TOP TEN GENETICS STORIES FOR 2014: INCREDIBLE ACHIEVEMENTS (DON’T COME CHEAP)

No question that 2014 has been a year to celebrate for the field of genetics. Stem cell therapy, gene therapy, next-generation sequencing as a reliable clinical tool: we may not be there yet, but surely we are close. We have reached the suburbs of the Promised Land. Technical milestones have been met, technical challenges surmounted – palpably, we stand on the cusp of a new era, where we will have means to treat the untreatable and cure the incurable.

The many success stories of 2014 bring along with them reminders of an important corollary:  that the cost of what we are capable of doing already exceeds our collective ability to pay. The idea that personalized medicine will pay for itself is a joke, and every $300,000 a year drug we produce is the punchline. As we recognize the many amazing ways in which genetics is poised to change medicine, there are other questions that must be raised, about who will benefit and who will be left behind.

10. $1000 GENOME? — YUP, GOT THAT.

In January 2014 Illumina announced the arrival of the HiSeq X, a sequencing platform that can produce 5+ genomes per day, and at capacity delivers the results for less than $1000 per genome. The new system is sold only in sets of ten or more, and a set of 10 costs around 10 million dollars. Congratulations, people! We have reached our arbitrary threshold and may now proceed with the genomic revolution.

 9. IT’S SNOT JUST A DREAM ANYMORE: PARALYZED MAN WALKS AGAIN WITH THE HELP OF NASAL CELLS

In October, Surgeons from Poland announced in Cell Transplantation that a 40-year-old patient paralyzed following a 2010 stabbing had regained the ability to walk after a transplant of olfactory sheathing cells grown in culture. The treatment seeks to capitalize on the unique regenerative capacity of mucosal stem cells.

Okay, there are caveats and concerns. The extent of his recovery is limited. He’s using a walker. We await replication. A woman who underwent a similar but unsuccessful procedure more than eight years ago was recently reported to have required surgery for a cystic mass in her back at the site of transplantation producing “thick, copious mucus-like material.” But GUYS!!!! Paralyzed man walks again.

8. WE FIND THE GENES FOR INTELLIGENCE!!!! (OR NOT)

There’s controversy regarding how much genes contribute to IQ, but most people would agree that genetics is involved, and studies of the heritability of IQ (the measure of how much genes contribute to the variance in test scores) put it somewhere between 50 and 80%. A genome-wide association study of more than 100,000 people published this summer looked at educational performance as a proxy for intelligence, and then checked those findings on a sample of almost 25,000 people using cognitive performance tests as a proxy for, well, cognitive performance. Did they find something? Yes: they found 69 SNP’s associated with educational attainment, three of which were significantly associated with cognitive performance. Something! But not much: each of the three was associated with, on average, a difference of 1/3rd of a point on an IQ test.

To recap, this was a big study with a lot of statistical power and it provided nothing adequate to predict individual performance or cognition. It did provide some proof in principle that genes affecting intelligence exist and that more might be found – maybe. Daniel Benjamin, one of the co-principal investigators, told Ewen Callaway of Nature News that explaining 15% of the variance in IQ would require over a million participants.

Sadly, the most important thing this study was not what it told us about genetics as it relates to our intelligence, but what it told us about our intelligence as it relates to genetics. A lot of the media coverage of this story missed the point – or buried it beneath misleading headlines.

Here are two soberer takes on this story, from Nature and Ars Technical:

nature smart genes ara technica genes

 

And by contrast, check out this headline from Business Insider:

bunsiness insider

Or these, from the Sydney Morning Herald, and Science 2.0:

science 2.0 sydney morning herald

Or this, from an editorial at RealClearEducation:

realcleareducation

C’mon media people. You don’t need rocket scientist genes to do better than that.

7. SEQUENCING JOINS THE FIGHT AGAINST EBOLA

Genetic sequencing has been put to work in the fight against Ebola, providing a surer method of diagnosis – crucial for a disease where isolation of the sick is a key step in containing the epidemic – and a method of tracking the origin and the path of the rapidly evolving virus currently ravaging parts of western Africa.

In September, fifty authors, led by Pardis Sabeti of the Broad Institute in Massachusetts, published a paper in Science describing rapid evolution of the Ebola virus found in the blood of 78 patients from Sierra Leone. What could emblemize the strange contradictions of 2014 more than this: machines reading a language written in single molecules, interpreted by programs that cost billions of dollars to develop, in the service of a battle fought in blood-spattered tents where people die for the lack of IV fluids.

There were 58 authors listed on the Science publication in September. As of October 24th, five of these individuals had died from the disease.

6. CRISPR GENE EDITING SYSTEM CORRECTS GENE MUTATION IN MICE WITH LIVER DISEASE

crispr

Oh come on, just give them the Nobel Prize already.

CRISPR, a top genetics story in 2013, could have made this list again for any number of reasons in 2014. The ability of the CAS9 gene editing system to efficiently target specific sites in human stem cells was reported in this Nature Communications article, suggesting that unintentional effects may be less of a problem than people had feared. Other experiments have explored the potential of CRISPR to cure muscular dystrophy, fight cancer, and make cells immune to AIDS. And that – no, I mean this – is only the beginning.

