Author Archives: laurahercher

Hobby Lobby Sounds Like Fun But It’s Really Yucky Sucky for Genetic Counseling

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Hobby Lobby sure sounds like something that would never harm you. As Ray the Ghostbuster said in Ghostbusters, “Something I loved from childhood…something that could never ever possibly destroy us…”   But sadly, it is true: a threat wrapped in adorableness, Hobby Lobby v Sibelius is the 100’ tall Stay Puff Marshmallow Man of legal cases.

 

On March 25th, the Supreme Court of the United States heard arguments for and against the claim that Hobby Lobby, a privately-held company run by a family with conservative Christian beliefs, should not be compelled to purchase insurance for its employees that includes coverage for contraceptives, as is mandated under Obamacare. Actually the company does not object to all contraceptives, only to those that they consider abortifacients, including IUD’s and the morning after pill. Because this case concerns their right to act in accordance with religious ideology, the question of whether or not these methods actually produce an abortion is moot – it only matters that the owners of Hobby Lobby believe them to be wrong. So while the particulars of their faith mean that some contraceptives would still be available to Hobby Lobby employees, the principle under review, untethered to any burden of proof or objective standard, is far more sweeping.

 

Although the contraceptives issue itself is important, people on both sides have emphasized that this decision will have broader consequences. For instance, advocates for gay rights have seen this as a foot in the door for state-sanctioned discrimination, giving companies the right to refuse service or employment based on prejudice dressed up as religious beliefs. Adam Winkler, UCLA law professor writing in the Huffington Post, describes a number of ways that anti-discrimination laws could be undermined if any employer could claim a “religion-based objection to the law.”

 

This case is something that genetic counselors and the NSGC should be watching with concern, as it is likely to impact our field as well. Employers who object to paying for coverage that includes contraceptives may take a similarly skeptical view of paying for insurance that covers prenatal testing, with the reasoning that prenatal testing is done only to provide the opportunity for abortion. You can (and we will) argue that prenatal testing can lead to therapy or better case management or simple reassurance, but others will assert that the point of prenatal testing is to open the door for termination and, right or wrong, this is an argument that is likely to be taken seriously by conservative justices. If that seems crazy to you, do this thought experiment: imagine that termination is not an option under any circumstances, and then picture trying to get insurance companies to pay for amniocentesis.

 

Why do I think that anti-abortion advocates will target prenatal testing? it’s simple: they’ve been talking about it for years. Remember Rick Santorum, who was for a time one of the frontrunners to be the Republican presidential nominee in 2012? He made a speech during the campaign where he talked about the fact that prenatal testing is included as a fundamental and required part of healthcare coverage under Obamacare rules. “One of the mandates is they require free prenatal testing in every insurance policy in America. Why? Because it saves money in health care. Why? Because free prenatal testing ends up in more abortions and therefore less care that has to be done, because we cull the ranks of the disabled in our society.” This speech shocked a lot of people in the field when it hit the presses, but it didn’t shock his Christian Alliance audience at all. This doesn’t come from nowhere. Prenatal diagnosis is on the radar of the anti-abortion movement in the United States, which is why Hobby Lobby should be on ours.

 

Want more proof? How about the law passed in North Dakota last year, which prohibits abortion for sex selection or genetic defect? This statute has gone unchallenged in large part because it is almost impossible to enforce, as opposed to — say — the law restricting all abortions past six weeks gestation, which was passed at the same time and (understandably) got the lion’s share of the press. But the genetic abortion law, first of its kind, is a clear manifesto expressing the intention of those who oppose abortion to limit the ability of women to terminate for cause. And t that end, eliminating coverage for prenatal testing is a far more effective tool than trying to pass laws that require prosecutors to prove something about a woman’s state of mind.

 

This is an issue that isn’t going away. In fact, I predict it’s going to get worse. Why? Because we are getting better at what we do. Keep in mind that all our steps forward (better sensitivity, better specificity, earlier results, less invasive testing) are threatening to a mindset that sees prenatal diagnosis as an ever more efficient way to identify and eliminate vulnerable individuals. When ACOG revised its practice guidelines in 2007 to increase the number of women eligible for prenatal testing, columnist George Will wrote, “what is antiseptically called “screening” for Down syndrome is, much more often than not, a search-and-destroy mission…” Will, the father of a son with Down syndrome, bemoaned the change in practice precisely because it would be more effective.

 

I know, not because I am psychic, but because I have had this conversation before, what genetic counselors will say when this line of attack is launched. First, they will talk about their own commitment to be supportive of all choices for their patients, including the choice not to terminate, which is incredibly important to your patients but doesn’t matter at all to anti-abortion activists.  They don’t care if you are a good counselor, or a good person, since it doesn’t change the fact that a large percentage (how large; under dispute) of all those who receive a diagnosis of Down syndrome, for example, will choose to abort. Second, they will argue that prenatal testing has a value beyond the opportunity to terminate, which is true but a bit disingenuous for the same reason as above. Prenatal testing puts termination on the table as an option.

 

What I don’t like about this defensive posture is that it implies that giving families the option to terminate is not a good enough reason to do testing, or that we are unwilling to champion it as such. I don’t think this is how most counselors feel, but it is natural to try and tiptoe around the sensitivities of others, especially when those sensitivities are emotionally charged and involve a lot of judging – judging of us, and of our patients, whose feelings as well as medical options we would like to protect. But ultimately I think it is a better and stronger position to argue on behalf of what we do without defensiveness. We shouldn’t base our case for prenatal testing on the need to provide reassurance or how it improves prenatal care because those are not our best arguments and it makes us sound ashamed.

 

And meanwhile, stayed tuned on Hobby Lobby, where a decision is expected in early June.

 

 

 

 

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It’s A Slippery Slope. Get Over It.

This week, the FDA is holding hearings to examine the use of a new IVF technique that could allow women with mitochondrial disease to have children who are genetically their own without the risk of passing along the condition.  The proposed treatment involves yanking out the nucleus of a donor egg and popping in a nucleus from the mom-to-be.  Studies of monkeys have demonstrated that this method can be used to produce healthy monkeys; studies of humans thus far have demonstrated the potential to create what appear to be viable embryos.  Shoukhrat Mitalipov, the Oregon-based researcher who has done both human and animal studies, is interested in moving to clinical trials – or as Dina Fine Maron puts it in Scientific American, “human clinical trials.”

 

The issue of oocyte modification was debated last year in the UK, where the government has opted to allow nuclear transfer to be used on an experimental basis.  The story got major play in the press there, as it has here, with catnip headlines about ‘3-parent babies.’  There are some serious questions to be answered about the risks – the first studies using human eggs showed an increased rate of abnormal fertilization, although zygotes with an appropriate number of pronucleii seemed to develop normally.  Minimizing the risk of harm to any child born of this technique is an important focus of the regulatory agencies and if we can’t do it safely, we shouldn’t do it at all – which brings me to the other question under debate: should we do it at all?

 

Marcy Darnovsky of the Center for Genetics and Society, a non-profit organization that leans precautionary on the use of reproductive technologies, has been waging a one-woman war against nuclear genome transfer, protesting the UK decision in Nature, circulating a petition to the FDA to decry human germline modification and penning an OpEd for the N.Y. Times entitled “Genetically Modified Babies.”  Darnovsky brings up safety issues but the heart of her objection is the slippery slope argument.  We have informally agreed not to make changes in the germline that will be passed down to subsequent generations – not to tinker with eggs and sperm.  This is a step over that line.  If we do this, what else will we do?  It could, she says, “open the door to further germline manipulations.”

