Medical Strategy or Marketing Strategy?

A well-known direct-to-consumer (DTC) genetic testing company now has FDA approval to include a very limited form of BRCA testing with its DNA genotyping product. I refrain from mentioning the company’s name because they already got enough free press from the announcement. You probably know what company I am referring to, and if you don’t, well, follow the above link. Sorry Unnamed Company, but I am not going to make the free advertising that easy for you, no matter how insignificant the source. Besides, I see it as a bigger issue than just one company’s policy.

For now, the analysis is limited to the three BRCA1&2 mutations that are more common among Ashkenazi Jews. Actually, the company offered the same 3 mutation test until they were slapped with a cease and desist letter from FDA in 2013 to stop all medically related testing. So this new announcement amounts to a resurrection of a nearly decade-old policy, not a groundbreaking innovation. Funny, though, that there was not this much to-do when the test was first offered.

The genetic counseling community is in a bit of a dither about this, including me, though admittedly part of the reason I am writing this blogpost is to help me figure out just what I am dithering about.

Some of the concerns are obvious. People may be under the misconception that a negative result = no increased risk of hereditary breast/ovarian cancer and thus some high risk women may forego potentially lifesaving surgery and appropriate screening strategies. Then there is the worry that patients will not follow through with genetic counseling if the testing is positive, or that high risk patients will not seek genetic counseling and more testing if the result is negative. If you are not Ashkenazi Jewish, the test does not seem to offer much benefit. And even for Ashkenazi Jews, the testing does not include the ~10 other genes linked to hereditary breast cancer and the ~10 other genes linked to hereditary ovarian cancer.

The company recommends verifying positive results with an experienced clinical lab.  For that matter, then, why not verify a negative result, if there is that much uncertainty? Why bother having a test if you can’t fully trust the result? I suspect though that there is probably little reason to doubt the test result and that the company makes this recommendation to keep FDA happy and to minimize their legal exposure rather than concerns about assay validity.

Incidentally, the cost of the company’s product is really not much different than the more comprehensive multigene hereditary cancer panels offered by some of the clinical testing labs, and in some cases more expensive.

Eight years ago I shared my first experience with a patient whose BRCA carrier status was detected through DTC testing. My patient’s experience and a few more cases I encountered since then have not been that different than my patients who went through the usual counseling and testing process. A 2013 study by the company  showed that the 11 women and 14 men who discovered their BRCA status through DTC testing had experiences similar to my patients. That last statement is brimming with caveats – small sample size, at least for my patients they were savvy enough to want to see a genetic counselor, personality traits of the earliest users of new products, no long-term follow-up, etc. But I am not aware of any independent, large-scale studies of patients who learned their BRCA status through DTC testing to more definitively address the pros and cons, other than studies offering BRCA testing that targeted all Ashkenazi Jewish women.

I readily admit that I may be proven wrong, but I am guessing that most of the consumers of this DTC product – note they are not patients because the test is not intended for clinical use – will opt to learn their BRCA status. After all, people have this testing to learn about their genetic makeup. I am also guessing that this may be the company’s proverbial toe-in-the-water; I would not be at all surprised if additional clinically useful testing is part of the company’s future product and marketing plans.

At heart, I don’t like the idea of DTC BRCA testing. I think about all the ways it can go wrong, and inevitably some of those ways will come to pass. But will it go right often enough, and go wrong infrequently enough, that there will be adequate benefit to justify offering DTC testing? Undoubtedly, some of my uneasiness stems from a professional conflict of interest; DTC eliminates my role as an interface between patients and testing. Personally, I think being a middleman is a good thing because it can help patients take a thoughtful deep breath before leaping into the gene pool. But that could be because I have been trained to think that way and because it supports the value of my professional career. What I really should want is for patients to have access to genetic information in a manner that is affordable, accurate, psychologically and emotionally appropriate, and medically useful. If DTC and other forms of offering BRCA testing works for many men and women, then I should swallow my professional pride and acknowledge it.

So having stewed on this for a while, I have come to the realization that my argument isn’t with this company per se. Other companies aggressively market hereditary cancer and other genetic testing to average risk people. For example, one company approached my institution with the idea of offering their product to all women coming in for breast imaging, with saliva kits kept in the mammography center along with a prescription pad with a genetic counselor’s name on it acting as an ordering provider for the test (legal in my state). Although many labs employ genetic counselors who work directly with patients to review test results, this is still not the same experience as meeting with a genetic counselor before undergoing testing to explore the complex medical and psychological issues surrounding genetic testing. And the highly respected Dr. Mary-Claire King has advocated for population based genetic screening for establishing hereditary breast cancer risk. Are DTC clinical testing and other consumer-friendly strategies disruptive ideas that will bring about much-needed change or are they just bad but well-intentioned ideas that will also fill company’s coffers and keep investors happy?

Having sifted through and weighed my thoughts and feelings about DTC testing or other genetic test delivery models, I have concluded that my problem is not with DTC or other models per se. My argument is with how these new testing approaches are introduced into clinical practice, typically under some version of the banner of liberating testing and bringing it to the people. I do not doubt the labs’ sincerity when they say they are trying to improve access to medical care and reduce the suffering from cancer and other illnesses. But these are as much marketing strategies as they are medical strategies. Labs should not be calling the shots on the introduction of new tests and practice models because, in the absence of well designed studies, we really have no idea if these new approaches are effective in reducing cancer risks and increasing high risk screening when indicated, or if they are in the patients’ best emotional and psychological interests. Just throwing a mess of tests out there and encouraging everyone to take one is, in my view, irresponsible.

A better approach is to first conduct controlled and ideally randomized studies that evaluate both new and novel testing strategies to determine the most beneficial one(s) for patients, or if different types of patients benefit differently from different strategies. For example, age, family history, medical history, psychological functioning, and socio-economic status could all conceivably affect outcomes, not too mention the all too real possibility that many Americans may lose health insurance in the near future. While labs should play a critical role in that evaluative process, to keep it as clean as possible the studies need to be conducted and overseen by researchers who have no financial benefit from the outcomes of such studies.

