Guest Post: Starting a discussion on severity and the merits of carrier screening

By Gabriel Lazarin, MS, CGC

Gabriel is the Director of Genetic Counselors at Counsyl, a laboratory that offers expanded carrier screening.

Discussions about carrier screening inevitably center around disease severity. Is the disease severe enough that it is worth offering screening? Who defines severity and then who decides whether that category of disease severity merits population screening?

These questions are easily recognized, but subjectively answered. Both sides of a complicated equation must be balanced. Physicians and public health officials desire screening protocols that address pressing medical concerns knowing that any screening program comes with costs, financial and otherwise. Parents-to-be have an interest in knowing what daily challenges they may face. Unsurprisingly, these sometimes competing interests result in conflicting perspectives on disease severity.

The focus on severity has increased as carrier screening panels have expanded the list of potential diseases for which a person may be screened. Despite the lack of consensus on definition of the word, severity is nonetheless cited in literature and referenced in conversations about carrier screening. In the ACMG’s statement on expanded carrier screening, the first criterion for consideration is, “Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having prenatal diagnosis…” Setting aside for the moment the stipulation that prenatal diagnosis should be considered (I, and many prenatal GCs, have many times encountered the patient that changes decisions once a hypothetical scenario becomes real), a paraphrase is that a disease should be severe enough so as to be “worth” screening.

The ACMG statement references severity again, saying, “The inclusion of disorders…associated with a mild phenotype should be optional…” A physician offering the test (and the laboratory supplying it) can reasonably question which specific disorders have a “mild” phenotype. Is hearing loss a mild phenotype, and who has the authority to make that decision? The recent joint statement on expanded carrier screening notably excludes commentary on severity, which further highlights the difficulties of its use in panel design. 

In December, PLoS ONE published a study conducted by myself and others at Counsyl that is a first attempt at defining severity. ACMG provided the backbone of this approach: severity was one characteristic assessed when developing a universal newborn screening panel recommendation. Nearly 300 people participated in this significant endeavor, including at least 3 experts for every disease. While successful, replicating that process — laboratories have been updating their screening panels at least once a year — is prohibitively labor-intensive. We aimed for a process that was easily replicated and did not require convening experts of rare diseases.

Our results validate an algorithm that incorporates easily identifiable characteristics such as shortened lifespan or sensory impairment, and places that disease into one of four categories (also derived from ACMG): mild, moderate, severe, and profound. This avails the following advantages: more consistency among laboratories for selection and presentation of screening panels, and a common vocabulary among providers for describing diseases (like the singular language offered by a tumor staging system). Furthermore, the survey was completed in just under 6 minutes on average, making it much more practical for frequent use.

The study population included GCs and physicians, the majority working in reproductive settings. We intentionally did not attempt to identify experts on the diseases surveyed. Instead, commonly known diseases (e.g., cystic fibrosis) and lesser-known diseases (Bardet-Biedl syndrome) were concurrently assessed. All were evaluated in a consistent manner, indicating that familiarity does not affect severity categorization. In addition, the algorithm is completed by identification of disease characteristics not disease names. Even if an evaluator was not familiar with homocystinuria per se, she would certainly understand a list of its characteristics, such as intellectual disability and shortened life expectancy.

So, what’s next? A status check on current expanded screening offerings seems reasonable – Counsyl GCs applied the algorithm to 63 diseases that are common to three commonly-used commercial panels and determined that 25 have profound severity (e.g., Herlitz junctional epidermolysis bullosa, Tay-Sachs disease and metachromatic leukodystrophy) and 38 are severe (cystic fibrosis, ataxia telangiectasia, primary hyperoxaluria). All being in the two most impactful categories, many providers would likely agree on their inclusions.

However, another reasonable next step is to identify and reconcile differences that might be discovered by surveying the reproductive-age patient population. We, the medical community, also need to determine the desired aims of a screening program and apply those aims with consistency and objectivity. It could very well be that expectant parents and obstetricians agree with the ACMG’s statement that interest in prenatal diagnosis should be an influencing factor in a screening panel (what patients want has historically been an absent consideration in constructing guidelines).

But what about those who are not yet pregnant? Without the pressures of pregnancy, is it reasonable to allow the opportunity to consider a wider range of diseases? Obstetricians and GCs are more accepting of pre-pregnancy expanded screening. In pregnant women, decision-making can be influenced by interests in reducing stress and delaying information until after birth in order to reduce anxiety. A carrier screening protocol should serve the interests of pregnant and non-pregnant women, perhaps utilizing different severity thresholds for each scenario.