 

Last winter, I attended a panel on the ethics of germline manipulation where participants debated a resolution to prohibit genetically engineered babies.  Lee Silver (Princeton) and Nina Farahany (Duke Law) represented the anti position (i.e., let’s NOT prohibit genetically engineered babies) and won the debate by focusing on – wait for it — nuclear transfer for mitochondrial disease!  Forbid genetic engineering, they argued, and you rule out this potentially game-changing therapy for afflicted families hoping to give their kids a life free from the burden of life-long, incurable disease.  In other words, another slippery slope argument, only the other way round – accept the concept of regulation in any form, let the bureaucrats in, and you cut yourself off from progress and doom families forever to suffering that could have been prevented.

 

The thing is, I am not at all convinced this example – like many other models we construct — represents anything other than itself.  I don’t mean to say it’s trivial.  But mitochondrial replacement therapy isn’t a reasonable stand-in for the complex issues associated with genetic engineering, like trait selection or eugenics.  You can make the case that mitochondria are more like the bacteria we harbor in our gut than they are like nuclear DNA , in terms of how they affect our health and well being.  Gut bacteria have DNA too.  If we gave the 3-parent child a fecal transplant, would we have a 4-parent child?  (Is that a bad thing?  Cool or creepy?) 

 

The problem with slippery slope arguments is that they don’t relieve the obligation to assess each and every situation on its own merits.  They don’t provide some easy moral clarity or regulatory guidelines.  Everything exists on some sort of continuum, whereby you can draw a straight line from the ludicrous to the patently unacceptable.  When does life begin?  It’s a tightrope, with one end tied around infanticide, and the other clasped in the hand of some guy out of a Monty Python sketch singing “every sperm is sacred.”  Every decision we make is about drawing a line.  And every ethical quandary worthy of the name is unique enough that it deserves its own weighing of the pros and cons.

 

Are you concerned about doing PGD for later-onset conditions?  This is a line some people have suggested, between what is a good and a bad use of preimplantation technology.  What if that condition is Huntington’s?  Okay, what if it is a BRCA 1 mutation?  Or what if it is a subtly increased risk of Parkinson’s disease?  Each of these is a very different scenario.  Every family is going to experience those risks differently.  The fact that you can draw a line from here to there does not automatically absolve you of considering the facts at hand in each case, the good that can be done, what stands to be gained, what may be lost.  It’s very hard to take away happiness for one person based on what might (someday, somewhere, possibly, in a related case) happen to somebody else. 

 

The thing is, it would be so much easier if we could find that certainty.  Slippery slope arguments are a plea to make things stand still for a moment, so a person can get their bearings.  Anyone who works in genetics can relate to that sentiment.  But history is itself a slippery slope from a turbulent past to an uncertain future, and we don’t have the luxury of stepping off.  So what should we do about nuclear transfer for mitochondrial disease?  Well, let’s make a decision based on mitochondrial disease and the very sensitive nature of the human embryo, which may not take kindly to this manipulation.  Let’s not make it the last word on anything.  Let’s not pretend we are now for all time choosing to abandon sufferers to their fate, or opting for GATTACCA.  It’s hard enough and scary enough without conjuring up the ghosts of battles to come.

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The Bumpy Road From Bench to Bedside: Top 10 Genetics Stories of 2013

10. 23andMe and the Thanksgiving Week Massacre

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You can get anything you want…except personal genome screening.

The Monday before Thanksgiving 2013 the FDA issued a letter to 23andMe directing them to cease and desist sales of their personal genome service (PGS) within 15 working days.  In shutting down 23andMe, the government agency was in effect shutting down an industry, since 23andMe was the last player standing of any significance in the fledging direct-to-consumer genetic health information services field.  This added some drama to the situation and some volume to the howls of outrage from libertarian-minded science geeks who not only liked but believed in 23andMe.  To be entirely fair, its hard to blame the FDA for taking down the last lonely cowboy, since 23andMe has helped a number of competitors out the door, dipping into their deep pockets and selling their test at a loss.

Of course this is 2013, and information never really goes away.  The FDA ban covers the PGS – the advice, not the SNP data.  There are no rules that prohibit giving back sequence data sans annotation.  Those willing to do their own digging can use promethease, a free online tool for SNP analysis.  And the FDA cannot regulate promethease because it is not for sale – impersonating a doctor for money is against the rules, but giving out crap advice for free is the god-given right of cranks and yoga enthusiasts and pretty much every neighbor I have ever had.

Destroyed or not (and we shall see; I’m expecting a resurrection, minus a few of the more controversial tests like BRCA 1 and 2), the entire personal genomics industry isn’t much more than a blip (the company claimed to have scanned 500,000 people since 2006, but did not say how many were paying customers).  For a more thorough discussion of the issues involved in this case see here, but for the purposes of this column, I would make two general points about why this story was significant.  First, it indicates that the FDA is willing to play a more active role than the heretofore have in the regulation of genetic testing as a medical device.  Second, and with all deference to point one and the need for some regulatory power, the story demonstrates the essential futility of trying to control the flow of information in the internet age.

9. The Supreme Court delivers a verdict in the MYRIAD Lawsuit, bringing clarity and … myriad lawsuits.

Three years after District Court Judge Robert Sweet shocked the genetics world by declaring gene patents a “lawyers trick,” the Supreme Court weighed in, ruling unanimously that naturally occurring DNA sequences are laws of nature, and thereby striking down a number of the patents held by Myriad Genetics on BRCA 1 and 2.  In their opinion, the Court distinguishes between genes as they appear on the chromosome and cDNA, the edited form obtained by working backwards from a gene product – a transcript of the performance rather than a copy of the script, so all the notes and stage directions are missing.  The Court’s reasoning – that cDNA is not found in nature – is not entirely true, and future cases may challenge that notion, but for the moment the message is clear: DNA patents are out, and cDNA patents are in.  This splitting-the-baby approach may have been a judge’s version of a lawyer’s trick, because it invalidated gene patents, which the justices clearly felt were problematic, but did not in a single swipe eliminate all claims relating to DNA, thus wreaking havoc in biotech.

Did I say things were clear?  Well….  This was a result that satisfied the genetics community, which was never comfortable with the restrictions and costs imposed by Myriad’s decision not to license its BRCA patents.  There was celebration in the air as rival labs announced the availability of BRCA testing, or maybe that was gunfire, since Myriad immediately declared its intention to defend its remaining patents.  Here is what clarity looks like in December 2013:

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Okay.  So perhaps not entirely clear.  But the decision does resolve some theoretical issues going forward, as we put to rest whatever anxieties there might have been about negotiating a genome littered with patents in the age of next-generation sequencing.  And if not the final word, it is still an important moment in the BRCA saga, a story that has kept us entertained for years, a story that has had everything: Mary Claire King, dueling labs, Mormons, the ACLU, Clarence Thomas, even a cameo by Angelina Jolie.  It is the story of a test that single-handedly brought into being the field of clinical cancer genetics.  It is a story that defines its time, and somehow to me, this decision, this imperfect and welcome decision, feels like the end of an era.

8. North Dakota passes an anti-abortion law that is the first of it’s kind (but may not be the last).

Remember the law restricting abortion that North Dakota passed last March — no abortions after the fetal heartbeat can be detected, about the 6th week of gestation?

No, not that one.

It’s the other North Dakota law, the one that makes it illegal for a physician to provide abortion:

“with the knowledge that the pregnant woman is seeking the abortion solely: a) On account of the sex of the unborn child; or b) Because the unborn child has been diagnosed with either a genetic abnormality or a potential for a genetic abnormality.”