We are in this together, so let’s work together.

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Is A Lab A Health Care Professional? An Update On “Everyone’s Worst Nightmare”

Two years ago I authored a blogpost, Everyone’s Worst Nightmare , about a family’s experience with genetic variant interpretation, communication (or lack of) by healthcare providers with families, and an outcome that couldn’t be more tragic – the death of a child. Here I am providing an update on the legal status of the lawsuit brought on behalf of the child by his mother. In my original posting, I did not identify the child’s syndrome or the specific court case. However, since then, the story has been picked up by a variety of media outlets (Turna Ray at GenomeWeb has done the best reporting on the details) and it now being a matter of public record, I have included some particulars here .

Briefly, the story began about 12 years ago when the child was experiencing multiple, intractable seizures and had a clinical picture consistent with Dravet syndrome. Unbeknownst to the parents, genetic testing was ordered and the child was found to carry a mutation in SCN1A, the gene linked to Dravet syndrome. The mutation was interpreted as a variant of uncertain significance, though at the time there was reason to believe that it could be pathogenic. Based on the genetic test result, it was felt that the child did not have Dravet syndrome and was kept on a sodium channel blocker, which unfortunately is contra-indicated for patients with this syndrome. Not long afterwards the child died of seizures at the age of two.

The patient did not find out that genetic testing had been performed until about 7 years after the test was ordered. Shortly after the mother learned of the test result and inquired into its meaning, the lab reclassified the variant as pathogenic.

In February 2016 the mother initiated a lawsuit on behalf of her deceased child in the fifth judicial circuit court in Richland County, South Carolina. The defendant’s lawyers requested that the case be dismissed on the grounds of restrictions imposed by the state’s statute of repose, i.e., a law that states legal action must be initiated within a certain period from the time the alleged offense occurred (it is similar to but slightly different from a statute of limitations). The defendants presented the argument that a genetic testing laboratory is a licensed health care provider and South Carolina has a 3 year statute of repose for lawsuits brought against licensed health care providers. Since the events took place a decade ago, the defendants asserted that the case should be dismissed. The plaintiff countered that, under South Carolina state law, a genetic testing lab that is separate from a hospital or a clinic cannot be considered a licensed health care provider and therefore the statute of repose did not apply. The plaintiff contended that this is a case of ordinary negligence, not medical malpractice, since the lab should not be considered a licensed health care provider and therefore the suit should be allowed to proceed.

The case was then sent to the US District Court in 2017 to rule on whether dismissal was warranted based on the defendant’s argument that the lab is a licensed health care provider and therefore the statue of repose applies. The federal judge then referred the case to the South Carolina Supreme Court to, as the legal lingo goes, certify the question of whether a lab can be considered a licensed health care provider under the specific provisions of South Carolina Code of Laws Section 38-79-410. Although we may have our individual opinions on this question, it is strictly a matter of law that varies by state. South Carolina law defines a licensed health care provider as “physicians and surgeons; directors, officers, and trustees of hospitals; nurses; oral surgeons; dentists; pharmacists; chiropractors; optometrists; podiatrists; hospitals; nursing homes; or any similar category of licensed health care providers.” (italics added)

The South Carolina Supreme Court heard the case on February 14th, 2018. For those of you who have never witnessed a state Supreme Court hearing, I recommend that you watch the ~40 minute video of the session. The court’s decision, which will be about whether the suit can proceed rather than determining liability, will depend on how it interprets whether a laboratory is a “similar category” to the health professionals listed in the state code. I thought that the five justices were insightful and asked thoughtful questions. As a side note, at about the 29-30 minute mark of the hearing, Justice Few gives a shout out to our genetics colleagues at the Greenwood Genetics Center.

The court does not have a set date on when they will issue an opinion; as the Supremes, they call that shot (the South Carolina Supreme Court’s motto is Nil ultra, which roughly translates as “Nothing is above us”). Typically, though, the time frame on a ruling is in weeks or months. If the court decides that the lab is not a healthcare provider, then the plaintiff’s suit will be allowed to continue, though I got the sense that the court felt that even if the ruling were in favor of the defendants that the plaintiff may still have alternate legal pathways to pursue a case. I will keep the good readers of The DNA Exchange posted on important developments in this case, which I suspect will continue to drag on for some time after the Supreme Court’s ruling.

With the rapid expansion of genetic testing in the clinical and consumer spaces, and the growing involvement of non-genetics professionals in ordering genetic testing, bad clinical outcome scenarios are likely to become more common. Critical questions about variant interpretation and legal liability aside, from a genetic counseling standpoint, this case highlights the importance of clear and ongoing communication with patients and their families about the limits and clinical interpretation of genetic testing. This can be extraordinarily difficult when a family is trying to cope with caring for a child with a life-threatening disease, but genetic counselors are trained to work precisely in those situations. Genetic testing may be simple to order and widely available but it benefits no one without good clinical care and counseling.

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Growing Pains

With the rapid growth of the genetic testing industry, professional opportunities for genetic counselors have expanded rapidly.  Not only are genetic counselors now working in nearly every area of healthcare, many are embracing new roles as laboratory specialists, clinical science liaisons, and in sales and marketing roles for genetic testing companies. Some are entrepreneurs founding their own companies and pioneering new models for access to genetic information. It’s not surprising to see genetic counselors embracing these new roles. Like the founders of our field, seeing opportunities in change and forging new trails in uncharted territory seems to be characteristic of genetic counselors.

But navigating new terrain isn’t often easy.  As written by Alexandra Minna Stern in her historical account of the profession, ”the emergence of the genetic counselor as a bona fide professional was neither inevitable nor smooth.”  