In mice with a mutated FAH gene and congenital liver disease, researchers led by Daniel Anderson at MIT reported that CRISPR machinery along with a template for the normally-functioning gene were inserted by high pressure injection and resulted in the production of enzyme-producing liver cells. For the first time, a designed, controlled, human-mediated process of gene editing occurred inside the cells of living animals. And it worked! Measurable improvement occurred in the health of the affected mice.

Another sign of how big this could be: the hotly-contested battle for control of the intellectual property rights, with the Broad Institute’s Feng Zhang and Zhang-associated biotech Editas Medicine taking round one earlier this year in the form of a broad U.S. patent. Final disposition remains in the hands of the judges, with co-discoverers Jennifer Doudna from UC Berkeley and Emmanuelle Charpentier from the Helmholtz Centre for Infection Research each having established relationships with competing start-ups, all of them angling to bring the power of search-and-replace functionality into genomic medicine.

In November, Charpentier and Doudna accepted several million dollars apiece as their share of the Breakthrough Prizes, funded by an assortment of Silicon Valley multi-billionaires and handed out by a bevy of Hollywood bold-faced names. Here they are, looking glamorous next to Cameron Diaz:

Screen Shot 2014-11-10 at 8.26.51 AM

So what do you say, Sweden? Make it official. They already have the gowns.

5. MOSAICISM

Photo Credit: graphia via Compfight cc

Photo Credit: graphia via Compfight cc

If you know ONE SINGLE THING about genetics, you know this: every cell in your body has the same DNA. Every cell in your body has the same DNA, except… well, of course there are always exceptions. If genetics was easy, everybody would do it.

Some exceptions are so rare as to defy belief: Washington resident Linda Fairchild found herself in jeopardy of losing custody of her children when a routine test suggested that none of the three boys she had given birth to was her biological child. Fairchild turned out to be a chimera – a single individual with two distinct genomes, in her case the result of a twin pregnancy where one fetus stops developing early on, and is absorbed into the body of the surviving twin. In Fairchild’s case, a second test, on her cervical cells, revealed an alternate genome that was a match for her boys. In effect, Fairchild was the children’s mother – and also their aunt.

Events that incorporate a whole alternative genome are unusual, but other changes that occur early in embryonic life can result in distinct cell lines in the body with subtle but sometimes important differences. Depending on when and where these changes occur, they may affect one organ or tissue type, or groups of cells scattered throughout the body like the patchwork fur of a tortoiseshell cat. Effects visible to the naked eye, like the large, irregular hyper-pigmented spots seen in McCune-Albright syndrome or the inconsistent areas of overgrowth in Proteus syndrome, have been recognized for years as instances of somatic mosaicism.

Trending in 2014: evidence that somatic mosaicism may not be as rare as we had thought. Newly available sequencing techniques show that the closer we look, the more variation we find within individuals. A study published in the American Journal of Human Genetics in July looked at the parents of children with small deletions that appeared to be de novo – that is, blood tests didn’t find the change in either parent – and found that 1 in 25 are mosaic for the variant in other tissues. Similarly, causal mutations in one cohort of individuals with brain malformations were found to be mosaic 30% of the time. Something to keep in mind when searching for the underlying genetic cause of a condition, or in advising a family about recurrence risk! Another 2014 report described an unaffected mother who had a second child with nemaline myopathy, which conventional wisdom suggests should be virtually impossible. A closer look after the fact found low grade somatic mosaicism – only 1.1% in blood leukocytes, but 8.3% in her fingernails.

Okay, but seriously, almost all of the time, most of your cells have (virtually) the same DNA – that’s our story and we’re sticking to it. Probably.

No numbers 4 or 3!  A three-way tie for second biggest story of 2014 goes to these, highlighting staggering technical achievements with equally staggering price tags:

2. STEM CELLS

Never mind that the field started the year on a sour note: a paper describing a new method of generating stem cells using an ‘acid bath’ generated its own acid bath of critical response and was subsequently withdrawn. Consider that a head fake, because 2014 was a banner year for stem cell research, the year we moved beyond rodents into human trials.

There are multiple contenders for stem cell story of the year. In France, a team led by Philippe Menasche announced plans to introduce cardiac progenitor cells using a patch in heart failure patients undergoing surgery, with hopes to improve heart function. In England, according to a fingers-crossed, early report in Stem Cell Translational Medicine, autologous stem cell therapy for stroke victims appears to be going well. Researchers testing stem cell therapy for blindness caused by macular degeneration or Stargardt’s macular dystrophy reported in the Lancet that over half of their participants have improved vision – an unexpectedly good result for a phase I trial of severely affected patients that was designed only to show safety.

Blind people seeing! It’s hard to beat that for drama. Still, my stem cell story of the year comes from California, where the stem cell therapeutics firm ViaCyte has announced that the first of forty patients in an FDA-approved trial has been implanted with pancreatic progenitor cells that are designed to mature into insulin-producing cells in situ. The cells sit in a sort of pouch made of a thin, porous membrane intended to allow insulin to pass into the bloodstream as needed, but insulate the cells from the destructive immune response that causes Type I diabetes. Here’s my reasoning: the work was supported by the California Institute for Regenerative Medicine, which has a lot to talk about right now after a slow start and a lot of snickering about government-run programs, and it involves a unique, creative delivery method and a common disease that starts in childhood and causes lifelong morbidity and expense. This might not turn out to be the solution that sticks (a group at Harvard recently announced a new method for reprogramming fibroblasts into pancreatic-like progenitor cells, so maybe we will have an East Coast-West Coast battle. Perhaps they can rap it out). But there are a lot of type-1 diabetics out there who should be feeling upbeat about their chances for a breakthrough in the near future.