Sure, there are loopholes here you could drive a Mack truck through.  It requires doctors to know the woman’s state of mind.  Isn’t ambivalence the natural state of all mankind?  In practice, the law is of so little significance that North Dakota’s only abortion clinic dropped their legal challenge to ND 14-02.1-02.  The clinic, like the media, has chosen to focus on the fetal heartbeat law, which a judge has blocked pending a ruling.  But google the story, and you will see that groups like LifeNews and American United for Life are paying close attention.  “Dismissal of the portion of the lawsuit challenging the ban on sex-selection or genetic abnormality abortions should be seen as a victory, for now,” said the New American.

Take home: prenatal diagnosis is on the radar of the anti-abortion movement.  This law is not a burst of craziness or the brainchild of some random legislator in North Dakota.  It is a response to the increasing capabilities of genetic and prenatal testing, an informed, calculated, ideological response, not just to abortion but to the idea of selecting against certain fetuses.  The eugenic capabilities of prenatal screening concern large swaths of the population: push those buttons, and they will push back.

7. Sequencing, The Next Generation: Oxford Nanopore offers researchers a chance to beta test the adorable MinION.

After many years of development and a couple of false starts, Oxford Nanopore seems poised to usher in 3rd generation sequencing.  It’s nanopore technology offers longer read lengths (and thus fewer alignment and assembly issues), relatively low costs and real-time capabilities, with the potential to bringing sequencing of DNA, RNA and protein expression to the bedside.  The company did a much buzzed show-and-tell at ASHG in October, and has issued an invitation to researchers to apply for up to 50 free MinION sequencers, in a tone that veers from infomercial (“additional shipping charges” will apply) to vague (“at least two days notice will be given of closure of the registration period. This will be noted on our website and on Twitter”) to zen (“We are requesting little information about your intentions for MAP and no supplementary information is necessary”) to hard-nosed (“Competitors of Oxford Nanopore and their affiliates need not apply”).

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The MinION is the smaller of two Oxford Nanopore products in development, and it’s so cute if they put a brushed aluminum bezel around it they could sell it at Apple (I hear the iphone 7 is going to have gene sequencing anyway).  For data reads, it plugs in to a computer via a USB port.  A larger-capacity product, GridION, is essentially lots of little minions in a bigger box (maybe they should have called it PlantatION).  To get a sense of how the technology works, check out the video on the Oxford Nanopore website.  “Oxford Nanopore designs and manufactures bespoke nanopore structures,” says the narrator in a lovely Downton Abbey accent strikingly at odds with a technology that has been called, in that most 2013 of phrases, “disruptive.”

6. “Anonymous” gets outed.

In January, Whitehead Institute fellow Yaniv Erlich and fellow MIT hacktivists announced that they had successfully identified participants in the 1000 Genomes Project whose DNA was published “anonymously” online, using only publicly accessible databases like genealogy websites, where DNA markers are linked to surnames.  Designed to test the limits of de-identification, the project was a wake-up call for any researcher, institution or biobank who offers donors hard and fast promises of anonymity.

With proof-in-principle established by the Cambridge crew, MTV tested clinical applications with its November premiere of Generation Cryo, a reality show following a young woman conceived by donor sperm who enlists a crew of half-sibs to find their collective donor dad.  “Perhaps he doesn’t want to be found,” suggests one adult to 18-year-old Breeanna Speicher, who pauses to think about that momentarily before ignoring it entirely and rededicating herself to her quest.

Will she find him?  Chances are she’ll be knocking on his door any day now.  Why?  Because DNA is THE BEST IDENTIFIER IN THE WORLD.  Anonymous DNA is an oxymoron.  And anonymous DNA donors are an endangered species.

5. Two-year-old girl gets a trachea manufactured from her own stem cells.

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Fabricated organs were everywhere in 2013.  In April, a team of Japanese scientists led by Takanori Takebe announced in Nature that they had succeeded in creating tiny but functioning livers from human stem cells, able to perform basic liver functions when transplanted into mice.  In April, researchers in San Diego produced what Gizmodo called “itty-bitty livers” using a 3-D printer; later versions lasted as long as 40 days.  In August, Nature profiled researchers in Kyoto who had managed to turn murine induced pluripotent stem cells into sperm and eggs – and to prove that they were real by using them, creating viable and fertile mouse pups.

But the organogenesis story of the year concerns a real treatment for a real girl: 2-year-old Hannah Warren, born without a windpipe.  A trachea is not as complicated as a liver or as sexy as sperm and eggs, but you can’t survive without one.  So the little Korean-Canadian girl who had never lived a day outside the ICU flew to the United States to be operated on by Dr. Paolo Macchiarini, the Italian director of a Swedish Institute.  They used a windpipe grown with her own stem cells on a matrix of plastic shaped to resemble a trachea.  The parents could not afford the operation, so Children’s Hospital of Illinois donated its services. There’s a lot of messages in this story: the incredible potential of the technology, of course, and the global nature of it all.  The fact that it was possible but unaffordable says something important about the future as well.  And finally, unhappily, it must be reported that little Hannah Warren died of lung complications in July, three months after her surgery.

And that’s the final message: it may sound like magic, but this ain’t no fairy tale.

4. The Archon Prize is cancelled for lack of interest.

In 2003, proponent of gladiatorial science Craig Venter announced a contest: $500,000 for the development of technology that would bring down the cost of genome sequencing to $1000.  Subsequently re-branded as the Archon X Prize for genome sequencing, the challenge helped make ‘the $1000 genome’ a meme that represented the future of the field.  The Archon prize, after serving for a decade as goal and talking point for rival sequencing companies, was scheduled to be held as a month-long competition in September 2013, until it was abruptly cancelled in August for lack of interest.

An event that did not happen is an odd candidate for a top ten story of the year, but think about what this cancellation suggests.  First, it suggests our technological horizons have changed so rapidly that we became bored with the goal even before we reached it.  Peter Diamandis, X-Prize chief executive, acknowledged in the Huffington Post that the $1000 genome remains elusive – costs still linger closer to $5000 — but suggested that the field has moved on.  “Genome sequencing technology is plummeting in cost and increasing in speed independent of our competition.”  Second, it suggests that in 2013 our ability to produce sequence data has so outpaced our ability to process and understand sequence data that a competition to produce more of it, more cheaply, seemed suddenly like not such a good idea after all.

3. First gene silencing drug approved by the FDA.

Gene therapy and gene silencing are mirror images – turning genes on, turning genes off – and for years they have shared the burden of great potential with not much to show.  But this may be starting to change.  And although the trickle remains a trickle, gene therapy continues to show progress in clinical trials, and in January a gene silencing drug was approved for the first time by the FDA.  Called Kynamro, the drug is intended for familial hypercholesterolemia homozygotes.  In preliminary tests, it reduced LDL levels by 25%.

Raising the stakes on gene silencing, Jeanne Lawrence of UMASS published an article in Nature in July, detailing how her team was able to use the XIST gene to silence a single copy of chromosome 21 in trisomic cell lines.  The authors expressed a hope that the technique will eventually lead to treatments for features of Down Syndrome.

2. The best thing since sliced bread?  Maybe better!  CRISPR slices genomes to order.

On December 12th, researchers operating out of an assortment of low-rent facilities in Cambridge, MA published a report in Science identifying genes involved in acquired resistance to chemotherapy, the first discoveries made by systematically testing human cell lines using the miraculous new technology, CRISPR.