Do other genetic counselors feel that we are currently in the midst of a most turbulent and rocky stretch of our profession’s journey through time?

Although we have had graduates from Master’s level genetic counseling training programs for more than 40 years, as well as a growing body of evidence regarding the value we bring to patient care, we are still reaching for recognition as healthcare professionals. While we seem to be making progress towards this goal, we have yet to be recognized by Medicare and many commercial payers as healthcare providers. Additionally, in many states the quest for licensure remains an incredible challenge.  

One of the biggest obstacles genetic counselors currently face is public perception of genetics and genetic testing. It seems that genetic discoveries that are part of evidenced based strategies to improve human health are increasingly being overshadowed by consumer genetic testing for entertainment. For example, screening for and treating familial hypercholesterolemia is considered to be a Tier 1 genomics application by the CDC given the level of evidence and potential to benefit public health. However it is estimated that less than 1% of the affected population in the US have been diagnosed.

On the other hand, consumer genetic tests are being increasingly utilized. Home DNA test kits through companies such as 23andMe and Ancestry.com were among the top selling holiday gifts this year. Consumer genomic testing claims to provide information about everything from personalized skin care recommendations, to what one’s ideal fitness regimen will work best, to what one’s hypothetical future children may look like. Some companies combine a mix of evidenced based health information with unproven claims related to entertainment and wellness information which leaves many in the field of genetics uncomfortable.

As genetic counselors, we are regarded as experts when it comes to genetic testing. So how should we respond to the flood of options in the direct to consumer space?  How should we be talking about these tests with our patients?  How should we be talking about these tests with other healthcare providers?  These are crucial questions for our profession, but ones that genetic counselors don’t seem to seem to agree on.

Through the media, through our professional discussion forums, and in conversations at genetics conferences over the past couple of years, I have heard two predominant and conflicting messages regarding genetic counselors’ opinion on consumer genomic testing. Some are enthusiastic, and believe the use of such tests should be encouraged as an opportunity for to engage people in the area of genetics, and hopeful that such engagement in any genetic testing will lead to better adoption of genetics into healthcare. Some are concerned about the proliferation of these tests and believe that they may cause more harm than good by blurring the lines between medicine and entertainment, leading to misinformed health decisions, compromising privacy, and creating new and unanticipated conflict for psychosocial family dynamics.

Our field is small with only about 4,000 genetic counselors nationwide. We are all only separated by only a degree or two of separation. A tight-knit community. So it is not surprising that with our profession expanding in so many directions, that we are experiencing some tension and growing pains with these emerging issues.

Whether we believe that consumer genomics is something to be feared or embraced, these tests are out there, people are using them, and it is crucial that we adapt to be able to help the public, our patients, and each other navigate this new terrain.

Do you see consumer genomics as an area that we should encourage, participate in, and guide?  Or should genetic counselors discourage the use of these tests, both on an individual patient level and in policy?  How do you see us adapting to the brave new world of consumer genomics?  

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Top Ten Stories in Genetics in 2017

Mark it in your calendar: 2017 was the year when gene therapy (broadly defined) became something more than hypothetical.  Hard to talk about 2017 as a great year, but that’s the storyline in genetics.  Here’s the countdown:

  1. Ohio Bans Abortions for a Fetus Affected with Down Syndrome

In December 2017, Ohio became the 3rd state to criminalize abortion to avoid the birth of a child with a genetic condition. The first law was passed in North Dakota in 2013 and remains on the books, and a similar measure in Indiana that focuses specifically on Down syndrome was enjoined by court order after an ACLU challenge.

Ohio’s law makes it a felony to perform an abortion if the patient’s motivation is to avoid the birth of a child with Down syndrome. These laws appear unlikely to be enforced: unconstitutional under Roe v Wade, they should not survive a court challenge, and if they did, they would be incredibly difficult to enforce. Still, there are several reasons why it is worth paying attention to what must now officially be called a trend.

First, these laws didn’t pop up organically, and they indicate that therapeutic abortion is on the radar of anti-abortion groups. Expect more of the same, and battles on related fronts, including insurance coverage for prenatal testing.

Second, even if the law is never enforced, it could affect practice. A woman’s motivation is hard to prove, but the motivation of a genetic counselor or a physician discussing termination after a diagnosis of Down syndrome is crystal clear, and could put them at risk. Even a distant and unlikely threat of a felony prosecution is a great disincentive to any clinician. Discouraging counseling may pr may not prevent abortion but it absolutely deprives couples of the good, unbiased information that Down syndrome advocates have been working on for years. And as usual, it increases disparities in care for individuals with fewer resources or less education.

Third, polling suggests that a slim majority of the country believes abortion should be available for pregnant women when the fetus faces cognitive impairment, but it’s emotionally tricky territory and norms may shift to make therapeutic abortion more stigmatized. There’s a reason why the second and third iterations of the law specified Down syndrome: this is a public relations campaign and Down syndrome kids present a sweet and photogenic face. “Every Ohioan deserves a right to life, no matter how many chromosomes they have,” said the head of the Ohio Right to Life, neatly eliminating the difference between a fetus and a child.

Fourth, expect a whole lot more of this if we lose Roe v Wade.

  1. STAT names the Swiss Army Knife the top CRISPR metaphorScreen Shot 2017-12-29 at 7.26.31 PM.png

Bacteria have been using CRISPR for aeons, but humans have only had it in their gene editing toolkit for five years. In that short span, technical advancements have occurred so quickly that 2012 CRISPR is starting to feel a bit old school. Some of these innovations improve the original CRISPR search-and-delete functionality – reducing off target effects, for example, or improving the odds of replacing deleted DNA segments with a scripted sequence delivered via a template. Other advancements add new types of functionality. In 2017, researchers introduced a modified CRISPR system uses the same search function but doesn’t cut; instead, it alters gene expression by changing the elaborate system of packaging that turns gene on or off. In another iteration of CRISPR search-and-don’t-cut functionality, scientists from Harvard and the Broad Institute have pioneered a technique called base editing, which locates a specific spot in the DNA sequence and replaces a single base through a series of chemical reactions without the riskier business of inducing a double-stranded break. In October, researchers from China announced that they had tested base editing in human embryos, and were able to correct a mutation that causes the blood disease beta thalassemia 23% of the time.