And given the cost associated with the disease, this might even be a stem cell therapy insurers pay for without a fight. Or – well, maybe not.

2. IN ARKANSAS, 3 YOUNG WOMEN SUE MEDICAID FOR ACCESS TO CYSTIC FIBROSIS MIRACLE DRUG KALYDECO

Two years ago, the introduction of Kalydeco from Vertex Pharmaceuticals made this list as the first ever pharmaceutical treatment designed to correct an underlying genetic defect. Although it is effective for only a single mutation, which means it helps only 4-5% of those affected with the disease, Kalydeco represents proof in principle that targeted therapies can provide a virtual cure for CF, and by extension, a sign that understanding the genetic underpinnings of disease can improve the lives of that big universe of affected people.

Now Kalydeco is back in the news for less happy reasons. This summer, three women sued the state of Arkansas, claiming that Medicaid violated their federal rights by refusing to pay for Kalydeco, although they met eligibility criteria established by the FDA. Arkansas’s Medicaid program claims it does not categorically refuse to pay for Kalydeco, which costs more than $300,000 per year, but requires applicants to prove that conventional therapy is inadequate. That’s a catch: the older therapies are less successful, more arduous and leave patients liable to repeated infection and lung damage that may permanently compromise their health, but they may be adequate to attain ‘acceptable’ lung function. Joseph Walker, writing in the Wall Street Journal, describes the rigors of one litigant’s “traditional” regimen, including hours a day in percussive therapy, where pounding on the chest loosens hardened mucus in the lungs. Vertex, which has a compassionate care program for those with zero coverage, which is another catch: they refuse to provide the drug unless the individual has no grounds on which to appeal – in other words, if they need it, they can’t get it. Otherwise, Vertex argues, all Medicaid programs would be incentivized not to pay.

So what is with the Catch-22’s? Medicaid and the drug companies are worried about setting policy, knowing that Kalydeco is the tip of an iceberg, with a slew of extraordinary and extraordinarily expensive targeted therapies on the way. This year, Genzyme has introduced a new pill for people affected with Gaucher disease that will cost $310,250 per annum, and researchers released data showing that the drug asfotase alfa could help form bone, rescuing infants with a rare and lethal condition called hypophosphatasia – at $200,000 per year, which suddenly seems like a bargain. This list is by no means complete, and it’s not getting any shorter. And limiting compensation, as the pharmaceutical companies constantly remind us, will make them less interested in finding treatments for rare diseases.

2. GENE THERAPY DRUG GOES ON SALE IN GERMANY AT 1.4 MILLION PER PATIENT

Most people want to be one in a million, but if you ask someone with lipoprotein lipase deficiency, you might get a less positive response. This rare disease leads to sky-high triglycerides, eruptive fat-filled lesions, frequent abdominal pain and bouts of pancreatitis. Glybera, a cure for LPLD and the first commercially available gene therapy in the western world, will be introduced by UniQure in Germany in 2015. It is estimated that 150-200 people in Europe could benefit from treatment, which will cost, on average, 1.4 million dollars per patient.

The most stunning thing about that number is that it might be considered a bargain. With targeted therapies clocking in at $200,000+ per year, the one-time fee represents a substantial savings if amortized over a decade or more. To get your money’s worth, just keep living.

1. COALITION OF RESEARCHERS SHARES DATA!

WHOLE EXOME DATABASE OF 60,000+ INDIVIDUALS GOES ONLINE

Photo Credit: Rikot via Compfight cc

Photo Credit: Rikot via Compfight cc

Kumbaya.

The Exome Aggregation Consortium (ExAC) released debuted its massive database of exomes at the American Society of Human Genetics meeting in October, and the response crashed the server on day one. Way to break the internet, guys. According to a post from the head of the ExAC production team Monkol Lek, the exome browser garnered 120,000 page view from over 17,000 unique users in the first month.

Several factors make this the top story of 2014. First, the remarkable technical achievement of turning over 15 data sets into a single, searchable entity, and the equally remarkable feat of getting all those research entities to turn over their hard-won libraries for universal access. “Here are a bunch of data sets that individually cost millions of dollars to generate, and you have people willing to make that data available to a shared resource, which is amazing” marvels ExAC principal investigator Daniel MacArthur, speaking to Nature’s Erika Check Hayden in October.

ExAC isn’t the first genomic database to be made available to researchers, and it won’t be the last. The Haplotype Reference Consortium, a resource for genotype imputation and phasing, will begin releasing data in early 2015. And the new resources aren’t sufficient – HRC organizers note that their current data set is European-centric, and getting a more even distribution of ethnicities represented is an important challenge going forward.

But the fact that these open access resources exist represents an acknowledgement by all concerned that clinically significant progress will require genotypic and phenotypic information on more individuals than any single research entity can assemble on its own. By implication, it acknowledges the significance of rare variants in human health and disease and the need to look beyond simple deterministic models of gene effect and give sufficient power to studies that encompass a subtler, more complicated vision of how phenotype emerges from genotype.

 

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Questioning the “genetic counselor” professional title

A few weeks ago, while listening to a presentation at the Canadian Association of Genetic Counsellor’s (CAGC) Annual Education Conference in Vancouver, I learned that a newly created genetic counseling clinic had decided to remove the term “genetic counseling” from their clinic name. The term seemed to be confusing potential clients, and it was ultimately determined to be a barrier to getting people in the door.