This powerful gene editing technique hijacks a component of the bacterial immune system – a sort of programmable warrior armed with enzymatic, DNA-snipping scissors and a list of targets written in a DNA code — snippets from viruses that attack bacteria.  The system, elucidated by Jennifer Doudna of Berkeley and Emmanuelle Charpentier of Umea University in Sweden, was re-jiggered to use as a guide an RNA molecule that could be made to order.  The result: a mechanism for cutting DNA at will throughout the genome, effectively repressing or even altering genes in a very specific and targeted fashion.

The new technique has drawn raves for its versatility and ease of use (“A total novice in my lab got it to work,” marveled Nobel Laureate Craig Mello) and has been used successfully in all five food groups of the genetics lab: yeast, bacteria, fruit flies, zebrafish and mice.  In February, George Church announced that he had used CRISPR to alter human induced pluripotent stem cells, adding: “results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.”

Potential uses for CRISPR beyond interrogation of cell lines include: development of model organisms, modeling the effects of specific genes and gene changes, somatic cell gene therapy, and new treatments for acquired diseases with genetic components such as cancer and AIDS.  And of course, as George Church points out – with an enthusiasm that may not be shared by all – as a platform for germline gene therapy and genetic enhancement of embryos.  But, I mean, besides that, it is hardly interesting at all.

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1. ACMG produces guidelines for reporting of incidental findings in whole genome and whole exome sequencing.

The ACMG guidelines are the genetics story of the year because both their existence and the controversy surrounding them illustrate exactly where we are today:

1. Desperately in need of guidelines, because exome and genome sequencing are a clinical reality today,

AND

2. So unready to deal with all the information that comes along with sequencing that we can’t even agree on what to call it: incidental findings; secondary findings; opportunistic findings; unanticipated news.

Here are some crib notes, without recapitulating the argument in its entirety (covered here and here, for starters).  Many people believe that access to genetic information is a right, and argue vehemently that doctors and other genetics professionals should not function as intermediaries, deciding what information is significant, what information is superfluous, and what information patients may be unable to handle or comprehend.  This is a sort of a power-to-the-people argument, wherein ‘power’ is defined as genomic information (which may be a bit of a stretch.  Jus’ saying).  The other side is concerned about the logistical and ethical complexities of giving out information which is not well enough understood – ‘well enough understood’ being one of those ill-defined metrics that, like Justice Potter Stewart’s description of obscenity, seems to come down in the end to “I know it when I see it.”

The ACMG came out somewhere in the middle, and has been soundly criticized by all sides, which I think means they must have done something right.

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THE FDA CALLS A PENALTY ON 23andMe

IS THIS THE GAME WE WANT TO PLAY?

On Monday, the FDA celebrated the start of the holiday season by sending a letter to 23andMe, informing the direct-to-consumer personal genomics service that they must cease and desist offering their signature test.  The proximal cause of this action, as described by the FDA and not disputed by the company, was that 23andMe had ceased to participate in a process of establishing their PGx test as “validated for its intended uses.”  They had, the FDA suggested, dropped the ball – well, not just dropped the ball, but kicked it out of bounds, an old soccer trick for delay of game, which Mya Thomae and Dylan Reinhardt suggest might have been exactly what the company had in mind, playing for time while they attempted to accumulate better data than what-all they have right now.

The FDA move prompted a vast twitterlanche of commentary, ranging from indignant outrage to smug satisfaction (Dietrich Stephan, founder of the erstwhile DTC competitor Navigenics, said, “Engaging the FDA as a partner to bring the most robust and safe new type of test to market is diagnostics 101”).  Genetic counselors might be suspected of indulging in a bit of schadenfreude, since the relationship between 23andMe and the GC community has inclined in the direction of mutually suspicious, if not downright frosty.   The company, which advocates for access to one’s DNA information with almost a religious fervor, sees GC’s as gatekeepers, as a self-anointed coterie of priestesses guarding the oracle at Delphi.  Genetic counselors, for their part, tend to perceive the very existence of 23andMe as an affront, as though the possibility that a subset of people might benefit from genetic testing without access to counseling was insult and injury — an existential threat.

To be fair, nobody reacts well to the suggestion that their chosen profession is a cabal that threatens the freedom and well-being of fellow citizens – not even investment bankers, and at least they get to soothe their wounded souls with lots of material goods.  But pettiness is unbecoming and unproductive, and we would all do well to remember that a groundbreaking organization like 23andme is a part of the energy and excitement of the field – an expression of an explorer’s mentality that draws people to the potential of genetics in 2013.  That’s not only fun and sort of cool but also incredibly powerful because it attracts the kind of intelligence and curiosity that makes big new ideas possible (David Dobbs does a thoughtful and balanced job making the case for 23andMe in this piece for the New Yorker).

So minus any animus toward 23andMe, was this a reasonable move by the FDA?  There are two main questions that have been raised: 1. can they regulate? and 2. should they regulate? (a third question, HOW DARE THEY?, has also gotten a lot of play but I am going to ignore that one because, c’mon guys get over yourselves this isn’t ONE STEP FROM TOTALITARIANISM).  The first one takes up the issue of whether or not a personal genomics test falls under the FDA jurisdiction.  I am going to say yes, but will not rehash those arguments here, since they have been more ably covered elsewhere – I particularly recommend this piece by Hank Greely at the Stanford Law School Center for Law and the Biosciences blog.

So, should they regulate?  The rationale for regulatory action in the letter to 23andMe is a risk of harm to customers, including the possibility that a customer might alter his medication without medical advice or misunderstand her risk for breast cancer and have an unnecessary prophylactic mastectomy.  While theoretically true, it seems wildly unlikely that very many people would insist on a mastectomy without getting more information than mail-order genetic results – and those cases might be more indicative of out-of-control anxiety issues and irresponsible medical practice than the power of a PGx report.  More commonly, misunderstanding the limits of the test in terms of risk reduction might empower a customer to skip out on appropriate preventative measures. Either way, this is nothing new — a rehash of concerns genetic counselors have had about DTC testing since its inception.  In practice, perhaps the best summary of the clinical impact to date comes from Anders Nordgren, who called it “Neither as harmful as feared by critics nor as empowering as promised by providers.”  Having spent hours poking through the generally well-written and thorough 23andMe reports, and spoken to some of their customers, I would suggest that misunderstanding the results that come from 23andMe could pose some risk — real risk, to be sure, but limited risk.

However, it is possible to envision a scenario where a genetic testing sold DTC did pose a significant danger to consumers, with inaccurate results, irresponsible advice, tests used to market scam treatments or preventatives.  None of this is farfetched, and some of it has already been documented.  For this reason alone, the possibility of FDA action is an important deterrent.  A company like 23andMe, which makes real efforts to be thoughtful and responsible, will ultimately benefit from the restraint on less scrupulous entities.  And of course, it is possible that 23andMe would have been less thoughtful and less responsible if they had not been motivated by the threat of FDA action.  So arguments against regulation in general based on the fact that 23andMe is well-intentioned are misguided.

But despite a bias in favor of showing some muscle, I have questions about how much time and energy the FDA should spend cracking down on the likes of 23andMe.  Is it, I wonder, the best use of resources?  For one thing, attempts to stop the free flow of information in 2013 are fingers in the dike. Razib Khan at Slate expands on this argument, suggesting that companies pushed by the FDA could simply move offshore, away from any regulation.