The proliferation of CRISPR varietals led writers at STAT to give top honors to “the Swiss army knife” in a ranking of CRISPR metaphors (runner up: “organic photoshop”).

 

  1. Harvard’s George Church opens up the George Church Institute in ChinaScreen Shot 2017-12-10 at 4.37.03 PM.png

Synthetic DNA made significant steps forward this year, starting with an announcement in January that researchers at the Scripps Institute in La Jolla have produced a modified a strain of E coli whose DNA has six rather than the usual four base pairs. The following October, in a story that my be the epitome of 2017, Harvard professor George Church traveled to China to announce the opening of the eponymous George Church Institute of Regenesis. This collaboration with Chinese giant BGI has plans to develop clinical applications of synthetic biology. The investment of substantial resources in artificial life forms and bio-manufacturing is one indication of where we are headed; sadly, the decision by one of America’s great science talents to launch an ambitious project halfway across the world may also prove to be a sign of things to come.

 

  1. Popular Culture Discovers CRISPR

This was the year I read my first sci-fi novel about a world where children (and pets) are routinely gene-edited. Although it was a dystopian vision, I have to admit I was intrigued by the tiger-ized house cat…

CRISPR has definitely captured the imagination of a good part of the universe, and my sense is that the jury is out on whether our new powers of gene editing are going to be viewed as cool or creepy. Meanwhile, here’s some unexpected places where CRISPR popped up in 2017.

On Jeopardy!

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In Ashton Kutcher’s twitter feed:

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Graffitied on the mean streets of San Francisco:

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This is a sleeper pick at number 7, but I believe it’s important to understand that people are paying attention, because (like the rest of us) they don’t yet know what to think. The early uses of CRISPR will have a great impact on public opinion, and very likely on support for research, development and commercialization of gene editing down the road. It’s something to think about.

 

  1. The FDA Changes Direction on DTC Genetic Testing

The FDA executed a remarkable about-face on direct-to-consumer genetic testing in 2017, beginning in April when the agency approved a new iteration of their SNP scan for liability to disease, 3 ½ years after they shut down sales of the alpha version, claiming it posed a risk to the health of those who bought it. In addition to signing off on testing for 10 complex conditions where the genetic contribution is important but not definitive, the FDA announcement established some ground rules that could be applied to other tests and other companies. First, the decision identified 23andMe as what they called a ‘trusted provider’ and indicated that having been so designated, they would not have to jump through regulatory hoops for every new test, and would be exempt from premarket review. Second, the agency created a category called “genetic health risk (GHR)” tests, as distinct from genetic tests that were diagnostic, which were explicitly excluded from exemption.

Presumably, the agency’s goal was twofold: to remove impediments to the growth of DTC, while carving out some rules for what belonged in that realm, as distinct from what belonged in a clinical setting. In November, the FDA made this explicit, announcing its intention to establish a new regulatory structure for GHR tests which would formalize the ‘trusted provider’ approach through a one-day FDA review, allowing them to introduce non-diagnostic tests and carrier screens without further premarket scrutiny.

This change in governance is likely a response to what is happening in Washington, where anti-regulatory sentiment is rife, and may also be due to changes in the marketplace, with major players like Illumina and Google making sizeable bets on DTC genetic testing ventures. There is little question that the FDA moves have had a big impact, and the fledgling DTC industry appears to have spread its wings and taken off. Strong Christmas sales for both Ancestry.com and 23andMe indicate that consumers are willing to give genetic testing a try; sustained success may be contingent on how that experience goes for the recipients.

 

  1. First RNAi Drugs Show Promise in Human Trials

Many of the early targets of gene therapy are diseases caused by a single missing or defective protein, and the goal in these cases is to introduce a gene that will produce what the body is lacking. Despite the fact that we have not been very successful to date, it is a simple model; often replacing a small fraction of normal production is enough to treat or effectively cure the disease. In some diseases, however, the problem is not the absence of a normal protein but the presence of an abnormal one which disrupts function or damages healthy tissue. In these cases, you can’t simply (‘simply’) replace what you don’t have but must find a way to silence the gene product that is causing all the trouble.

One way to do this is to intercept the RNA messages before they are made into protein via RNA interference – designer RNA’s that find and bind to specific transcripts to prevent translation. Like many other forms of what might broadly be called gene therapy (I’m not into fights about semantics so don’t @ me), RNAi has not fulfilled it’s conceptual promise to date, but that seems to be on the verge of changing. In October Ionis Pharmaceuticals launched the first human trials of a RNAi drug for Huntington’s disease, and in November a Cambridge-based company called Alnylam announced that its RNAi drug for hereditary ATTR amyloidosis was showing success in phase 3 trials and might be up for FDA review in 2018.

 

  1. In Vivo Gene Editing Mitigates Deafness (in Mice)

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In another late entry into the Top Stories of 2017, researchers from the lab of David Liu published a December article in nature describing the use of in vivo gene editing to facilitate hearing in mice bred to exhibit a form of genetic deafness found in humans. Mice injected with CRISPR-Cas9 complexes showed more hair cells and improved response to auditory testing. While it is always good practice to remind ourselves that not everything that works in rodents works in people but… in vivo gene editing is a remarkable technical achievement with incredible potential. Brought to you, by the way, by a co-founder of Editas Medicine, so this maybe this blog post can double as a stock tip. 2017, ladies and gentlemen.

