor thinks it is the right thing to do and really wants me to have the test.”
  • “The world can be cruel to people who are different. I remember how a boy with Down syndrome was mercilessly teased in my neighborhood when I was growing up. I would not want to put my child through that.”
  • “It would put too much of a strain on our marriage. I know I could deal with it, but it would be devastating to my spouse.”
  • “I want to take advantage of advances in medical testing and information to make sure my baby is healthy.”

As a counselor, there is nothing to be gained from criticizing any of these as being invalid justifications. Indeed there is a measure of truth to them that provides plausibility. Patients are not concocting nonsense reasons or blatant falsehoods. But they also transform the less desirable urges of the unconscious mind into a message that allows the conscious mind to maintain its self-image of a Good Person and to avoid the negative judgment of family, friends, and social networks. On top of this, a well-oiled medical and economic machinery capitalizes on negative attitudes toward disability and reinforces the idea that prenatal screening is a wise choice for responsible parents.

This also has implications for critics of prenatal testing who claim that if pregnant women better understood the quality of the lives of people with disabilities, then more people would reject prenatal screening. This is true only to an extent. The unconscious mind is not usually persuaded by mere facts and will ignore them, reframe “truth” to make it more compatible with the motives of the unconscious, or filter out the parts that it doesn’t want to hear. Bias against physically and cognitively different people is found in all cultures and over time, though there is variation as to which conditions are the focus of a society’s prejudices and fears. People with albinism have been traditionally well-integrated into Hopi society and often play special roles in ceremonial dances; in parts of Africa they fear for their lives. Education alone is unlikely to alter attitudes. Change will require large-scale cultural shifts in views towards specific disabilities and conditions.

Unless we appreciate how the unconscious mind drives behavior and choices, we will never understand our patients – or ourselves.


  • – The day after I drafted an early version of this posting, I came across the same allusion to the Wizard of Oz in Leonard Mlodinow’s Subliminal – How Your Unconscious Mind Rules Your BehaviorIncidentally, in L. Frank Baum’s Oz books, Professor Marvel explains that his full name is Oscar Zoroaster Phadrig Isaac Norman Henkle Emmannuel Ambroise Diggs, the acronym of which is OZPINHEAD. In yet one more example of bias towards people with disabilities, he chose his name by using the first two letters of that acronym – Oz – and dropping the “pinhead” part.

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When Perfection Causes Imperfection: A Potential Non-Genomic Complication Of Germline Editing

There is wide consensus that we should not only treat but also try to cure genetic conditions that cause profound suffering. CRISPR and related technologies have descended on us like a deus ex machina from the heavens and made it possible to “cure” genetic diseases through germline editing. Precision molecular microsurgery has stimulated provocative discussions about which diseases are serious, where we draw the line, the acceptance of people who are different in appearance and abilities, increasing the disparities between wealthy and poor, religious concerns, etc. I don’t have any helpful insights into these issues but I hope that vigorous debate continues and that if germline editing becomes a reality, we proceed veeerrrrrryyyyy slowly, cautiously, and incrementally.

The more ardent “germline utopians” envision a world where all fertilized embryos undergo germline editing to prevent the resulting offspring from developing genetic disorders. Of course, this will never happen universally. Even in a fantasy world of full acceptance of, and unrestricted access to, germline editing, pregnancies have a habit of, well, happening on their own. But for argument’s sake, let’s make the unlikely assumption that many parents will utilize germline editing to prevent their children from developing genetic conditions. Given that Western societies place great value on individual autonomy and considering the conditions that are currently screened for through prenatal diagnosis and carrier screening, it is likely that prospective parents would choose to “correct” traits ranging in severity from hearing loss to profound physical and developmental disorders, and all points in between. And to twist the complexity we might see the reverse scenario where deaf parents choose to “correct” a hearing-abled embryo. Should genetic enhancement – adding a few IQ points, tacking on centimeters of height, a slimmer habitus, Faye Dunaway zygomatics – become a reality then a goodly number of parents will take advantage of that as well (please I hope never because it will bring out the worst in us).

Of course, this model of genetic disease prevention depends on whether the technique actually works and that it is safe. There is reason to believe that germline editing and “correction” of genetic conditions are technically achievable. Safety, however, is more open to question. Off-target genetic effects, among other safety issues, could relegate germline editing to the What If category of debate.