Just two days earlier, I had sat in a room with the CAGC board of directors while we undertook a brainstorming exercise to try and come up with a simple and straightforward definition of “genetic counselor.” Led by a local PR & communications professional, our goal was to try and get the definition to less than 10 words. After 3 hours of lively discussion and long contemplative silences, we decided we had done the best we could do: our sentence was 17 words long. It was interesting to watch the response of the communications professional throughout the process. Clearly she has hosted similar sessions with countless organizations, but I sensed our challenge was unique. “You really do have quite a dilemma here, don’t you?” she noted more than once.

Communicators with a communication problem

Genetic counseling isn’t simple and genetics isn’t straightforward. Unfortunately, we live in a society that seems hell-bent on fitting genetics and genetic testing into a nice, neat, easy-to-handle box. As a result, we expend a lot of energy trying to describe why genetics is rarely nice, neat and easy-to-handle. We explain ad nauseam how complex, intricate and emotionally and ethically charged genetics can be. So, how do you simplify a message, when the message itself is intended to express the complexity and complicated nature of the subject?

As the chair of the CAGC Media and Communications committee, I have spent the past two years contemplating this question. The irony is not lost on me: communication is one of the most fundamental skills of our profession. We are highly trained to translate complex scientific information into manageable lay-mans terms. Yet, we continue to struggle to effectively communicate who we are to the public and other healthcare providers.

Which brings me back to what we call ourselves: Genetic Counselors. Our name is our first impression, our lasting brand and its descriptive nature should easily and accurately reflect the work that we do. As Sean Hazell argued in his recent guest post, the time is right to make a push for increasing our professional awareness. Given the huge communications challenge we have at hand, I think it is crucial we ensure our name is helping our cause, or at the very least, not hindering it.

As is highlighted by this recent tweet by a genetic counseling student researching GC awareness for her thesis project, it appears we certainly have a lot of work to do:

Screen shot 2014-12-16 at 10.01.21 PM

The name game

I’m sure we have all had the conversation at some point or another. I remember during my training a pretty heated class discussion about whether the name “genetic counselor” is the most appropriate title for our role. As Bob Resta has previously pointed out, the name is not technically correct; as he explains “genetics counselor” is a more grammatically appropriate term. And many argue that we should consider replacing “genetic” with “genomic” to represent a more contemporary reflection of the times. Further, some believe that using the terms “consultant,” “specialist,” or “associate” in place of “counselor” more accurately reflects the broad range of roles we now hold.

While distinct, this subject is intricately tied to the discussion about expanding roles that genetic counselors now hold and will potentially hold in the future (For more on this see Bob Resta’s post: Who the hell do we think we are?).

The way forward

As far as I know there has yet to be a formalized discussion or review of the name “genetic counselor” by our professional organizations, despite the fact that this has been the topic of informal conversation since the establishment of the profession in the 1970’s. I think it is time we officially take a look at this subject. While our professional organizations are accustomed to creating an internal task force to manage this type of task, I think this particular issue may warrant a unique approach.

Specifically, I’d suggest:

  • The project would ideally be a collaboration between US, Canadian and potentially international organizations—as creating one united brand would benefit all of us (and creating different names in different countries would likely hurt us).
  • We conduct research and engage external stakeholders— patients, physicians and the general public—in the process. If the goal is to ensure our name accurately reflects what we do to the outside world, then the “outside world” should most certainly be at the table.
  • We partner with professionals to help with this task. Whether it is a communications consultancy, a naming firm or a branding agency, there are trained professionals dedicated to helping organizations solve these types of problems.

Changing our professional title would be messy and fraught with logistical issues. And I’m aware that at the end of this type of exercise we may learn that “genetic counselor” really is the most appropriate name for us. Alternatively, we may learn that creating one single term to describe the range of work we now do (or may do in the future) is just not feasible. Whatever the case, I think we owe it to ourselves and to future generations of genetic counselors (or whatever they might be called!) to take a good in-depth look at this issue, in order to ensure we are doing everything we can to enable our professional awareness.

I’m keen to see how others feel about the idea of considering a professional name change. Putting logistical issues aside, do you feel the time is right to officially evaluate our professional title? Cast your vote in the poll below.

Do you have an alternative name you favour? I look forward to reading your thoughts and suggestions in the comments section.

 

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The Downside of the Downside of Resilience: A New York Times Oped Ventures Into Dangerous Territory

Although we take seriously the threat of genetic discrimination, there aren’t a lot of examples you can offer. In my ethics class, I discuss the Burlington Northern Santa Fe Railroad case — everyone discusses the Burlington Northern Santa Fe Railroad case, not because it is such an interesting precedent but because it is all we’ve got. BNSF secretly tested their employees for genetic liability to carpal tunnel syndrome. The fact that it was genetic testing was almost beside the point. Can ever you secretly test your employees? No, you cannot. But the genetic testing angle made it extra creepy. Why? Because we are primed to worry about genetics. It is too new and too powerful not to carry with it the seeds of some unspecified disaster. We just don’t know what it is yet. We are heading out into the wilderness here, the wilderness within. How can we set about to tinker with the machinery of life without wondering if we run the risk of turning our tears acid and drowning our good intentions in our own rising tide?