 

  1. A Gene Therapy Ready for Prime Time at Last!

We’ve been talking about gene therapy for so long it seems like old hat, except that this particular old hat has never been thrown into the ring… until now. On December 19th, the FDA approved Luxturna, a gene therapy for blindness. First of its kind, Luxturna introduces a gene into retinal cells by a viral vector and, in cells where uptake of the wildtype variant increases the production of normal protein.

Eyeballs are a uniquely accessible body part, making them low-hanging fruit for gene therapy, but low-hanging fruit is the place to start, and the take-home point here is that the new and improved gene editing technology and gene delivery systems are for real, as is (finally) gene therapy. Coming soon: gene therapies for blood-based diseases such as hemophilia and sickle cell. Still to be determined: how much all of this will cost.

 

  1. Immunotherapy Delivers a One-two Punch

The cancer field has been buzzing about Car-T therapy for years, hopeful that this new class of therapies designed to harness the body’s own immune system would not only expand the range of cancers we could fight, but do so in a targeted fashion that would reduce the toxicity associated with current chemotherapies. Immunotherapy has been through several rounds of hype-and-hate before getting out of the clinical trial phase, as stories about patients rescued from the deathbed have sent up smiley face trial balloons and deaths from unanticipated side effects have popped them.

After all the anticipation, approval of the first two Car-T drugs came only weeks apart, with Kymriah, a drug for pediatric leukemia, approved in August and Yescarta, for some forms of B-call lymphoma, following close behind. All the usual caveats apply – real-world safety and efficacy still to be worked out over time, and price price price price price plus access, but without setting that aside, I want to take a moment to congratulate everyone who worked to create and validate this new and important class of cancer therapies.

 

  1. The Boy who Got New Skin Is Everything You Ever Hoped For in a Stem Cell Success Story

Screen Shot 2017-12-29 at 7.38.53 PM.png

I was six paragraphs into Ed Yong’s story about a boy with epidermolysis bullosa when I realized it was going to be my top story in genetics for 2017. How many things are there to love about this story? First of all, it’s about a cure for EB, a disease that disrupts the normal structure of the skin, making it fragile, so that it is prone to rupture and blister. In bad cases, people are plagued with open sores that will not heal. It’s a biblical plague of a disease, and this kid was in terrible shape – shape – seven years old, and headed to hospice care.

And they fixed him.  This is also a stem cell success story, joining the list of finally-finally-at last therapeutic success stories in 2017. Doctors removed a small patch of precious intact skin from seven-year-old Hassan and sent it to researchers in Italy, who isolated and corrected skin stem cells, and then used them to grown sheets of skin in which to sheath the dying child. They replaced an astounding 80% of his old skin and – here’s the part from paragraph six – less than a year later he is back in school, playing sports and living the life of a normal child.

I promised myself never to talk about these high tech miracles without discussing cost and access, so here I raise relevant questions: what’s this going to cost, and who will be able to get it?   Honestly, I have no idea.   And for the record, this technique won’t work for all variants of the disease.  But there is a lot to celebrate.

It seems strange to talk about 2017 as a series of victories for humanity, but the year in genetics was full of hope and promise, and nowhere was that contrast more on display than here, in the a story of a global community coming together to save a life. A Syrian child, treated by German doctors together with Italian researchers who were mentored by an American pioneer…  It was the epitome of 2017 in genetics, though sadly not the epitome of 2017 in any other sphere.

 

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The Rhythms of Silence

“It was a silence filled with many things going on in it.”

– Dorothy Parker

Shut my mouth.  That is one of the hardest things for me to do during a genetic counseling session, though paradoxically it is among the simplest. Despite decades of experience as a genetic counselor, I still have a tendency to dominate my interactions with patients. Maybe all of us are guilty of this to varying degrees. To some extent, it is a natural by-product of a clinical service with a significant educational component. Dialogue easily morphs into monologue.

But genetic counseling does not end at education. Instead the counseling component simultaneously flows from and shapes the educational aspects. I sometimes need a virtual dopeslap upside my head from Jon Weil’s or Seymour Kessler’s spiritual avatar to get things back on track.

How We Talk, a book about conversational analysis by the linguist N.J. Enfield, has helped heighten my awareness of my tendency to dominate counseling sessions. And it is a lot less psychologically painful than Jon’s or Seymour’s dopeslaps.

A typical conversation flows with a rhythm guided by timing cues. Speaker A says something and then Speaker B seamlessly follows with a response to what Speaker A just said, and so the conversational turn-taking flows through to the conclusion of the conversation. In normal everyday conversation the average length of the transition between when Speaker A stops speaking and Speaker B responds is ~200 milliseconds. Literallly in the blink of an eye Speaker B recognizes that it is the appropriate time to speak and has a response ready. The brevity of the silence interval is mute testimony to the stunning complexity of the human brain. Conversation is like a John Cage musical composition based on a pattern of silences. Silence is to conversation as zero is to numbers.

Of course, there are within- and between- individual variations in any conversation. There are also differences between languages, but the differences are slight. For example, in the Mayan language Tzeltal, the average transition time is 67 milliseconds, in Italian it is 310 milliseconds, in Lao it is 420 milliseconds, and in Danish it is 470 milliseconds. English is just above average at 236 milliseconds. No doubt a Dane would drive a Tzeltal speaker crazy with the extended transition time, but the difference between the languages is under half a second, within the range of an eye blink.

The dialogue from the screwball comedies of the 1930s and 1940s move along at dizzying speed because we perceive the transition times as almost non-existent. The great screenwriters intuitively understood this and Cary Grant, Katharine Hepburn, et al., effortlessly deliver witty repartee that leaves your brain gasping for breath.