But let’s posit a world where efficacy is proven and off-target effects are negligible. There would still be another safety issue, unrelated to genomics. Germline microsurgery requires in vitro fertilization/intracyoplasmic sperm injection (IVF/ICSI) in order to gain access to the gamete or the fertilized egg and to achieve a pregnancy. And therein lies the rub – IVF/ICSI is associated with a higher risk of complications in singleton and multiple gestations, such as prematurity, low birthweight, small for gestational age, perinatal mortality, and congenital anomalies. It reminds me of the introduction of a phenylalanine-restricted diet to reduce the impact of PKU that eventually created the phenomenon of maternal PKU, in which maternal hyperphenylalaninemia produced babies with microcephaly, heart defects, and intellectual disabilities. The attempt to cure one problem can create a whole new set of problems.

Now maybe the complications of IVF/ICSI are in part due to the underlying causes of the parental infertility, and thus fertile couples may have lower complication rates. Maybe. Perhaps IVF/ICSI will become safer. Perhaps. Still, it is likely that some parents will be willing to accept the risks of pregnancy complications in return for not having a child with Tay-Sachs disease or severe ichthyosis. But are the pregnancy risks worth it to prevent genetic hearing loss, increase a child’s IQ, or create a child with movie star beauty?

You might understandably say “My God, we finally have the chance to prevent serious genetic problems and improve people’s lives. How can we not take advantage of it? We are just trying to do good in a world full of suffering.” Indeed, the goal of reducing suffering is as old as the field of Medical Genetics. But when we march beneath the banners of Cure, Good Intentions, and Highly Ethical Motivations, and throw in an unhealthy dose of hubris, our enthusiasm may blind us to the harm that we might do. Perfection comes with a price.

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Work Shift: A (Wrong?) Prediction

Genetic counselors are engaging in a bit of preening now that CareerCast has listed our profession as the top-rated career for 2018. Actually, it’s a bit of history repeating itself. Back in 1980, the genetics equivalent of The Neolithic, I learned about the profession when I came across an article in Working Woman magazine (now defunct, and not to be confused with Working Women magazine, which is still in circulation) touting the top 10 careers for the modern woman of the 1980s. My other time-killing choices that day were People, Reader’s Digest, and Ranger Rick. If I had picked up a different magazine, well, just imagine Ranger Robert. Funny how our lives play out.  Incidentally, even today, National Society of Genetic Counselor (NSGC) membership is 95% female, so that article in Working Woman really had its finger on the socioeconomic pulse.

Ranger Robert. Graphics by Emily Singh

 

The CareerCast story appeared just a few weeks after the publication of the latest Professional Status Survey (PSS) by the NSGC. The two pieces got me to thinking about historical changes in the employment picture of the profession and eventually, perhaps after a beer or two, a prediction popped into my head about a trending shift in who employs genetic counselors. I am not the first to notice the trend, so my contribution is to suggest the extreme to which the trend will run as well as its implications.

My prediction is that within the next 5-10 years, a significant majority of US genetic counselors will be employed  by laboratories and other biotech firms, in both patient contact and non-contact roles, and, to a lesser extent, by private practice groups that offer their services over the Internet or whatever communication technology is predominant in 2025. Until about a decade or so ago, the vast majority of genetic counselors were employed by private and academic medical centers. This is still true; if I am interpreting the 2018 PSS correctly, about 2/3 of genetic counselors are employed by medical centers, public hospitals, HMOs, private hospitals, and physician private practices. However, there were also changes in the percentage employed by laboratories and biotechs. In 2010, 10.5% of genetic counselors were employed by labs and biotechs. By 2018, that percentage more than doubled to 22.5%, and another 2% of genetic counselor were employed by telegenetics companies in 2018 (the 2010 PSS did not have an equivalent category). In other words, about a quarter of the current genetic counseling workforce is employed by labs, biotechs, and telegenetics companies.