Sometimes I wonder if genetic discrimination is a Yeti, a word we whisper around the campfire to give shape to our fears of the great unknown. After all, formlessness does not diminish fear, it makes it worse. If you don’t know what you are looking for it could be anything. It leads us into a state of vigilance that is both laudable and incredibly annoying, since every step forward is met by cheers and then, at the back of the crowd, a sideways glance and a muttered, “what could possibly go wrong?”

This is why I was so struck by Jay Belsky’s article, the Downside of Resilience, published in the New York Times Sunday Review this past week. Belsky points to work, his own included, that suggests some genes that may predispose children to do badly under stressful conditions – abuse, trauma, etc – are not so much “bad” genes as “responsive” genes – and that the same genetic inheritance makes them equally responsive to good parenting or helpful interventions. It is called the orchid and the dandelion theory, with the idea being that some kids do fine in all circumstances – the dandelions, growing like proverbial weeds – while others are hothouse flowers, dying in adverse conditions and blooming in the right hands. If this interests you, read more in this article from the Atlantic by the inimitable David Dobbs (and really just read anything the man writes; you can’t go wrong).

Belsky goes on to propose that we identify children with this genetic predisposition to responsiveness and target them – a good use for our “scarce intervention and service dollars.” We’re not ready to do that, he concedes. But, he asks, “if we get to the point where we can identify those more and less likely to benefit from a costly intervention with reasonable confidence, why shouldn’t we do this?”

Well, okay. A few reasons. First of all, the proposal implies a level of genetic determinism that is unsupported by the facts and fundamentally misleading when it shows up in a place like the NY Times. These are population-based observations, very interesting as to the nature of the genes and how they work, but not valid predictors of individual performance. There are too many confounding variables in the lives and the genetic makeup of individuals. As genetic counselors could tell him, even when you have the same variant in the same gene in the same family, outcomes may vary wildly.

However*, as I said in a response to the Belsky editorial, arguing the science suggests that if we could get that right it would be a good idea. History, on the other hand, suggests that creating classes of people based on what genes they carry is a dangerous proposition and not something to which scientists should lend credibility. The Belsky proposal is obviously well intended. He talks about benefitting the children who have the genes to respond, not disadvantaging the others. But, as he says himself, intervention dollars are scarce. Scarce resource are a zero-sum game. To give to one, you take away from others. You designate certain people as more worthy based on their genes. You incorporate genetics into social policy in a way that is ripe for abuse and prejudice masquerading as scientific facts. We have been down this road before. We know where it leads. It’s not a pretty place.

What does genetic discrimination look like? It looks like this.

*This is what I wrote but not what they published, because the NY Times doesn’t like sentences that start with ‘however’ and changed it to ‘but’. Whatever, NY Times.

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Guest Post: NIPS: Microdeletions, Macro Questions

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetics. 

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At the recent National Society of Genetic Counselors Annual Education Conference in New Orleans, a presentation raised some important questions about noninvasive prenatal screening (NIPS). According to the speaker, a woman with a vanishing twin pregnancy underwent NIPS with an expanded microdeletion panel and the results showed findings “suggestive” of a chromosomal microdeletion syndrome.

The patient underwent amniocentesis with a SNP microarray and the results were normal. In a follow-up call with the NIPS lab, the genetic counselor learned that multiple copy number variants were observed (not originally reported) in the original sample. The lab suggested that these variants could be associated with a malignancy or fibroid tumor (and were of course unlikely to be associated with a microdeletion syndrome in the fetus).

As a result of this genetic counselor’s follow-up phone call and due diligence, the patient underwent an extensive work up for possible cancer, but no explanation was found. NIPS was repeated and this follow-up study was normal.

My first thought in hearing this case was – That poor woman! First a lost twin pregnancy, then concern for a severe condition in her baby, anxiety about the amnio, and worry that she may have Cancer. Although I am not a health economist, my second thought was – Holy Cow! How can our healthcare system afford all of the follow-up testing that may come downstream from these tests? NIPS is promoted as a test that will lessen the need for follow-up procedures such as amniocentesis, but will that remain true as the list of screened conditions increases?

In October 2013 Sequenom expanded their NIPS test to include screening for microdeletion syndromes and Natera followed suit in Spring 2014. Some new companies entering the NIPS market are also advertising screening for microdeletion syndromes.

The addition of microdeletions is a brilliant business strategy for expanding the testing market to include all pregnant women. Even though microdeletions are rare, their incidence—unlike that of Down syndrome –is not linked to maternal age. Women who are currently not offered NIPS because they are not included in the high-risk categories proposed by the American College of Obstetricians and Gynecologists (ACOG) guidelines could now be given a reason to undergo NIPS—even though the predictive ability of the NIPS for rare conditions is less than impressive.

Women who elect the test because of an interest in Down syndrome or because they are eager to learn fetal gender may unknowingly be screened for rare microdeletion syndromes which they know little to nothing about. To add to the complexity, a maternal microdeletion condition may be an incidental finding. In a poster presented at the NSGC meeting this year, Sequenom presented a series of 22q11 deletions detected with their MaterniT21 PLUS test. Included in this report were two mothers who were themselves incidentally diagnosed with 22q11 deletion syndrome. Based on the consent form on the Sequenom website it seems unlikely that these women had any idea such a result may occur.

Where is the evidence to support this expanded screening?