When the transition time exceeds a half second, and especially as it approaches one second, Speaker A perceives the response as taking too long and tends to jump back into the conversation, “out of turn.” This One Second Rule is called a standard maximum silence. It is often more than a matter of Speaker B needing more time to formulate a response to a complex statement or question. The longer than expected delay can communicate that Speaker B thinks the response is “non-preferred,” that is, something that Speaker B feels may not be the reply that Speaker A wants to hear. And when Speaker A jumps in out of turn, Speaker A will re-phrase in a way that makes it easier for Speaker B to give a non-preferred response. Subtle non-verbal emotional interplay takes place in the space of a silent second. The silence of the iambs. The following fictional counseling scenario demonstrates this:

Scenario A

Counselor: So, do you think you want to undergo this genetic test?

(1 second pause)

Counselor: You don’t have to make up your mind right now.

(800 millisecond pause)

Client: Well, the test could be helpful. I am not sure about my insurance coverage, though.

Here, the 1 second pause suggests that the patient may not want the test, and the “long” pause pushes the counselor to jump in and say something that makes it easier for the patient to decline testing. The patient replies in a way that that the patient feels the counselor prefers to hear – the test is important – but bringing up insurance coverage gives the patient a “legitimate” reason to decline testing. Even though the counselor may feel that she or he was non-directive, the patient may have picked up on a message that perhaps the counselor thinks the patient should undergo testing, even if the counselor is not saying it in so many words.

Generally, Yes/No responses that occur within the first half second of a transition are perceived as more definitive whereas responses that are closer to one second or longer are usually interpreted as ambiguous. The following fictional exchanges between a counselor and a client illustrate this:

Scenario B

Counselor: So, do you think you want to undergo this genetic test?

(200 millisecond pause)

Client: Yes.

 

Scenario C

Counselor: So, do you think you want to undergo this genetic test?

(1 second pause)

Client: Um (3oo millisecond pause) it might be a good idea.

In Scenario B, the short transition time of the client’s response suggests a strong desire to have testing. However, in Scenario C, it takes the client 1.3 seconds to arrive at a form of Yes, the hesitancy in the response possibly reflecting a hesitancy to undergo testing. The interjection “Um” before saying “Yes” reinforces the perception of ambiguity. This 1+ second difference in transition time is a clue to skilled counselors to more deeply investigate the patients’ desires and reasoning, even though the counselors and the clients may not be consciously aware that clients are communicating clues to their ambiguity.

Of course, in the context of a counseling session, a delayed response could be due to the cognitive processing required to comprehend technical medical information or it could be due to psychological processing of an emotionally laden discussion. Which, to some extent, is the point here. A genetic counseling session is not usually an ordinary conversation (though a skilled counselor can make it appear that way), so the turn-taking of the speakers can be expected to have a different rhythm and follow different timing cues. But because we are so subconsciously attuned to the rhythm of normal conversation, the tendency for genetic counselors to sometimes dominate a session may stem in part from relying on the wrong timing cues and to speak out of turn before patients are ready to articulate their thoughts.

An interesting research project would be to record counseling sessions with the purpose of timing transitions between counselor and client. This could then be correlated with outcomes such as patient satisfaction and uptake of recommendations to see if they were influenced by conversational transitions. Transition times could also be used to guide the development of better counseling skills by helping the counselor to understand ways that transition times were used appropriately or inappropriately during the course of a counseling session.

To be sure, transition times are not the only non-verbal influence on the rhythm of a conversation. Posture, gestures, facial expressions, and eye gaze can influence the flow of conversations and serve to articulate the psyche. Reading the body of clients is as important a skill as being attuned to their verbal language. People are generally less aware of their body language and thus it can more “honestly” and directly reveal underlying psychological and emotional processes than verbal language.

It is extraordinarily difficult to be keyed into what Enfield calls “the inner workings of conversation,” especially in the moment of the conversation. It involves unlearning, or more precisely becoming aware of and being able to manipulate, a language protocol that has been subconsciously engrained into us since we burst out of our amniotic sacs. Becoming a good counselor is not simple nor is the path always straight. The graph of professional growth follows a jagged and at times recursive line. There is no breakthrough moment when you permanently become the genetic counseling equivalent of a Jedi Master, able to manipulate the Counseling Force to your will and you are infused with Yoda-like wisdom. Easy it is not.

 

 

 


Thanks yet again to Emily Singh for help with graphics.

 

 

 

 


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Imperfect Pregnancies: What Ilana Löwy Has To Tell Us About The History of Prenatal Testing

“It seems to me that all the gentlemen agree, some more explicitly than others, that to abort is a good thing and should be encouraged.”
– from a discussion reported in Early Diagnosis of Human Genetic Defects: Scientific and Ethical Considerations, Maureen Harris (ed). National Institutes of Health, 1970.

I sometimes feel like a lone voice howling in the wind-swept darkness when I argue that any opinion, policy, or analysis of prenatal testing must be rooted in historical context. Often these endeavors are informed by technical aspects of a test, such as sensitivity, specificity, cost, and positive predictive value, sometimes accompanied by vague mumblings about “ethical considerations” and “women’s choices.” But these discussions are inadequate unless they also take into account the historical, social, cultural, and economic factors behind the development, expansion, acceptance, and critiques of genetic testing technologies.

To develop a full understanding of prenatal testing, we need to ask difficult questions with thorny, complicated and uncomfortable answers. What was the impetus for the introduction of prenatal diagnosis in the 1960s and 1970s? Why were researchers studying birth defects, cell culturing techniques, and karyotypes at that particular time? How have changing attitudes toward disability, abortion, and reproductive rights shaped, and been shaped by, prenatal diagnosis? What path does a test follow from being offered to a very small and select percentage of the pregnant population to becoming a routine part of every pregnancy? Why are there regional and historical differences in the acceptance, application, and history of prenatal testing? Why is it nearly impossible to have a discussion about prenatal screening that is not also a discussion about abortion?