There are several factors driving this trend. First off, more laboratories are offering direct genetic counseling services to patients and thus need to hire more counselors  – Counsyl and its new owner Myriad Genetics, Color Genomics, LabCorp, and Invitae, to name a few. Second, salaries of laboratory genetic counselors are typically a good 20% higher (plus more to be made in bonuses and stock options) than those offered by medical centers, making labs more enticing to prospective employees. Third, more medical centers and large medical practices are looking to include genetic counseling among the services they provide to their patients. Since genetic counselors don’t typically generate enough income to pay their costs, medical centers may be relieved to have a laboratory provide genetic counseling to their patients, either on site or via telegenetics. Clinics would bear minimal costs and labs would get a pipeline for specimens. This in turn will create a competitive environment among labs to offer their genetic counseling services to more clinics to ensure they maintain reasonable share of the testing market. A lesser trend will be the growth of telegenetic services offered by dedicated telegenetic counseling companies and individual private practitioners (together, currently 2.2% of genetic counselors). I suspect this latter group will be limited in its employment share, in part because they will have a hard time competing with the deeper pockets of large corporations. The net effect will be that the percentage of genetic counselors employed by medical centers will decrease significantly.

A natural extension of this trend is that bigger labs will continue to swallow smaller labs, and mega-corporations will swallow the bigger labs. Its hard to fight economy of scale. Konica Minolta owns Ambry Genetics. Eventually BGI may get in on the act (then watch out!). Heck, it’s not out of the question that many genetic counselors could one day work for Amazon (see my posting Sour Grapes, a dystopian satire about this possibility).

Both good and bad will emerge from these trends. More patients will have access to genetic counseling through telegenetics, whether from labs or dedicated genetic counseling companies. With genetic counselors on staff, labs and medical centers can be confident that testing is ordered and interpreted appropriately, improving patient care and reducing economic waste. More career opportunities will open up for genetic counselors as corporations recognize their skills and smarts. Salaries and other benefits will likely become more generous.

There is plenty to worry about too, at least for professional fretters like me. With more mergers and acquisitions, there will be fewer employers of genetic counselors and so the field will lose some of its practice diversity. Employers will expect their employees to adhere to certain business practices and philosophies unique to each employer. Practice diversity has been a rich source and testing ground for new and different ways to conduct genetic counseling. More concerning to me is the potential loss of  carefully considered patient decisions about whether to undergo a genetic test. Acquisitions and mergers are driven by the desire to increase market share and market penetration, not by an altruistic urge to ensure that patients carefully consider the benefits, downsides, and psychological impact of genetic testing (although undoubtedly labs support the right of each patient to make independent decisions). This will become even more concerning  as labs are subsumed by larger corporate entities that are further removed from the practice of medicine and the ethos of genetic counselors, generating real concerns about conflicts of interest. Another possibility is that large labs will either set up or help finance genetic counseling training programs. Why not have a steady source of prospective employees who can be trained to develop skills and a counseling approach that are shaped to a particular corporate milieu?

I acknowledge that this is a very America-centric view of the genetic counseling profession. This trend may not play out to the same degree, or at all, in other countries. On the other hand, telegenetics knows no borders. Conseil Gènètique Sans Frontières. Governments are looking for ways to cut health care spending in the UK, Canada, and Australia, among others. International mega-corporations – Big Genoma – can offer enticing cost-savings to legislators looking to reduce expenses without increasing taxes.

Of course, like most prophets and self-appointed pundits, my predictions will be off, and perhaps even laughably so. The thing about the future is that nobody knows what it’s going to be like. So if you disagree with me, or are outraged by my thoughts, take solace in knowing that I will likely be wrong yet again. But I think there is enough meat on this bone that it’s worth chewing over.

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DTC: Direct to Children?

Last week Phil Rogers, of Chicago NBC News reported that he submitted a DNA sample from his dog, Baily, to the laboratory, Orig3n for analysis. This made headlines because a test report was issued on his dog for a test that was designed and marketed for humans. In follow-up to the story, Orig3n spokesperson, Karmen Conrad stated that, “…since October Orig3n has acquired a CLIA Certified laboratory and upon hearing about this issue has implemented controls to assure that nefarious samples such as this are rejected from further processing. We are sorry there was an error in reporting this one particular sample.”

I know firsthand that Phil’s experience was not an isolated case.* Last December, I submitted my dog Ginger’s DNA swab for the “Bloom Child Development” test, also by Orig3n, and I also received a completed test report. According to Orig3n’s website, “the Child Development DNA Test is a gene profile that will start you and your child on the path to lifelong discovery. From fitness to natural abilities for language and learning, the results help you get to know your child even better.”