And more importantly from my point of view, the emphasis on negative action diverts us from the possibility of doing something positive.  Rather than keeping consumers away from tests we think are insufficiently documented, how about providing a resource to the general public that endorses tests that are ready for prime time?  After all, a few bold individuals may be excited at the prospect of downloading Promethease to query their own exome data but most people would rather not, thank you very much.  Most people would be happy to have some guidance.  They can get that guidance from the company, but even the classy companies have a vested interest in hyping the significance of their results – that’s what they’re selling, right?  There is an opportunity here for the government and the genetics community to create a trusted source of information that is neutral, unbiased and supports a best-case scenario use of genetic testing by those eager to take the plunge.  Hell, you could imagine tying in such a resource to something like ClinVar or GenVar, so that early adapters could contribute to publically accessible databases rather than giving it to 23andMe to sell.

After years of running up and down the pitch, the FDA has demonstrated that it knows how to blow the whistle – that’s good.  I’m pretty sure 23andMe will be back – and that’s good too.  But if we really want something great to come out of this discussion, let’s stop doing color commentary on the FDA action, and imagine what it could be like if we changed the game.

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A SCIENCE WRITER USES HER CHILD’S 23ANDME TESTING EXPERIENCE AS A HOOK, AND CATCHES MORE THAN SHE BARGAINED FOR

Once, when out fishing for flounder, my mother caught a shark.

That story arose in my mind yesterday, as I was reading an article published in FastCompany by a science writer working under a pseudonym.  The writer (who calls herself Elizabeth, so let’s go with that) has a five-year-old daughter adopted from Ethiopia.  Her editor suggests that she do a piece 23andMe from the point of view of a mother considering testing her own little girl.  As for the decision about whether or not to test – that was up to her.

But it’s a better story if you do the test, right?  An even better story if you find out something interesting.  Which is not so likely, since the experts you contact are telling you that most of what 23andMe has to offer is not clinically significant.  A few things that are meaningful, a few things you might not want to know… but Anne Wojcicki, founder of 23andMe, says it is a parent’s duty to arm herself with her child’s genetic blueprint.  Ultimately, Elizabeth says, she finds the ‘knowledge is power’ argument persuasive.

So, anyway the kid turns out to be a ApoE 4 homozygote.  23andMe quotes a 55% chance of ApoE 4 homozygotes being diagnosed with Alzheimers between the ages of 65 and 79.

I spoke with Elizabeth while she was writing the article, but before the test results came back.  “Do you judge me for having my daughter tested,” she asked?  I said no at the time – and for the record, I stick with that.  We were talking then about privacy and confidentiality issues, and in that context I have concerns about the DTC industry in general and 23andMe in particular, but I can completely understand the desire of a mother raising her child without access to any medical or family history to get whatever information she can.  We talked about the limitations of SNP data on common disease.  This wasn’t a genetic counseling session, but I am a genetic counselor, and I am extremely regretful that I didn’t think to discuss ApoE, and perhaps urge her not to unlock that box.

Elizabeth spends the last third of the article grappling with the downstream issues that follow from that significant result.  She acknowledges difficult decisions they will face around when and if to tell the child.  “Never!” suggests a psychologist friend of mine with whom I share this story.  But in my experience information finds it’s way out, no matter how deeply buried, as if knowledge were a seed searching for the sun.  And in this case it is only shallowly interred – after all, she has shared her story in print.  The pseudonym makes it more private, but won’t the ruse – and the reason — be an open secret among her close friends and family?

Interesting to me that 23andMe publicized this story, tweeting about it yesterday morning:

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I would have thought this particular personal journey represented something of a worst-case scenario for them.  Judging by reactions among my friends (not very scientific, I know) it was not a great advertisement for their product.  But then, I do them a disservice to suggest that they are simply marketers.  No question, the folks at 23andMe are true believers.  Emily Drabant, a neuroscientist at 23andMe, tells Elizabeth that their database will help pharma locate people with her daughter’s geneotype who don’t get sick, so they can uncover the reasons why some people stay healthy despite their genetic predisposition.

Wherever you stand on DTC, it is easy to see Elizabeth’s story as a parable.  For enthusiasts like Wojcicki, it is a tale about embracing the power of information as a call to action and an opportunity for intervention.  For haters, it is a harbinger of exactly the type of harm they picture when they think about DTC: inappropriate testing of minors, lack of pre-test counseling (that one makes my stomach hurt), post-test distress.   For me, having planted my standard awkwardly in the muddy soil of ambivalence, I see it as further evidence that DTC is a decent option only for a select few, and should not be mistaken for a new world order.

Here is the model set forth in this article: mother tests child, discovers disturbing information, goes on a mission to find out what it means and – hopefully – how to use what she has learned to her kid’s advantage.  This makes for a lovely read (it’s actually a very good article: balanced, well-written, funny at times).  But it’s important to note that to the extent something good comes out of this, it is because Elizabeth has access to resources and information beyond the factually accurate but necessarily limited and impersonal explanation on the 23andMe website.  “Our daughter is going to get Alzheimers,” she wails to her husband, after ‘blundering past the notes of caution’ to unlock her results.  Next steps for a science writer doing a feature on 23andMe?  First, a personal conversation with Anne Wojcicki, who cancels her next appointment when she hears about the ApoE finding.  Discussions with Drabant, the neuroscientist.  Discussions with geneticist Ricki Lewis, and with Bob Green up at Harvard, who spearheaded the REVEAL study that investigated the impact of receiving ApoE results on individuals and family members.  A conversation with Jennifer Wagner, a lawyer specializing in issues related to genetics and genetic discrimination.  We cannot hypothesize that this is the experience of the average consumer.  Wojcicki and the legion of science bloggers who can’t understand why everyone doesn’t want to test their children should consider the likely experience of a parent receiving this result with no more resources than Google and a distant memory of high school biology.

Ultimately, we are informed, Elizabeth comes to terms with the good and bad of genetic testing for her child.  “I choose to think of this as a potentially beautiful new world opening up for her–but one that requires an extraordinarily thoughtful bravery from all of us.”  Even so, she notes that the “best advice” she got was to “burn that damn report and never think of it again.”  Despite the positive rhetoric, her enthusiasm for that advice suggests she learned something she would in retrospect choose not to know.  Elizabeth went fishing for flounder, and caught a shark.  At least my mother could throw her fish back.

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When Numbers Do Not Tell The Tale: A Tribute To My Friend

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Holly Osman 1959-2013

There is an emotional toughness one must have, working with cancer patients.  Oncologists tend to be pretty well-armored.  You don’t, for example, expect the head of Clinical Genetic Services at Memorial Sloan-Kettering Cancer Center to get emotional when a student asks a question about surveillance after prophylactic mastectomy.  So it was a surprise when Dr. Robson paused, and raised his eyes, with a blank expression that might have been masking tears.  “I used to say no more surveillance was necessary,” he said.  “But then I had a patient who rocked my world.”

Sitting in the audience, a chill ran down my spine.  You see, I knew her too.  Not as a counselor but as a friend.  A BRCA 1 mutation ran in her family.  She had tested positive for it years earlier, so after she had her beloved Sarah and Eric she did the surgery – smiled her way through it, no problems, no complaints, no second guesses.  “No big deal,” she said, with a smile that dared you to doubt her.  She was going to get the gift her own mother was denied: a little more time.  Time to watch her kids grow up, get married, have children of their own.

It’s never an easy business telling women to cut off their healthy breasts and put themselves into an early menopause.  No matter how deeply you believe in what you are offering, these are hard conversations to have.  But it wouldn’t have been hard with Holly.  She would have smiled from ear to ear and waved away all the negatives with a flutter of her left hand.  She was brave like that, and certain.