Well, I don’t feel so lonely anymore after having read Ilana Löwy’s new book, Imperfect Pregnancies: A History of Birth Defects & Prenatal Diagnosis (Johns Hopkins University Press, 2017). The title pretty much tells you what the book is about, but it is more than just a recitation of discoveries and events. The author, an emerita research fellow at the French National Institute of Health and Medical Research, argues that prenatal testing can best be understood in the context of Michel Foucault’s concept of a dispositif – loosely speaking, the institutions, social factors, laws, regulations, scientific and professional practices that create, maintain, and reinforce a body of knowledge and give it power (no doubt some Foucault scholar will take issue with my description, but you get the general idea). But Löwy’s book is not a high falutin’ study of abstract theories of knowledge. It is concretely embedded in a richly detailed analysis – some of it original and some of it summarizing the work of others – of how we have arrived at the point where prenatal testing, particularly ultrasonography and now NIPT, has become integrated into the routine care of nearly all pregnant women in many Westernized countries.

Let me acknowledge some intellectual conflicts of interest up front: the author cites some postings to The DNA Exchange by me and others, references some of my publications, and thanks me – among many others – in her introductory section. No doubt these small ego strokes influenced my perceptions of the book in ways that I can’t fully recognize.

Imperfect Pregnancies opens with the somewhat artibitrary but reasonable starting point in the late 19th century and the work of obstetricians John Ballantyne and Adolphe Pinard, in Scotland and France respectively, on the nature and causes of birth defects and the medical supervision of pregnancy that they felt was necessary to ensure the delivery of a healthy baby. From there she ties in the history of cytogenetics and karyotyping, congenital malformations and dysmorphology, the emergence of amniocentesis and prenatal ultrasonography in the 1960s and 1970s, the introduction of serum and sonographic screening for Down syndrome in the 1980s and 1990s, and right up to the  latest testing technologies of the early 21st century such as comparative genomic arrays and noninvasive prenatal testing (NIPT).

This is not a scolding work that draws a straight historical line from eugenics to prenatal diagnosis. While eugenic criticisms are certainly valid concerns about the potential ramifications of prenatal testing and that is true that the development of prenatal diagnosis was a clear reflection of negative attitudes toward disability, the Eugenics Movement per se was not a driving historical engine behind prenatal testing. Still, Löwy makes it clear that prenatal diagnosis was established in the context of a public health model to permit and passively encourage abortion (as the introductory quote at the start of my posting suggests) of aneuploid or otherwise “defective” fetuses under the justification of allowing parents to have as healthy a baby as possible, and that was maintained by the social, ethical, medical, legal, and economic factors that made this possible (i.e., the dispositif). Pregnant women were enticed by tests that offered reassurance but some were left with the messy situation of what to do when the testing did not come back with normal results and had to make extraordinarily difficult decisions about how to proceed in largely uncharted territory, a situation genetic counselors know all too well. In the words of one researcher, women were forced “to become skilled managers of fetal risk.”

The author brings an international perspective to her narrative, including experiences with prenatal testing in the US, the UK, France, Israel, Brazil, and Scandinavia, among others. Prenatal testing is managed differently in each country according to unique local circumstances and this has an impact on uptake of testing and abortion. For example, in the Netherlands, where a detailed discussion of screening is routinely incorporated into pregnancies largely by midwives in a non-medical setting, the uptake of testing is much lower than in countries where there is less discussion and is physician driven. In Brazil, where abortion for fetal indications is limited to anencephaly, the uptake of NIPT is much greater among upper socio-economic status who have access to safe (if technically illegal) abortion compared to poorer women who do not have such ready access. Laboratory marketing has taken advantage of the social status associated with having the latest medical tests among Brazilian women, especially during pregnancy, to further integrate NIPT into routine care. In places around the world where women are likely to leave the work force and devote themselves full-time to child rearing, the uptake of prenatal testing and abortion is lower than in areas where women continue to work after childbirth.

The limitations of the early technologies are somewhat shocking from the biased perspective of today. When John Edwards analyzed the unbanded karyotype of  the first patient with his eponymous syndrome, he thought the underlying cytogenetic abnormality was trisomy 17 rather than trisomy 18 until Klaus Patau (who first described trisomy 13) set him straight. In Riis and Fuchs first reports of prenatal diagnosis of fetal sex among hemophilia carriers in Denmark in 1960, one woman proved to have a female fetus that she miscarried after amniocentesis, went on to have another female fetus that also miscarried after amniocentesis, a third pregnancy that was a male and was aborted, and finally had a fourth pregnancy in which the patient successfully carried the pregnancy to term after a female fetus was correctly identified by amniocentesis (I can envision many prenatal genetic counselors simultaneously nodding and shaking their heads right now). Of the first 20 attempts at identification of fetal sex among hemophilia carriers in Riis and Fuchs series, 17 were successful, two resulted in failure to establish fetal sex, and one female fetus was mistakenly identified as male and the pregnancy was terminated (I can hear many prenatal genetic counselors now saying “Ouch!”).

There are a few areas I think the author leaves largely under-explored. Although she gives thoughtful discussion to genetic counselors, I think she understates their importance in ushering in, shaping, and managing each new prenatal testing technology. We have been the boots on the ground as each test was introduced into clinical practice, more or less left alone with patients to negotiate the complicated medical, ethical, and psychological ramifications of “simple blood tests” and “routine sonograms” gone awry.

In the early sections of the book Löwy details the role that obstetricians played in the historical pathways leading up to prenatal testing. However, there was little mention of the obstetricians who worked closely with clinical geneticists and sometimes became board certified in genetics themselves in the 1970s and 1980s – Mickey Golbus, Larry Karp, Mike Mennuti, and Joe Leigh Simpson, to name a few.