Nothing was flagged as out of the ordinary with Ginger’s DNA. From the looks of her genetic test report, Ginger appears to be a pretty average kid in terms of her intellectual and athletic potential.

samginger

* Pictured on the left is Ginger. As you can see from the grey temples of my canine child, Ginger is safely over the requisite 13 years of age.  On the right is my colleague’s dog, Sam, who also submitted a sample to Orig3n for the “Superhero” test. Sam also received a complete test report. According to Orig3n, Sam is likely to be good at endurance activities such as triathlons. 

 

Genetic testing from the kitchen sink

This brings me to the second part of my experiment which proved to be much more troubling. It seemed plausible to me, given the homology between human and canine genetics, that the lab could have obtained results for at least some of the SNPs on their panel with Ginger’s sample. So, I decided to try the Bloom Childhood Development kit again, but this time I sent a blank. Using gloved hands, I carefully removed the swap from the sterile envelope and quickly ran it under the tap water of my kitchen sink, packaged it, and mailed it to the lab. In less than two weeks, I received a report for my imaginary tap water child. Like Ginger’s report, the results for the water sample was a 35-page report that varied at six of the 24 SNPs from Ginger’s results. But a much more disheartening difference between Ginger’s result and the water sample was that the report on the water sample was signed out by a DNA Laboratory Director, PhD Geneticist and fellow of a major American genetics organization.  

This is worth repeating – a  boarded geneticist signed out a report on a genetic test promising to predict the athletic and learning abilities of a child, from a sample of tap water.

Of the many tests offerings available through Orig3n, I chose the Bloom test in particular because I am deeply concerned that this test encourages parents to send in DNA samples from their children. I sent away for this test because I wanted to see for myself if there was a consent form or written information included with the test kit beyond what I could find online to caution consumers about the potential risks and limitations of this testing. Not surprisingly, there was nothing of the sort. Just instructions on how to obtain the sample and a simple postcard asking for a name, email and phone number.

 

Children are a target market for these tests

To me, the most disturbing part of the story is not doggie DNA but rather that children are the target for this and others tests like it, thereby compromising individual autonomy and privacy of genetic information. Regulatory gaps allow labs to boast of their CLIA Certification, which should provide some assurance of analytical validity, but may only serve to give an illusion of credibility. There are serious ethical concerns with this shift in “personal genomics” and allowing these unethical practices to go unchecked risks undermining the legitimacy of medical genetics.

Through social media, Amazon.com, and promotional events, companies are targeting parents of young children. Even Readers Digest gave the Bloom test a plug.  This company encourages people to submit their children’s saliva sample to gain information about their health, “enlightenment” and fitness information. While their Terms of Service and Privacy Policy say the testing is not directed at kids under 13 years of age, the child pictured on the test kit box appears to be years away from double digits. The Orig3n twitter feed is full of cute pictures of preschool age children. And this Instagram post on the Orig3n sight with a mom blogger  proudly swabbing her infant and toddler’s cheeks raised my genetic counselor anxiety through the roof.

Since genetic testing first became possible, the medical community has carefully deliberated the ethical ramifications of genetic testing in children and has recommended caution about how and for whom these tests should be used. Generally, it is held that a child’s autonomy and privacy should be protected when it comes to their genetic information. Unless the results could change medical management towards a better health outcome for the child, genetic testing of children is considered ill-advised. One can imagine the unintended consequences that may result from the use of these tests. It is not unfathomable that parents with great faith in the “science” of this technology may use results to determine how to allocate attention and resources in the family, investing more in one child or another based on the genetic results that may inaccurately suggest differences in intellectual or athletic promise among siblings. I believe that parents that are using these tests genuinely want all of the best for their children. They are seeking out these tests with the goal to give their kids the best possible advantage for their gifts and talents.

That being said, it is very difficult for me to imagine how such information could be beneficial to families and very easy for me to imagine the harms of growing up in a family guided by the results from a DTC test.

And what about privacy? It feels incredibly wrong to me that through no decision of their own, the DNA samples of many children are now in the hands of corporations to be bought and sold. We can only begin to imagine the possible unintended ramifications of this for the future, but only need to look as far as the recent Facebook news to get some ideas of what may be possible.

And while Orig3n may be the laboratory that is most direct in targeting children, it is not the only lab allowing for casual genetic testing of minors. Many people are sending in their kid’s samples to labs such as 23andMe, and in some cases inputting the raw data into 3rd party applications that provide an output of information related to possible mutations in genes for adult onset disorders such as cancer susceptibility.  Many of these results are false positives, but that is a story for another day.