Through this study and blog post, I hope to open the conversation about what diseases should be screened, who should be screened for them and when that screening should happen. Without a standardized, objective vernacular, these discussions are colored by personal beliefs (which may not align with patient beliefs) and assumptive interpretations of important criteria. This is but a first step that needs to involve all stakeholders – providers, patients and professional societies. By first developing this standard language, we can begin this important discussion.

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Make Me Wanna Holler

Oh, make we wanna hollerHollerin' Man

And throw up both my hands

Make me wanna holler

They don’t understand

Inner City Blues, written by Marvin Gaye and James Nyx, Jr

Multigene panels have perked up the world of hereditary cancer testing. After 15 years of Myriad-dominated BRCA testing as pretty much the only testing option for at-risk families, cancer genetic predisposition testing has been reinvigorated by a whole slew of labs offering a bewildering array of testing options – panels focused on a specific type of cancer, panels limited to highly penetrant genes only, multi cancer gene panels, panels that include moderately penetrant genes, and even design-your-own panels. This isn’t a perfect world and the pick-up rate of new mutations is a bit disappointing. Still, sunshine and fresh air are starting to flow through some of the dark and musty corners of hereditary cancer risk testing.

But all of a sudden health insurers are starting to rain on the parade of new tests. Over the past year, a number of health insurers – local and national – have backed off from covering multigene panel tests after having  previously provided coverage. Regence Blue Shield, First Choice, HMA, CIGNA (with a few rare exceptions), BlueCross BlueShield of Kansas, and now Federal Blue Cross and Aetna (which doesn’t even cover large genomic rearrangement testing!), among others, have put policies in place that specifically exclude coverage of multigene panels. What’s going on here?

I don’t want to stereotype health insurers as amoral profiteers looking to cut a few corners to increase their bottom lines by denying recommended medical care (though admittedly the temptation to do so was strong). That is foolish name calling that gets us nowhere. The policy changes are presumably based on a lack of data on our part rather than a lack of conscience on the part of the insurance industry.  Why should insurers cover  multigene panels if care providers can’t demonstrate that they improve patient outcomes or make for more economical use of medical resources? Health care costs are expanding at a quicker rate than the visible universe and any new tests should have clear-cut medical or economic benefits.

universe v healthcare, courtesy of Emily Singh

The problem lies in the very nature of genetic disease. Genetic conditions are rare. Even with the BRCA genes, the most common highly penetrant cancer risk genes, it took nearly ten years to accumulate convincing data on clinical utility and cost effectiveness. All of the other cancer risk associated genes are far less common. It is impossible to conduct clinical and cost-effectiveness studies on each gene, especially for the moderately penetrant genes. Simply put, we will never be able to provide the data that insurers are demanding.

But enough kvetching. Let me offer some ways to address this problem.

  1. Insurers need to understand that this is a whole new world in genetics and therefore they must use different standards for determining coverage for testing for uncommon conditions. An alternative way of thinking is to look at genetic diseases as defects in pathways rather than as isolated genes. Given what we have learned about the BRCA/Fanconi pathway, it is reasonable to assume that many genes in the pathway – NBN, PALB2, ATM, etc. –  will have some impact on cancer risk. If research can demonstrate the benefits of testing for one gene in a pathway, this should provide solid ground for assuming that testing other genes in the pathway will likely be beneficial as well. Adding more genes to a testing panel should result in greater medical benefits, though admittedly to varying degrees. Sure a few genes in a pathway may eventually turn out to have little clinical value, but those can be discarded along the way.
  2. Insurers must realize that adding more tests to a panel does not substantially increase the costs. Thanks to massively parallel sequencing, it costs no more to run four genetic tests than it does to run forty genetic tests. While the greater number of positive genetic test results may result in greater indirect costs because more patients will test positive for a mutation and will be undergoing screening and risk reducing procedures, this will be partially offset by eliminating the need for screening and prophylactic measures in family members who test negative for familial mutations. In a high risk family where no mutation has been identified, everyone in the family needs testing. However, if a mutation is found in the family, on average only half as many people will be high risk.
  3. Insurers should make multigene panel testing contingent on genetic counseling with a qualified professional to help assure that patients are provided with the most accurate and up to date information about the clinical implications of the test results.
  4. Clinical guidelines of professional organizations such as the NSGC, ACMG, NCCN, ASCO, should endorse multigene panels. Not necessarily specific gene panels, but rather the concept of multigene panels in general. Insurers will have a harder time denying coverage for a test if is widely recommended by groups that help set standards of care.
  5. We must continue to conduct clinical and economic studies to help determine the utility of multigene panels. The studies will require broad cooperation among labs, research institutions and individual researchers, patient organizations, and international consortia. And genetic counselors should be at the forefront of these studies. We are the boots on the ground for almost every new genetic test and are in a prime position to lead research efforts. We should be driving this mule team, not sitting in the back of the wagon hoping that we don’t fall off at the next bump.
  6. As I have discussed previously, there is reason to believe that some labs may be engaging in deceptive billing practices if they do not let insurers know that a panel is being but the insurer is only billed for BRCA analysis. This, in my view, is frankly unethical and creates an atmosphere of distrust. I would not be surprised if this has partially contributed to insurers’ reluctance to cover multigene panel testing. Such practices, if they are taking place, must be discontinued. Honesty and openness are sine qua non in any relationship.