These tests are being performed despite there being no published clinical validation studies. There have been some case reports and proof of concept studies; however given that this testing has been commercially available for over a year now, there is shockingly little published about cell free DNA screening for microdeletions. An abstract from a poster presentation at the ACOG annual meeting in April 2014 evaluated 6 samples (or is it 7? – it is not clear from the abstract) from pregnancies known to be affected with microdeletions and 8 simulated samples. They conclude, “This is the most comprehensive, accurate validation of noninvasive microdeletion detection hitherto… This approach will enable accurate, noninvasive, prenatal population screening for these severe disorders.”

Proof of concept is one thing; proof of clinical validity is another. If we value evidence-based medicine, a sample of six (or seven) affected pregnancies is a long way from being a basis for population screening. Whether population-wide screening for extremely rare disorders is worth paying for is, of course, a question in itself.

But in the unregulated environment of laboratory-developed tests, we adopt first and report out results later. Accompanying this process is a lack of transparency – labs performing NIPS with microdeletions have not made performance statistics publicly available and thus patients and providers have no way of determining the accuracy of microdeletion NIPS. In a webinar hosted by Sequenom , the presenters were asked about the positive predictive value (PPV) of Sequenom’s screen for microdeletions. One speaker replied, “We have calculated them. However, what we would like is essentially to wait a little bit to give you more clinically relevant results. Because so much depends on the fetal fraction of the sample and so on and so forth, so we feel that the more appropriate number to release is after we have done 50,000 samples, how many have we found, how many have we reported back, how many were confirmed, how many were in line with the clinical picture.”

Shouldn’t the accuracy of the test be publicly known before it is run clinically on 50,000 women?

Labs have given us only a glimpse of their performance statistics. I was previously provided information from Natera regarding estimated PPVs for the microdeletions on their panel, but I cannot locate this information anywhere in the public forum. The table I was provided stated a 1/19 PPV (5.3%) for 22q11 with a Fetal Fraction >6% and dropping much lower (to 1/45) with decreased fetal fraction (interesting thread here of multiple women with a 1/19 chance of 22q11 on their NIPS result).

In a letter to the editor, former CMO of Sequenom Allan Bombard and colleagues reported that they had evaluated 264 samples from pregnancies with known microdeletion and microduplications or “enriched genomic mixtures” and report a 100% sensitivity and 99.3% specificity. Applying these statistics to 22q11.2 deletion syndrome (the most common microdeletion syndrome on the panel with an incidence of 1 in 4,000) indicates a PPV of about 0.036 or 3.6% . The overall PPV would be expected to be lower given the very low incidence of the other microdeletions on the panel. At the NSGC meeting this year, Sequenom presented some preliminary data from a series of 120,726 samples screened from October 2013 – July 2014 with test performance that exceeds those estimates. Although they did not have complete follow-up data for positive and negative results, a press release from the company following the NSGC meeting reports “high positive predictive values (estimated combined PPV ranged from 62% to 94%)”.

The limited information available suggests PPVs for microdeletion syndromes fall within a broad range of <3% – >90%. Published peer-reviewed studies are needed to help clarify the PPV associated with this testing so that healthcare providers and patients can make informed decisions about utilizing and interpreting this testing.

About a year and a half ago I published a piece on the DNA Exchange that discussed the importance of PPV in interpreting NIPS results. This was written for an audience of genetic counselors, but the posting is being increasingly used as a venue for patients to share their stories and seek information about their test results. Many patients report considerable anxiety – “the waiting is killing us…we have been devastated for the better part of 3 weeks now” – and some express regret for undergoing this testing at all, “I too wish I would of just done the typical old fashion test so nothing was in the back of my mind and hours of my life would be given back…” Recently, a woman remarked that she did not consent to additional testing for microdeletions and indicates her frustration with not being able to find information about the PPV for this test, “Not only are they essentially experimenting on us…they are not transparent about the potential problems with validity or low PPV.”

As genetic counselors, we are implicated in these companies’ approach. We should be demanding better evidence before leading our patients towards testing that could create this kind of distress. We need to be asking good questions, and we should demand good answers. If we cannot figure out how reliable a screening test is from a thorough review of the literature, I think we really need to ask ourselves if we should be offering it in a clinical setting.

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Guest Post: Going Public

By Sean Hazell

Sean is VP Brand at Idea Couture, a global innovation consultancy, where he leads teams through the design of new products, services, and programs for Fortune 500 brands. Prior to joining Idea Couture Sean held strategy and communications planning roles at some of North America’s top advertising agencies.

A view from the sidelines

Full disclosure: my wife, Allison Hazell, is a contributor and one of the co-creators of the DNA Exchange.

Prior to the days of the DNA Exchange I would comment to Allie how fascinating I found it that GCs were involved in such innovative health services, and yet the field as a whole felt a bit traditional. Today, however, the community appears more open-minded than ever. From my view, it’s been amazing to observe how much has changed over these past 6 years.

Today, genetic testing is more culturally relevant than I can remember. The levels of testing-related coverage across major media is evidence of the growing public interest; to say nothing of the mentions the DNA Exchange has received. The world of genetics is growing at an almost unfathomable pace, and as we know, with that speed comes complexity and risk of misunderstanding.

Advertisement supporting the Globe & Mail's recent "DNA Dilemma" series.

Advertisement supporting the Globe & Mail’s recent “DNA Dilemma” series.