Now genetic counselors are seeing patients for consultation on raw data of DTC tests that indicate the presence of mutations associated with Lynch syndrome and other genetic cancer susceptibility in young children. Historically, genetic counselors have taken great care in working with families to convey the potential implications of testing of children for adult onset conditions. Now, thanks to DTC testing, children everywhere are being tested for any number of genetic conditions, without counseling and without consent.

 

Gaps in regulation allow opportunistic genetic testing labs to operate and risk delegitimizing the field as a whole

This is not the first time that Orig3n has been in the news. Many may remember the planned “DNA Day” to be held at the Baltimore Raven’s game in 2017.  Maryland shut this event down due to regulatory concerns, one of which was the fact that Orig3n was not CLIA Certified.  The company remedied this problem late last year through their acquisition of Interleukin Genetics, a CLIA Certified laboratory that is now apparently the site where Orig3n processes their DNA samples.  Many DTC labs tout their CLIA certified lab as a symbol of quality. It is one measure, but CMS’s oversight of labs under CLIA is quite limited. And from the tap water experiment, I am not so confident that CLIA certification provides much assurance of analytical validity.

The lines between clinical and nonclinical labs are increasingly blurred. With lack of transparency in lab practices and enormous gaps in regulation, the ability to confidently assess lab quality is becoming impossibly difficult, even for genetics professionals. It is our responsibility, as part of the medical genetics community, to take a close and critical look at how genetic testing is developing, to shine a light on unethical practices, and push for regulatory standards that will better ensure integrity in the field of genetics. Our patients deserve nothing less.

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Is Test Uptake A Good Measure of Genetic Counseling Effectiveness? I Don’t Think So

The last few years have seen a growing trend for patients to undergo genetic testing without first seeing a genetic counselor or other genetic specialist. As I have commented before, genetic counselors are no longer the gatekeepers of genetic testing. Anyone can obtain DNA analysis through non-genetics specialists or any health care provider, on Amazon.com and other internet sites, and at their workplaces (which, honestly, makes me very uneasy; it is going to be awfully difficult for some employers to keep their noses out of their employees’ genetic information and it may provide an opportunity to chisel away at the protections afforded by GINA). Many genetic counselors have accepted this as a fact of life, even if we are not altogether comfortable with it.

Historically, the genetic counseling profession has done a poor job of demonstrating its value to the health care system. Our importance seemed pretty obvious to us and because we didn’t have much in the way of competition we were never strongly motivated to undertake large scale studies to prove our worth.

Comparative studies are starting to address the value of pre-test counseling by a genetic counselor, particularly in the field of hereditary cancer genetic testing. This as a good thing.  Still, it bothers me if studies claim that genetic counseling is failing patients because fewer people undergo genetic testing if they need to see a genetic counselor first. Sure, genetic testing should be readily available to those who need it, and barriers need to be removed. If seeing a genetic counselor turns out to be one of those barriers, then we need to do something about that. But test uptake may not always be in the best interests of patients.

For example, the most common reason an unaffected patient declines genetic testing after seeing me for hereditary cancer counseling is that, for the moment, they are the “wrong” person to test to most accurately determine their hereditary cancer risks. Even though the patient may technically meet standard criteria for genetic testing, they may still not be the best person to test within the context of their specific family history. Not undergoing genetic testing is not due to a lack of timely access to me, the cost of my services, or me somehow talking them out of testing. Instead, after reviewing their family history, it turns out that testing their mother with breast cancer or their brother with colon cancer is the most appropriate person to test before deciding if the patient and other unaffected relatives should undergo testing. If that affected relative has a normal genetic test result, then testing my patient and other relatives is usually a waste of money.

It is also difficult to interpret a negative test result in a family where a mutation has not already been identified. Now, I am a grizzled veteran of the Family Dynamics Wars, and I realize that sometimes that affected relative is deceased or just not willing to undergo testing, and you have to make do with the realities of the situation at hand. And, of course, this argument does not apply to testing patients who have been diagnosed with cancer (although it may apply in situations where patients meet NCCN guidelines but not their insurer’s criteria for coverage, but an affected relative does meet their insurer’s criteria). Still, testing an affected relative should be utilized whenever feasible because it is clinically and economically the most effective strategy. Therefore, if a study finds that test uptake is increased when patients do not first see a genetic counselor, the researchers are obliged to demonstrate that this is not simply due to more cases of the “wrong” person being tested or the providers not willing to take the time to work with the extended family.