If your prior risk of breast cancer is 85%, and a mastectomy removes 98% of the breast tissue, your posterior risk should be approximately 3%.  That’s a risk reduction of 96.5%.  Wonderful numbers — but only numbers.  Numbers didn’t matter when Holly was diagnosed with breast cancer in 2004.  Or when it came back in 2006 (stage four, incurable).  I spoke to Dr. Robson and one of the genetic counselors from MSKCC after the lecture.  “I know Holly too,” I said.  There was pain in their faces.  “She did everything right.  It’s so unfair.”

“It’s not just that,” said the counselor.  “She is the nicest person.  Whenever someone really needs support we have them talk to Holly.  She never says no.”

What can I tell you about Holly Osman?  She would not forgive me if I did not describe her as happy and successful.  A great family.  A husband who adores her.  Two wonderful kids – almost adults now.  Her daughter looks just like her, but with a hell of a lot more attitude, and Holly loved that.  She loved it when her kids were independent and she loved it when they needed her.  Her son is ridiculous: handsome, smart, poised and kind.  ‘Screw up a little,’ you want to say.  Stop making the rest of us look bad.

If I had to pick one word for Holly it would be effortless.  Some of us clean up nicely, but Holly looked great all the time, in a classic way that required no adornment. Roll her out of bed at 3 AM, and she would still be beautiful.  And effortless wasn’t just her style, it was her way of being – ask her how things were going and she said “great!”  You could try and empower her to complain a bit — good luck with that.  Holly wasn’t very interested in complaining — which was annoying for me.  I myself would have whined.  Not Holly.  Her life was SO fabulous.  Her doctors were SO great.  If you asked her about how treatment was going she would look blank for a moment, as though she didn’t remember what you were talking about.  She had this look that seemed to say, ‘Oh yes, chemo – I had forgotten.’  Did she need anything?  Could I drive carpool for her this week?  “Why?” Holly said.

She was the luckiest person in the world.  She insisted on that right until the last moment, until last Friday, the day she died, in Holly-fashion, quietly and without drama, nestled in the heart of the family she had nurtured on every level imaginable.  I don’t know; maybe she was the luckiest person in the world.  I can tell you that the rest of us left behind feel a little bit less lucky now.

She did have a lot of luck, it’s just that some of it was bad.  As a friend who happened to be a genetic counselor, I always felt a little guilty, as though we had let her down.  We counselors love the safety of numbers, of facts, of things we know.  We told her the truth, it just wasn’t her truth.  As predictive testing goes, BRCA analysis is one of the best.  It has, as we say, clinical validity and clinical utility.  Holly understood that too; even after her own diagnosis she counseled a much-adored younger sister to have the same surgery, the one that had failed to save her.  Holly’s story is not a repudiation of what we have to offer.  It is a reminder of the limitations of the fortune-teller’s art.  Percentages are true only for epidemiologists, while people live out their lives as a series of n=1 experiments.  There is an arrogance in the certainty of numbers that will always be undone by the stochastic process that is life.

Here’s how I know: I had a friend who rocked my world.

Rest in peace, Holls.  Rest in peace.

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Bye-Bye Bi-Polar: A New Nosology for Psychiatric Disease — What Does It Mean for Genetic Counseling?

Tom Insel, director of the National Institute of Mental Health (NIMH), roiled the world of psychiatry in a blog post (how very 21st Century of him!).  The post concerned the revised Diagnostic and Statistical Manual of Mental Disorders – the DSM V, due out in a matter of weeks – and it was not a good review for the ‘bible of psychiatry’: “Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.  In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment.”

“It’s weakness, “ said Insel, “is its lack of validity.”

Wow.  That is a pretty bad weakness.

Insel’s statement is not news to anyone who studies the genetics of psychiatric disease.  Although many psychiatric illnesses have high heritability, it is increasingly obvious that current list of diseases as defined do not line up neatly with genetic risk factors, whether those risks are established through family history or molecular testing.  A first degree relative with obsessive compulsive disease is a risk factor for Tourette’s as well as OCD; a deletion in 22q11.2 is almost equally likely to lead to a diagnosis of schizophrenia or bipolar disease.  We might think of this as overlapping genetic inheritance, but in fact it illustrates how badly our current labels function when it comes to identifying etiology.

What was news was Insel’s plan to re-orient research funding away from the diagnoses defined by the DSM and towards a new system based on biomarkers like genetic findings, gene expression and brain imaging along with categories of phenotypic information like anhedonia or psychosis without regard to diagnosis.  To this end, the NIMH has launched a campaign to establish research domain criteria (NIMH being an arm of government, it has an acronym: LDT EGAP IVDMIA RDoC).  Researchers are encouraged to base their inquires on RDoC that cut may across, or subdivide, traditional diagnostic categories.

NIMH, as virtually every article, blog or twitter post on this subject pointed out, is ‘the world’s largest funder of research on mental illness.’  That makes this a high-stakes announcement, and change of this magnitude is complicated – after all, valid or not, all the existing literature is based on these diagnostic categories.  Ongoing research is based on DSM diagnoses, as is clinical practice, billing and reimbursement.  So to some extent we are stuck with what we have, warts and all, for the time being.  Insel knows this, just as the authors of the revised DSM know that their system is flawed.  The take-home story here is not a fight between two sides, but a demarcation of a significant moment in time, as the ocean liner that is psychiatry begins a slow turn away from labels based on symptoms and towards a alternate world where diagnosis is based on biological causes, markers and measures of disease.

Someday, designations like schizophrenia or major depressive disorder may sound as quaint as rheumatism or dropsy.  For genetic counselors, it presents a dilemma in the near term.  What goes into the pedigree?  We don’t want to make it more difficult, since we know that genetic counselors are already disinclined to tackle psychiatric illness as a part of the family history.  But possibly this too is a symptom and not a cause: perhaps one reason genetic counselors are hesitant to ask about mental illness is that the associations between disease and recurrence risk are too complicated.  Because anything you can say is squishy and vague and threatening and non-specific.  Who likes that?  Not science people.

Would it be an improvement, if we recorded information about phenotype and test results as defined by RDoC?  Do we need to think about that?  Is this simply a research designation, or is it going to bleed into clinical care sooner rather than later?  I don’t have answers for these questions, but I am directing them to the wonderful and small but highly motivated cadre of genetic counselors who work primarily in psychiatric genetics (I know who you are!  No hiding).  Can you weigh in for us on what all this means for genetic counseling?

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Morality and Reality: Two Arguments in Favor of the Recommendations for Return of Incidental Findings Released by the ACMG

Recently, the ACMG released recommendations for return of incidental findings  following genome or exome sequencing, garnering a great deal of attention in the science media and some in the popular media as well – most of it stressing two points: the fact that the guidelines call for certain results to be returned regardless of patient preferences, and that they call for the same results to be returned regardless of patient age.  These are big departures from current practice, and they have drawn a lot of fire for going too far (or for not going far enough).

The reasons for the paradigm change were explained at length in the ACMG report, which is well written and worth reading in it’s entirety.  I am going to discuss a few of those reasons here, but first let me emphasize one thing I believe was often obscured in the first-reaction coverage: the report does not suggest that all incidental findings should be reported.  Not even close.  The list of conditions is relatively short (about 35, although the authors acknowledge that it will inevitably get longer) and strictly curated.  In each case the result in question has a well-established risk of likely and serious harm, at least potentially amenable to intervention.  Likely, serious, preventable: the criteria echo the language of duty to warn, stemming from the famous Tarasoff case in the 1970’s.  In duty to warn cases, the danger is such that it demands action even when that action violates a patient’s right of confidentiality – a serious breach, and as such the bar is set high.  In this case, the competing right, as it were, is the right not to know – or to state one’s preferences – and the danger is to oneself and one’s family rather than to a stranger.  But the model is the same, as is the commitment to reserving this option for circumstances where the risk is compelling.