As the spouse of a GC I can’t tell you how many times I’ve participated in the dreaded “what do you do?” conversation. Recently, the number of blank stares returned is dwindling. This isn’t to say everyone is fully versed in the role of GCs. Rather, its still surprising how unfamiliar most are with the field. But the levels of public awareness around testing are clearly rising. Of late, “what do you do?” is likely to lead to a dozen follow-up questions for Allie – representing a very wide range of understanding on the subject (if we don’t take it upon ourselves to beeline for the veggies and dip).

Which brings me back to the opportunity I see from the sidelines. For all of genetics recent popularity, public understanding is still very low. This gap between interest and understanding will likely only continue to widen, at the rate at which new findings are being reported. Today the GC field has the opportunity – and you might even argue the responsibility – to help to interpret the latest ongoings in genetics for the general public. It’s an opportunity for GCs to repurpose your one-to-one counseling skillset to help to inform public discourse and grow mainstream literacy.

The GC community could become Gen Pop’s go-to source for unbiased interpretation on news and notes of human genetics. With a mandate to narrow the gap between professional and public understanding, the field could not only tackle its own awareness issues, but perform a social service that’s increasingly essential.

If you’re nodding along, the likely next question is… how? There’s never a quick solution to increasing public recognition, but here are a few starter suggestions to spur thinking:

  1. Identify the existing cultural conversations where a GC’s perspective can add value. It’s a lot easier to earn attention through existing conversations rather than finding followers for entirely new ones.
  2. Connect with people and parties who are driving related dialogue. Find ways to collaborate with peripheral parties, even if your perspective differs. Responding through an official statement is far less compelling than having a constructive conversation.
  3. Develop awareness initiatives that help to demonstrate what you do, versus those that simply state what you do. Good comedians don’t tell you they are funny. Find creative ways to show the general public how valuable your role is today.

I realize the notion of inserting GCs into the public arena is not a new idea (most recently, see #3 in Bob’s future post). But the timing feels right to make a push. Whereas many GC awareness initiatives I’ve followed have focused on physicians, the bigger opportunity could lie in aiming straight for the mainstream. An age of health information overload is emerging. As direct-to-consumer services increase awareness, there’s a corresponding need for a direct-to-consumer approach to increasing genetic understanding. And from where I’m standing, there seems no group better suited to guide that conversation.

Thanks for having me. I’d love to hear your thoughts, responses, or related experiences.

Advertisement supporting the Globe & Mail's recent "DNA Dilemma" series.

Advertisement supporting the Globe & Mail’s recent “DNA Dilemma” series. Read the full series here (scroll down to ‘Genome’).

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VUS iz dos? Suggestions For A Reasonable Policy On Reporting Genetic Variants of Unknown Significance.

In a previous post, I raised questions about the appropriateness of certain billing policies for multigene cancer panels. As expected, it evoked some thoughtful and strongly felt comments and disagreements. But one thing we can all agree on about multigene panels is that the rate of detecting variants of uncertain significance (VUS) is way too high, usually in the range of 30-40%.

It will be many years before we will be able to determine the clinical significance of most of these variants, even if collaborative VUS reporting among labs becomes a reality and – more concerning to me – the public databases are properly curated. Indeed, the high frequency of VUS may prove to be the Achilles heel of multigene panels particularly as genetic testing increasingly takes place outside of the realm of genetics specialists.

What benefits do patients get from knowing about VUS? Absolutely none that I can think of. Knowledge of a VUS does nothing to enhance their medical decision-making or psychosocial well-being. For some patients, knowledge of VUS may contribute to short-term anxiety and uncertainty. Despite our best efforts, many patients have a look on their face that suggests something along the lines of “I am not exactly sure what was just said to me but I think I have a mutation in a cancer causing gene and how can that not be related to my family history of cancer?” Even more concerning, we all have one too many stories about patients who made surgical decisions based on a VUS, particularly when patients have not been counseled by a genetically sophisticated clinician, in direct contradiction to our dictum that “These results should not be used to guide patient care or cancer risk assessment for the patient or the patient’s family.”

So let me offer a solution that many genetic counselors will think is heresy and antithetical to basic genetic counseling philosophy. Stone, spitball, egg, and tomato me if you will, but my recommendation is that VUS should not be reported out by laboratories.

Instead of reporting specific VUS, I suggest that all genetic test reports – and pre-test counseling notes and result letters that are sent to patients and care providers – include a clearly written and highly visible general disclaimer along the lines of: Variants of unknown clinical significance are very commonly detected on genetic tests. These variants cannot and should not be used to guide medical care or help better understand cancer risks, and therefore are not detailed here. We continually monitor and study these variants. In the uncommon event that a variant is eventually re-classified as pathogenic or otherwise important for guiding your medical care and assessing your health risks, you and your doctor will be promptly notified.

A variant  should be reported when the lab feels that there is a reasonable possibility that the variant might be clinically important. In those cases, labs should offer family studies if they think that the functional and clinical significance of the mutation can be clarified by studying families that segregate the specific mutation. Of course, labs should be able to provide the VUS result – along with their rationale for classifying it as unknown rather than benign or pathogenic – if a patient or provider requests it.

By the way, I prefer Variants of Unknown Significance over Variants of Uncertain Significance. Maybe I am nit-picking, but uncertain seems to leave more psychological wiggle room for patients and care providers to think “Hey, maybe this is important” while unknown suggests that we really do not know what it means.