Along these same lines, in many situations, even genetic test results of an affected relative are often uninformative for risk assessment. Such families may still need to be followed as high risk, with screening and risk reducing protocols based on family history and clinician judgment. Effectiveness studies therefore need to investigate whether there are differences in clinical recommendations provided to patients who see a genetic counselor compared to those who do not.

Studies of genetic counseling vs. no genetic counseling also need to provide data on patient adherence to screening and other risk reduction guidelines. Increased test uptake is not particularly helpful if patients do not have the motivation or wherewithal to undergo breast MRI, salpingo-oophorectomy, join the Annual Colonoscopy For Life Club, or whatever else is recommended. Other outcomes that effectiveness studies should address include communication of test results to family members, interpretation of variants of uncertain significance, and patients’ psychological adaptation to their risk status. I imagine many of you reading this posting can suggest additional outcomes that need to be addressed.

My other concern about reduced genetic counselor involvement with pre-test counseling is that “counseling” will eventually be reduced to a pamphlet or a brief video, perhaps provided by the testing lab itself. This is already a major concern with how NIPT is presented to pregnant women, and I can see it becoming a problem in other areas of genetic testing. No matter how earnestly labs may claim that their educational material is not a subtle sales pitch, they are only human and can easily be blinded by their business needs. This is an area where GCs can develop better and less biased educational materials.

If research demonstrates that other genetic testing delivery models are more effective than, or at least non-inferior to (non-inferior sounds like a back-handed compliment,doesn’t it?), the traditional approach of First See A GC Before Your Test, then the genetic counseling profession should re-focus itself and use our many other skills to work towards improving patients’ lives and the medical care system. Besides, I have never liked conflating genetic counseling with genetic testing.

I do worry, though, that either the research will not be conducted, or that, even in the face of evidence to the contrary, market forces will dictate testing strategies. I am not concerned that it would portend the end of the genetic counseling profession. Genetic counselors are forever expanding their professional roles, and in fact have continually reinvented themselves since, well, we first invented ourselves in the 1970s. Like David Bowie, we never stood still and as soon as you had us pinned down as Ziggy Stardust, all of a sudden we were Aladdin Sane, and already sprouting within him are the seeds of The Thin White Duke (well, okay, it’s a stretch comparing genetic counselors to David Bowie, but you get my point). What matters is that all patients affected with or at risk for hereditary disorders receive the most competent and compassionate care delivered effectively, equitably, and timely.

Bobbin Sane
(Graphic by Emily Singh)

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The Hidden Costs of “Free” Genetic Counseling

A Guest Post by Eleanor Griffith, MS, CGC

Eleanor is the founder of Grey Genetics, a telehealth genetic counseling and consulting company.  Find Eleanor on twitter @elo81.

 

A lot of genetic testing companies are now offering genetic counseling along with genetic testing. That’s great, right? Great to see genetic testing companies hiring genetic counselors. Great for patients because it expands access to genetic counseling services to patients who wouldn’t otherwise receive genetic counseling.

Or actually, maybe not so great. Concerns related to conflicts of interest have been discussed on the DNA Exchange and elsewhere and are worth discussing further and at length. For starters, see here, here, and here.

But my gripe is that when a lab offers “free” genetic counselingit’s not really free. The cost is just hidden, bundled into the cost of the test. Hiding the true cost of genetic counseling in turn diminishes the perceived value of genetic counseling services.

Genetic counselors providing “free” genetic counseling get paid for their work. And they should. But the amount that it actually costs to provide genetic counseling vs. the amount that it costs to run a genetic test is not transparent—not to the patient, not to the physician, and not to the insurance company—which may or may not cover “genetic counseling.” Or may or may not realize that they do, in fact, cover the cost of some sort of genetic counseling(-ish) services by covering the cost of the test.

From a business perspective, for genetic testing labs, “free genetic counseling” is a no-brainer. It’s a big selling point and increases the odds that a healthcare provider will keep sending tests to the laboratory that is able to meet the very real counseling needs of their practice. As long as laws and regulations allow it, I don’t see this changing.