One difference between a duty to warn scenario and incidental findings is that with IF’s, you have the option, theoretically, of asking the individual for his or her preferences in advance, and then using that as a guide.  That has always been our default recommendation, and the ACMG report explains several reasons why they deviated from this standard:

1. The information is THAT important.

 Driving the issue of incidental findings is a better understanding of what certain gene changes mean – not perfect, but better.  Mutations of significant prognostic value used to be the exception and not the rule – okay, they still are.  A lot of the information we have about genetic variation is suggestive rather than diagnostic.  Only a limited number of known gene changes produce risks in the manner of, say, BRCA 1/2 mutations.  But some things do.  Hypertrophic cardiomyopathy.  MEN2.  Familial hypercholesterolemia.  Remember, the right not to know – the acknowledgement that someone might reasonably assume they were better off not knowing – is predicated on the inherent uncertainty of genetic information, and our inability to change the outcome.  And while I would be the last person to suggest that is no longer the case as a rule, we have made some progress on both of those fronts.

We still have a way to go to understand the relationship between genotype and phenotype, especially where medical or family history are uninformative.  For some if not most of genetic variation, I personally doubt we will ever reach the point of acceptable or compelling certainty.  But we have come to the point where BRCA 1/2 is not the ONLY example of a relatively common genetic variant with real predictive utility.  The list assembled by ACMG is going to get added to – and perhaps subtracted from – over time.  But there are a limited number of circumstances where the risk of harm is so great and so well substantiated that in the event of a bad outcome, our justification after the fact for not identifying and disclosing those results would ring hollow in our own ears.

2. Setting a standard that relies on pre-test counseling is unrealistic as the use of genome-based testing expands beyond the genetics clinic.

 The best thing about the ACMG recommendations is that they are what I like to call reality-based.  First, genetic testing is increasingly used in all sorts of subspecialties (cardiology, pediatrics, audiology, oncology, etc).  We can’t dictate to them how to do pre-test counseling, and even if we could, they are not necessarily prepared to explain genetic concepts.  We imagine a world where sequence-based testing is a first-line alternative in all sorts of medical situations, from emergencies to routine medicine.  If you assume that an expert and careful process of informed consent does not occur, as it absolutely will not in many circumstances, then you need to establish what happens by default, when the clinician does not have any information on patient preferences.  This set of recommendations doesn’t close the book on that process, but it does provide a really well thought out starting place.  It gives you a baseline: if nothing else don’t miss these.  That’s tremendously valuable.

Additionally, standards that rely on pre-test counseling may sound ideal, but often prescribe procedures for the informed consent that are problematic in their own right.  Informed consent is not a junk drawer where you cram everything that does not fit somewhere else.  Beyond a certain point, pre-test counseling becomes a process of wearing down rather than educating a patient – in writing or in person, the moral equivalent of ten pages of fine print is a bludgeon and not a tool.

3. Inconsistent reporting from laboratories is dangerous.

 No question but that the thrust of the ACMG recommendations is to suggest that this is information that should be delivered to the patients and their families.  But in fact, the guidelines don’t dictate what a clinician should tell a patient; they spell out what a lab should give to a clinician.  They set standards for what a lab should be obligated to look for and report in all uses of exome and genome sequencing.  And even if you take issue with the list, there is still a benefit to establishing uniformity.  Currently, the labs that do commercial exome sequencing vary widely in reporting procedures – some give back a great range of results, others only those relevant to the diagnostic question, and others provide a choice.  For the clinician, this means that advising a patient for what to expect from testing must be tailored to each lab’s protocol.  And it leaves a lot of room for confusion.  For instance, a physician accustomed to getting incidental information on – say cardiomyopathies – might see the absence of that information as a clean bill of health, when it might merely represent the typical practice of a certain lab.

Clinicians, the ACMG report acknowledges, will put the results in context for patients and families.  Therefore, the recommendations as written provide more room for clinical judgment than the headline suggest.  It is at the clinical level that family history, medical history and immediate context are integrated into how, what and when information is given out.  Patient preferences can be taken into account, as can the priorities of a patient or a family in times of stress.

Furthermore, since most incidental findings (including carrier status, pharmacogenetic information, etc) are not included in this list, there is a lot of room for a clinician who design a process based largely on patient preferences.  The recommended list is a floor and not a ceiling; it begins but does not end the dialogue between the provider and the patient.

In reviewing the current debate over the return of incidental findings, the ACMG report categorizes the two sides thusly: there are genetic libertarians and the genetic empiricists.  Libertarians wish to give individuals unfettered access to their genomic information – all the hits, Google-style – and trust the algorithmic magic of search engines and accumulated wiki-wisdom to bring test-takers closer to the truth than physicians can by doling out information according to their own judgment (in support of which, the libertarians are likely to cite the lack of genetics expertise among physicians, and you can’t argue with that).  Empiricists – and I am a little less certain about how well that word applies – are more concerned with the dangers of over-sharing, and they typically point to the potentially misleading nature of results with a small or unsubstantiated effect size and the loss of autonomy that occurs when information is thrust unrequested upon patients or given out to parents and caretakers on behalf of minors.  The good news for ACMG is that their recommendations have come under attack from both sides, so they can reasonably assume that they are doing something right. 

This libertarian-empiricist divide can reflect many prisms: age; personal experience; East Coast establishment values versus a West Coast ethos of let-the–information-run-free.  In any event, it is the more protective point of view that emphasizes the value of genetics expertise and counseling, and the genetic counseling community tends to identify strongly with norms that stress caution in terms of what, when and how information is shared with patients.  But we should be carefully not to become reflexively protective of our own practices so that we cannot reexamine them to reflect changes in what we know, or the best interests of our patients and their families.

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What New Laws in North Dakota Tell Us About the Anti-Abortion Movement in 2013

Follow abortion law long enough, and you will begin to appreciate its Talmudic qualities.  Figuring out what the literal meaning is only the beginning.  For a deeper understanding, you must decode the text.  Consider these recent examples:

Earlier this month, Arkansas passed a law banning abortions after 12 weeks gestation.  Then, on March 15th, the North Dakota legislature passed a law banning non-emergency abortions after 6 weeks gestation.  So you ask yourself: are the North Dakotans really that competitive?  Quite possibly.  But that’s not what’s at issue here.  Actually, both bans are tied to the idea of fetal heartbeat, which can be detected by vaginal ultrasound at 6 weeks and abdominal ultrasound at 12 weeks.  Arkansas changed the terms of its law from 6 weeks to 12 weeks to avoid the whole ‘politicians want to stick a wand up your vagina’ brouhaha, while the North Dakota legislators hedged by sidestepping specifics on gestational age and declaring it a felony to do an abortion procedure after the heartbeat could be found, which means that any procedure after 6 weeks – or possibly even 5 – puts the doctor at significant legal risk.

Textual analysis requires a little context: these two laws are not without detractors within the anti-abortion community. Blatantly unconstitutional, they will not go into effect unless the Supreme Court chooses to overturn Roe v Wade altogether – or to redefine its standard of viability.  Since this law puts the state on the line for substantial legal costs if the challenge fails, it is entirely possible that North Dakota’s Governor Dalrymple will veto the law as fiscally irresponsible.