I can think of two reasons that help explain why we continue to report VUS to patients. One reason stems from our tendency to over-explain, the original sin of genetic counseling. In our desire to adequately inform patients we often overload them with a compressed course in advanced biology and genetics. In a form of counter-transference, we think of our patients as some version of ourselves and we sometimes unconsciously speak to them as if we were speaking to ourselves. Many genetic counselors are science nerds at heart and we tacitly assume that any rational person (i.e., someone who thinks like me) would want to know all those gloriously fine technical and scientific details.

The second reason that we report out VUS is that our concept of a gene is stuck in about 1995 or so. Back then we envisioned genes as highly stable structures which would occasionally have a few mutant alleles, and therefore Mutation = Bad. In fact, mutations are strikingly common and only a few are of clinical or evolutionary significance. Mutations are the norm for genes, not the exception.

This policy would require broad acceptance by the genetics community – genetic counselors, medical geneticists, genetics labs, and others. Perhaps a first step could be to conduct studies that randomly assign patients to two groups, one that receives VUS results and one that does not. Those patients could be followed for a period of time and then compare the two groups for differences in utilization of surgery and screening, as well as psychosocial adaptation and quality of life.

Let’s modify our counseling philosophy to fit into the 21st century. Many of us may kick and scream at first because, well, it is so different from what we normally do. But once you get past the initial shock,  relax and kick off your shoes, sip a beer, and think about it more clearly and calmly, you may begin to feel differently.

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Benefits, Beneficence, and Bending Ethics: Questionable Billing Practices for Multigene Panels?

Germline multigene panel testing is the new hot thing in genetic counseling circles. For the last 15 or so years, the equation has read “Breast Cancer Genetics = BRCA Testing,” with the occasional TP53, PTEN, STK11, or CDH1 test thrown in when we thought we were being clinically astute and smarter than the non-geneticsts at Tumor Board. But now, thanks to the discovery of other genes linked to hereditary breast cancer along with the miracle of massively parallel sequencing, we can test patients for a bucketful of genes in one fell swoop without significantly increasing the cost. We debate the wisdom of including some of the genes on these panels, differences in laboratory quality, the clinical value of the information, and – everybody’s favorite – high rates of variants of uncertain significance. These are  important issues but here I want to discuss an ethically gray practice that has not received much public airing – billing health insurers for multigene panels.

Here in the beautiful Pacific Northwest, roughly half of the health insurance companies cover multigene panels. Not uncommonly, patients will request “that new gene test” that their friend told them about. Counseling issues aside, many patients are disappointed when they learn that if they want a multigene panel, their insurer will not pay for it and they will have to fork over $1500-$4100 of their own hard-earned money. But word on the street – and I am not naming names since I don’t have personal experience with this phenomenon yet – is that some patients are managing to get gene panels covered by their insurers even when their carriers have explicit policies against such testing.

I have been told – and again I acknowledge that I do not have hard proof of this – that some labs are running the panels but not letting insurers know that a multigene panel test was performed. This is partially due to the insurance coding game. The billing codes for BRCA testing are the same as the billing codes for multigene panels, so on one level, insurers are blind to the distinction between the two tests and might never know that their policyholders are not exactly getting the test that the insurer paid for. If  labs eat these costs in full, well, that’s their own business decision and not an ethical lapse (although I wonder how many write-offs a lab can absorb while still maintaining profitability).

If this deceptive billing practice is indeed taking place, it is hard to believe that labs are doing this strictly out of the goodness of their hearts or entirely out of concern for the health and well-being of patients. Genetic testing for hereditary breast cancer has become highly competitive and labs are intensely vying for market share since the US Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics opened up BRCA testing to all labsIf labs are engaging in this practice, it is likely because they want to win the favor of major cancer centers that can provide millions of dollars of business.

Billing an insurer for a test when the lab is aware that the insurer does not cover it, and not letting the insurer know which test was actually run, strikes me as dishonest rather than just bending the rules. And if we genetic counselors stand silently by and allow this to transpire, we are accessories to this moral – and legal? – infraction. It may also cause insurers like Cigna to rethink their policy of requiring a consultation with a genetic counselor before approving coverage for genetic testing. We are, after all, supposed to be conscientious about their guidelines when we order genetic testing for their policyholders.


RULES2

Now let me be clear. I am (mostly) a supporter of gene panel testing and think it should be a covered benefit, though I must admit that I am a bit disappointed in the low yield of actionable positive results beyond BRCA. I have spent an inordinate amount of time appealing these policies, with little success. It is frustrating for me and it makes patients unhappy when their insurer does not cover a test that care providers think could be useful.

Sure, we want what we think is best for patients, and yes insurance company policies can be maddening. But that does not provide moral justification for deceiving insurance companies. The ends do not justify the means. Instead, it should put the burden on us to continue to appeal the policies through established channels and to perform research studies that assess the clinical value of testing for genes such as NBN, RAD51C, or PALB2. Insurers have a valid point when they say that there are inadequate data to determine the clinical utility of multigene panel tests for their policyholders.

I hope that what I have been told is incorrect. If so, then we can write this posting off as based on unverified rumors. But if there is some truth to it, then we need to have a hard and thoughtful discussion. I am interested in hearing the experience of others with insurance coverage for multigene panels.

 

- Thank you to Emily Singh for help with the graphics.

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