If the recognized product is the genetic test, and the main (or only) source of revenue for genetic testing labs is insurance reimbursement or out-of-pocket payments from patients, then the salaries of genetic counselors working for genetic testing laboratories are basically being paid by insurers + patients. If you follow my logic, this means that insurers will cover and patients do in fact pay for the (hidden) cost of lab-based genetic counseling, bundled into the cost of genetic testing. But insurers often don’t cover the cost of independent genetic counseling. Conflict of interest aside, this strikes me as ridiculous.

Away from the morass of insurance, patients and consumers of healthcare are being trained to see price tags attached to direct-to-consumer genetic testing products of dubious value, while genetic counseling is “free with purchase!” Even for clinical genetic tests ordered through physicians, self-pay prices are becoming more accessible. The logic, of course, is that labs will have a high enough volume of tests to scale and still make as much or more of a profit from testing…. Genetic counseling, however, cannot scale in the same way. This is why widgets get cheaper and cheaper while the cost of most professional services that require advanced degrees and involve working with clients one-on-one—lawyers, doctors, psychologists, financial consultants—remains relatively high.

While building up my private practice, I work part-time for an agency offering “free” genetic counseling to patients who respond to a quiz on facebook. I love it and I hate it.

I love it because I speak with high-risk patients who have never been referred to genetic counseling in a traditional way—many of whom have never heard of the BRCA genes. Patients who are interested in going forward with testing receive a copy of my consult note (yep, and a test kit) to take to their healthcare provider. Those who decline testing still receive a consult note with a copy of their family history and are encouraged to share it with their healthcare provider. Their healthcare provider has the option of including my name on the test requisition form so that I can receive and review results with their patient. Initially, I’m scheduled for an hour with each patient. If the patient needs more time to gather family history or to speak with someone in the family who would be a more appropriate candidate for testing—no problem, I just schedule her for a second call. I’m connecting with patients who would otherwise never have known of the option of genetic testing, would never have guessed that their insurance would cover the cost of testing for them, and had no idea of the impact it could have on their medical management and the value it could provide to their family members.

I hate it because the agency of course has a relationship with a specific laboratory. That laboratory happens to be the laboratory that I would recommend above others for hereditary cancer testing. This makes me feel good about the quality of testing that patients actually end up having—but also means that my professed recommendation should be looked upon with skepticism. Although the modest amount I’m paid is not affected by whether or not a patient goes ahead with genetic testing, and although I’m not privy to the details of the arrangement  between the agency I work for and the genetic testing laboratory—in reality, I’m obviously still being indirectly paid by the commercial testing laboratory. I’m just part of their operating costs.

I address patients’ questions about the costs of genetic testing, the likelihood that it will be covered by insurance. But there’s never a question as to how I’m getting paid, or why I’m getting paid. There’s no price tag assigned to the 30-90 minutes I spend talking with them. Sometimes patients are in a quiet place for our phone conversations. Sometimes they’re washing dishes, driving a car, picking kids up from school. After all, it’s a free call related to an impulse click on facebook. I have a Master’s Degree in Human Genetics, but my time costs them…. absolutely nothing. Or rather, the cost of my time is bundled into the cost of the agency’s services which is in turn paid by the laboratory which is in turn paid by insurers, which is in turn paid by my patients’ insurance premiums and/or taxes.

I feel less icky about this set-up than I had expected. (See the love paragraph.) Conflict of interest aside, however, this is a nasty bandage on a broken system in which the cost of genetic counseling is bundled along with the cost of testing rather than being recognized and billed for as a service provided by specialized medical professionals.

As uncomfortable as I feel getting indirectly paid by a laboratory, I feel equally but differently uncomfortable with charging patients for genetic counseling—which is exactly what I’m doing in private practice. The first patient who paid upfront and told me how valuable my time had been to her and how appreciative she was made it easier. But I still feel awkward asking patients to pay me. Most of us who have worked in hospitals have been similarly used to having the cost of our services swept up into other hospital costs and have not had to tell patients, “It will cost $X to see me.”

I think our time and services are worth $$$. Whether we work in industry, private practice, or for a hospital, I think we need to learn to be unapologetic about the fact that even if we love and find meaning in our jobs, we also work to make a living. The value of genetic counseling services should be accurately reflected in an associated cost. We’ve come a very short way from being a collection of mostly white, upper-middle class housewives who are happy to do volunteer work and don’t need to make an income. We need to take another step and get comfortable with transparently charging for the work we do.

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