Deeper truth: in recent years the organized anti-abortion movement has eschewed direct challenges to Roe in favor of enacting an all-you-can-eat buffet of restrictions and regulatory hurdles that make the process of getting an abortion more difficult, humiliating, expensive and time-consuming – all of which serves to reduce access without making abortion illegal, and presumably to avoid triggering a popular outcry, a likely outcome if Roe v Wade was in obvious jeopardy.  What’s more, this smorgasbord approach (waiting periods, mandatory counseling, special requirements for abortion facilities, parental notification, etc) affects mainly the poor, the young and other vulnerable populations – leaving the empowered classes free to find abortion distasteful without giving up any of their reproductive rights.  The stealth approach, orchestrated by a sophisticated and media-savvy crew, has been largely successful at limiting abortion regionally, while chipping away nationally at popular support for abortion rights.

The new laws then, as a departure, represent a throw of the dice on the part of the anti-abortion movement’s country cousin, looking to win big on a game-changing Supreme Court decision – a long shot, though hardly impossible.  And not unlike the Tea Party with its candidates that win in the primary and lose in the general election, the constituency that launched these laws is a tail-wagging-the-dog phenomenon that illustrates hardening fissures within the conservative movement – a quasi-rebellious move on the part of ideologically motivated individuals who are not prepared to compromise or prioritize strategy over gospel.

While the prohibitions on first trimester abortion is sucking up most of the media oxygen, a second legislative initiative out of North Dakota presents an alternate window into anti-abortion sentiment in 2013 – and one of particular importance to genetic counselors.  The second bill prohibits any abortion for purposes of “sex selection” or “genetic abnormalities.”  Of course, intent is a tricky thing to prove and for the moment abortion is available for no reason, making these provisions hard to enforce, but it could vastly complicate a counselor’s ability to discuss options in the event of a fetal anomaly.  Would it be illegal to even suggest that abortion was an option, in the context of a prenatal diagnosis?  Could you raise the subject?  What if the patient brought it up?  How would you handle the informed consent for prenatal testing, if you could not mention termination?  Why even test?

Why indeed.  Was that not exactly ex-presidential candidate Rick Santorum’s point one year ago, when he criticized the system for forcing employers to provide insurance coverage that included prenatal testing?  Sure, he got some details wrong – but to point out what he does not understand is to miss what he does understand.  There was nothing random about his comments — or this law — and the heart of the problem is not an absence of science literacy.  This is a revolt aimed at what we do, based on a reasonably accurate understanding of what we do.  It reflects the hard truth that, for people who genuinely believe that a fetus is morally indistinguishable from a child, prenatal diagnosis amounts to a war on handicapped persons.  It suggests that we think that some people are more valuable than other people, and that some lives are more worth living than other lives, and that therefore parents deserve a choice about whether or not to have a child whose health or abilities or prospects are compromised.

Improvements in prenatal diagnosis – the innovations we celebrate because they allow us to do what we do more safely and effectively – are threatening developments for a significant minority.  The better we get at our jobs, the more blowback we can expect to experience.  The North Dakota statute may not survive a challenge – it may not even get signed into law – but the rallying cry of anti-abortion forces against the use of genetic testing for eugenic purposes is a sound we will hear again, and louder.

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VARIATIONS IN A MINOR KEY: SOME THOUGHTS ON PRENATAL TESTING IN AN ERA OF WHOLE GENOME SEQUENCING

James Watson is many things – geneticist, Nobel laureate, agent provocateur – but in the realm of psychiatry he is first and foremost the parent of a son with schizophrenia.  So when he spoke in 2007 at the World Congress of Psychiatric Genetics, it was as a family member, albeit a family member with an unusually good grasp of the science.  And it was as a family member that he exhorted the scientists in the audience to keep up the good work, so that “someday we could identify those individuals destined to suffer from mental illness in utero, and weed them out.”

How often do you hear an audible gasp in the midst of a plenary talk?  The dismay and the indignation were palpable.  Researchers throughout the day interrupted their talks on GWAS to express in the strongest possible language that the goal of their work was to understand the pathophysiology of the disease and perhaps to aid in diagnosis – not to provide pre-symptomatic risk  assessment and not – no, never – not to be used prenatally.

“But if this is what families want,” I asked one speaker later that day.  “How do you propose to restrict testing, once the means to test is available?”

“They can’t,” he replied.  “They must not.”

Ah.  Of course.  They must not – I will pass that along.

Five years later, it is not GWAS but whole exome sequencing and whole genome sequencing providing all the buzz at conferences.  Solving the diagnostic odyssey!  Revolutionizing cancer treatment!  Ushering in an era of personalized medicine!  It’s very exciting.  Prenatal testing is rarely mentioned, and then only in passing – while prognosticators sing happy songs of a not-so-far-off day when every baby will be sequenced at birth.

Sequenced at birth?  Will it even be necessary?  Maybe Mom and Dad have baby’s DNA already, on a hard drive or a memory stick or downloaded onto their cell phones along with the ultrasound pics.

This is not the genome sequencing story you are seeing in the papers or the blogs.  It’s not what researchers are excited about.  The ones we hear are all about science journalists getting their DNA decoded and setting off on odysseys of self-discovery that involve hours of consultation with clinical and academic superstars who donate their time. We hear about kids with strange constellations of symptoms finding answers after years of disappointment.  Those are heartwarming tales: anecdotal and difficult to imagine at scale, but hopeful and exciting nonetheless.  But there is another theme playing, in a minor key, and I hear it faintly, hidden beneath the violins and the trumpets.

I hear it, an unspoken question, when we debate the utility of genomic information.  What does to mean to say that information is actionable? (Prevention? Treatment? Cure?  Prenatally, there is only Yes or No.)  Can patients handle uncertainty?  (And what will we lose, when pregnancies are terminated just to be on the safe side?)  Doesn’t everyone have the right to know what is in their own DNA? (The information is available – why not use it?  What could possibly go wrong?)

Whatever tests are available postnatally will find their way into prenatal use.  The gateway technologies – PGD, cell-free fetal DNA testing – are in place. And there is no use saying, “they can’t, they won’t, they shouldn’t” because they can and they will – and sometimes they should.  There will be good uses too: success stories and disasters averted.  A blanket “no” is not an option, and granting anyone authority to pick and choose which uses are worthwhile vests altogether too much power in the hands of any one person, or profession, or bureaucratic entity.

The same tests can be done before or after birth, but the experience is entirely different.  Uncertainty after birth is an opportunity.  The least useful information is that which will absolutely come true, no matter what you do.  Uncertainty before birth is a crisis.  Anyone who has ever discussed a variant of uncertain significance with a pregnant mother can tell you that.  But what are the chances there will be developmental delay?  Are you certain that the heart will be affected? How sure are you that this means anything?  Not nearly sure enough.  Please understand that.

In general, notions of genetic determinism increase the likelihood that genomic testing will have negative consequences.  Fatalistic attitudes about the power of genes could lead people to overestimate the meaning of elevated risks and underestimate the meaning of reduced risks.  Anxiety, stress, missed mammograms – you have heard this before.  Shrug.  People are grown ups.  They will figure this out.  Information is power.

But we are in a whole new universe trying to reconcile underpowered and often misunderstood predictive testing in the context of prenatal use.  So please, in telling tales of all the wonderful things that genome sequencing will do, save space for a mention of what it cannot do.  Make sure they understand that there are great wide cracks in our crystal ball.  Do not oversell the value of genotype in the absence of phenotype.  Remember that in the end neither researchers nor physicians nor genetic counselors will dictate how this new technology will be used.  Others will make that call, and we will be in the choir, singing songs of praise laced with sorrow.

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