Patients have the potential to benefit greatly from advances in genetic testing. But new technologies also create new challenges and require new ways of thinking about the care that we provide and how we justify paying for it.

 

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Resta’s Rules of Genetic Counseling

You will not find these pearls of wisdom in Psyche and Helix, Psychosocial Genetic Counseling, A Guide To Genetic Counseling, or the Journal of Genetic Counseling. I am certain that they will never be the source of correct responses on genetic counseling board certification exams. These insights are based on personal observations made during my 3+ decades of genetic counseling practice. There is almost no research to back them up but they are gospel truth nonetheless. Well, at least they seem true.

 

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1) All interactions with patients are primarily psychosocial encounters, no matter how much we or patients consciously or unconsciously try to focus on facts and figures.

2) All research studies are flawed in some way. Therefore, all facts, figures, and risk predictions that we so confidently quote are wrong, with the possible exception of Mendelian segregation ratios (but even there…). Quite often, several seemingly well designed studies about the same topic will produce conflicting results.

3) Which risk figures we choose to quote reflect more about our own unconscious biases, training, and professional influences than it does about the robustness of the statistics themselves.

4) It often turns out that patients with the lowest a priori risk have the highest chance of actually testing positive for a gene mutation and, conversely, the highest risk patients actually have the lowest chance of testing positive for a gene mutation (and I am not altogether making this up).

5) In a family that looks like it could have two different genetic syndromes, one syndrome highly likely and the second syndrome fairly unlikely, if you don’t test the family for the less likely syndrome they will inevitably be tested by another care provider some day and test positive, and then you will foolish and insecure (especially if the other care provider is not a geneticist). But if when you initially see the family you do the testing for the less likely syndrome, the testing will be normal and you will kick yourself for wasting healthcare dollars. Perhaps this is a corollary to Rule Number 4.

6) As I have previously pointed out in The Resta Paradox* there is a sub-set of patients who believe that the most improbable things will happen to them. If you say to such a patient “The odds of this happening are one in a thousand” the patient will inevitably respond “Well, I will be that one in a thousand. Rare things always happen to me.” To some extent, this is an example of Abby Lippman’s key insight from 35 years ago that patients inevitably dichotomize odds – either it will happen to me or it won’t. It may also be a defense mechanism, a way for patients to prepare themselves for the possibility of an unlikely undesired outcome. Trying to reassure such patients with even more statistics is an exercise in futility; these situations require good basic counseling skills. Really, when it comes down to it, who cares what numbers they choose to believe? A better counseling approach is to acknowledge the patient’s viewpoint and then explore why they believe these numbers and how that perception affects their decision-making.

Graphics by Emily Singh

 

7) If you make a clerical error, no matter how tiny and seemingly insignificant, it will come back to haunt you in unforeseeable and kafkaesque ways, and it will be nearly impossible to undo the error. My father, a career clerk, used to tell me ad nauseam “The world would be a better place if there were more good clerks.” Dad, bless his clerical heart, was right.

8)  The patients for whom you put in the most effort – or pre-appointment preparation – are the ones most likely to complain about you or to no-show for their appointments.

9) Nobody – not our billing departments or even health insurers themselves – understands insurance coverage for genetic counseling and genetic testing. Genetics itself is far simpler to understand than billing for genetics.

10) There will be at least one genetic counselor at your institution who is on maternity leave or planning a wedding.

The Resta Paradox  (graphic by Emily Singh)

* – The astute DNA Exchange reader may have noted a tendency on the author’s part to name things after himself – Resta’s Rules, The Resta Paradox, RestaEZ Gene Panels. Admittedly this is shameless ego stroking. But it is better than an eponymous syndrome. With all due respect and apologies to our genetic counseling colleague Ann Smith, my preference is for a medical cure or a clever theory to be associated with my surname.

And, once again, a special thanks to Emily Singh, daughter extraordinaire, for help with graphics.

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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 Technica:

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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