I would also like to have seen fuller discussion of the Professional Liability Alert issued by the American College of Obstetricians and Gynecologists in May of 1985, which stated: It is now imperative that you investigate the availability of these tests in your area and familiarize yourself with the procedure, location, and mechanism of the follow-up tests to screen for neural tube defects. Although to the best of my knowledge no one has ever studied the impact of this Alert on the uptake of maternal serum screening in the US, I know that the immediate  impact in my neck of the woods was profound and long-lasting. Most of the obstetrical care providers in the Seattle area suddenly started strongly recommending AFP screening to their patients and it set the tone for the ready acceptance of most other prenatal screening tests that followed over the next 30 years. Although the book briefly mentions obstetricians’ concerns about legal liability, she does not go further down this street and I believe incorrectly attributes it to the AMA’s “concerns.”

But these latter points do not detract from the overall achievements and arguments of Imperfect Pregnancies. If you are a supporter or a critic of prenatal testing, or, like many people, decidedly ambiguous, there is much that you will learn and much that will make you pause and re-examine your own views and knowledge base.


NEWS FROM AROUND THE DNA EXCHANGESupport The Genetics Literary Community

I am delighted and excited to announce that The DNA Ex’s own Laura Hercher is now also contributing an online column for Genome magazine called GenomeCulture. Read her first installment When Genetics Race Problems Rears Its Ugly Head.

Tony Holzman, now retired from Johns Hopkins and who contributed so much valuable research on the social, ethical, and psychological aspects of genetics, is now a novelist. He has published several novels including Blame, about murder and intrigue in genetics research at the NIH. Tony is now working on publishing his newest novel, The Bethune Murals. The novel is based on the true life story of a physician who was diagnosed with TB and was confined to the Trudeau Sanitarium in the 1920s and who produced a remarkable set of murals on paper used to wrap laundry at the institution. Tony is looking to self published his book through Amazon but needs to get enough votes in an Amazon competition. If you have an Amazon account, you can vote for Tony here.

 

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The Routinization of Prenatal Testing and the Erosion of Patient Autonomy

As a long time admirer, reader and guest blogger, I am thrilled to have been invited to write as a regular contributor for the DNA Exchange.  Some recent statements about prenatal testing in the news brought to mind my very first guest post on the DNA Exchange, Information Detoxification, published 5 years ago.  So I am going to start this new chapter by going back where I began as a guest blogger, on the topic of the risks of routinizing prenatal genetic testing.

 

Last week, a genetic testing lab released a statement about their intention to use recent investments “with an eye toward making expanded carrier screening as routine as taking folic acid, noninvasive prenatal screening as routine as an ultrasound, and hereditary cancer screening as well-known as a pap smear.”  While this vision is quite positive for the lab’s investors, it is concerning for the future of reproductive autonomy. The underlying goal that all pregnant women should have prenatal testing is not unique to this lab.  In fact, there is increasing pressure towards expanding the use of these tests by many labs, likely representing the intense competition in the genetic testing business right now, driving the need to increase test uptake to the largest possible market.

 

I have mixed feelings about population screening for hereditary cancer, but the implications are completely different when considering prenatal carrier and cfDNA screening.  Although prenatal testing is important to many, it is crucial that women and their partners be given the opportunity to make autonomous and informed decisions about whether or not to take these tests.  The routinization of prenatal testing is problematic for several reasons: from a social and public policy standpoint, in regards to healthcare economics, and also for individual patient care.

 

Social and Public Policy

Advocating for reproductive autonomy and informed decisions around prenatal genetic tests was one of the first guiding principles of the genetic counseling profession.  This is in part due to the fact that the start of the master’s degree trained genetic counselor coincided with social movements in women’s reproductive rights and also the emergence of the field of bioethics.

The prioritization of patient autonomy in reproductive genetics also arose from the rejection of eugenic ideology and practices that were common in the early part of the 20th century which sought to encourage reproductive of the fittest and to discourage (sometimes forcibly) reproduction among those deemed as defective or unfit.

This history supports concerns that the routinization of prenatal testing may effectively stigmatize those who have an increased chance to have a child with a genetic condition, thereby limiting reproductive freedom.  This is especially troubling in the context of the current political and social climate with so many expressing racist, xenophobic, and ableist views, as well as increasing threats to health care security and social services.

 

Healthcare Costs

Issues regarding the cost of prenatal testing are complex and studies regarding the economic impact of expanding prenatal screening are needed.  Such data analysis is complicated by the variability and a lack of transparency in the costs of these tests.  While labs vary in their pricing, patients report receiving explanation of benefits representing that the amount billed to their insurance was many thousands of dollars –  amounts that likely exceed the entire cost of the prenatal care in some cases.  

Without peeling back all of the layers on this topic, there is one clear explanation for why routinization of prenatal testing does not make good financial sense.   Given that the purpose of prenatal genetic testing is to inform personal reproductive decisions, in order for these tests to be of value, they must first be desired by the fully informed patient.  No matter the price of a prenatal genetic test, it is a needless healthcare cost if the patient does not want it.  

 

Patient Care

Should all patients be routinely counseled about their options for prenatal genetic testing?  Absolutely.  Practice guidelines for prenatal genetic testing support offering these tests to all women in the context of counseling that supports informed and value-consistent decisions.  But this conflicts with the model that the testing labs seem to be promoting, which is to test everyone first and provide the information in follow-up, after testing has already been done.  This undermines patient autonomy and can cause harm.

 

When an individual would use results to facilitate reproductive decisions, testing can be empowering. What is often overlooked in our well-intentioned goals to provide patients with knowledge however, is the potential harm and disempowerment that may result when testing information is not desired.  Patients deserve the opportunity to make a choice about whether the information these tests provide is something they want to know or not.
It is imperative of genetic counselors to resist any suggestion that reproductive genetic testing should be routine.  I hope that all of us, whether working in the clinic or the lab, will continue to advocate for reproductive autonomy for our patients and hold firm in the goal that all patients should have the opportunity to make informed choices regarding prenatal genetic tests prior to testing.   How we move forward with this challenge in both practice and policy is a defining question for our profession.

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