Author Archives: laurahercher

by | May 8, 2013 · 12:50 PM

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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by | April 3, 2013 · 11:36 AM

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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by | March 19, 2013 · 11:24 AM

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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by | March 13, 2013 · 10:54 PM

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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by | January 1, 2013 · 2:04 PM

GENETICS and The Year in Review: My Top Ten Stories of 2012

In casual conversation, the phrase “it’s genetic” can mean any number of things.  It can serve as an excuse (‘don’t blame me, blame my parents!’) or a humblebrag (‘it’s a gift; I take no credit.’).   But most often, when people say “it’s genetic,” what they imply is: ‘that’s the way it is and there is nothing to be done about it.’

One promise of the Human Genome Project was to give us the means to fight back against this inevitability of genes, through prevention, mitigation and cure.  The first ten years post-HGP were full of revelation and technical achievement, and yet fell far short of that goal: for all that we learned, the lives of patients with genetic disease were essentially unchanged.  Now, news on a multitude of fronts brings the tantalizing prospect of progress.  Will we remember 2012 as the year when genetics fundamentally changed clinical medicine?  Probably not.  But the signs are there: treatments popping up like crocuses in the snow, new tests making their way from research only into the clinical realm, beta versions of technology that can — and will — do better.  And the other signs too: a growing intransigence from those who fear where these changes will take us, and a popular interest in testing that often takes the form of overestimating the scope and specificity of what genetics can tell us.  Progress – and pushback – is the story of 2012.

10.  IT CAN’T GET MORE PERSONAL THAN THIS: A GENETICIST ANALYZES HIMSELF AND SHOWS US SOMETHING ABOUT THE POTENTIAL OF PERSONALIZED MEDICINE – AND EVEN MORE ABOUT IT’S COST

In Cell, Stanford Professor Michael Snyder published a study with an n of 1 that, despite its limitations, effectively captured the yin and the yang of personalized medicine.  The ”n” in this case was Dr. Snyder himself, who followed himself over a 14-month period using “genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles” – a staggering array of tests, with an equally staggering price tag. Long story short, Dr. Snyder’s genomic information suggested an increased risk for type II diabetes, so despite the absence of any family history or other risk factors, the medical profile was expanded to include a state of the art glucose test.  And in fact, following a viral infection,  Dr. Snyder’s blood sugar did rise.  Diagnosed with IDDM, the doctor’s blood sugar levels normalized after several months with changes in diet and exercise.  What didn’t normalize?  His life insurance premiums, which rose precipitously after the diagnosis was made.

What is wonderful about this story?  Dr. Snyder – who, it should be said, is a co-founder of company producing interpretive tools for genome studies – says the study saved him from months of damage, and may have saved his life.  Of course, you don’t really know, which is the thing about anecdotal reports.  Consider that, in a sense, all of medicine up until now could be viewed as one giant study with a massive ascertainment bias – after all, most of what we know about treatment comes from sick people.  Does it make sense that early and focused intervention worked?  Yes, it does.  Do we know that cutting out desserts and doubling down on his bike riding actually “cured” him?  No, we don’t.  Because this sort of testing is unprecedented, I’m not sure we know if transient changes in glucose levels are so abnormal following a virus.  Is this what risk means in the context of skinny guys with no family history?  Because in the context of obesity and family history, I am not convinced that cutting out pie is a game-changer.

But despite all the questions that remain, the Snyder study demonstrated proof in principle that the combined power of clinical measures and genomics – genes and gene expression – creates more value than either of these two alone.  And unfortunately it also demonstrates proof in principle that personalized medicine approaches are, at present, prohibitively expensive.  Bringing down the cost of sequencing is only a first step – it will take across the board reductions in the cost of testing, analysis and follow-up medical care if personalized medicine is not to be a niche service for the fabulously wealthy (and a few lucky academics with funding from NIH!).

9. RICK SANTORUM BRINGS THE CULTURE WAR TO AMNIOCENTESIS

In February of 2012, former Pennsylvania senator Rick Santorum went on the CBS News show Face the Nation and argued that employers who disapproved of prenatal diagnosis should not be compelled to pay for insurance policies that cover, say, amniocentesis.  An incremental extension of the argument against mandating insurance coverage for birth control which had become a hot button issue on the campaign trail, Santorum explained his opposition thusly: “Amniocentesis does, in fact, result more often than not in this country in abortion.”  Santorum, undeterred by the (modest) firestorm that greeted his results, doubled down on this position in a speech to the Christian Alliance: “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.”

Okay, sure – it was silly season (aka, the Republican presidential primaries.  Remember Herman Cain?  Newt Gingrich and Ellis the Elephant?).  You might be inclined to dismiss this attack on prenatal diagnosis as nonsense.  Santorum certainly encourages us in our spirit of dismissiveness by getting his facts wrong – obviously MOST amnios don’t result in abortion.  Most amnios result in a reassuringly normal result.

But you know and I know that wasn’t what he meant.  Santorum is the father of a 4-year old with trisomy 18 (note to all

Photo credit: People.com

Photo credit: People.com

genetic counselors: yes, I agree with you; she probably is mosaic.  But I don’t know and neither do you.  So please stop asking).  He is a hero to a not inconsiderable segment of the population.  And his sentiments are not an anomaly.  And I am willing to bet that Santorum’s stand is not some last vestige of an outdated and ill-informed resistance to genetic medicine, but an early sign of the sort of intransigent hostility that advances in prenatal testing will engender.  The Obamacare requirement that insurance plans pay for amniocentesis is, Santorum said, “another hidden message as to what President Obama thinks of those who are less able.” Many people – real people, not caricatures, not Republican primary candidates – are worried about how genetic technology will be used, and what those choices say about how the world sees them.  Their fears will grow as our capabilities improve.  In focusing only on what Santorum got wrong, we risk ignoring the more significant subtext.  There are questions here that deserve a real response, minus the snark.  Genetics professionals need to be prepared to define themselves, or risk being defined by someone else.

8. CLARITY CHALLENGE: BIG DATA GETS COMPETITIVE

For years, discussion of the Archon X Prize for DNA sequencing has dominated sports-radio coverage of competitive genetics.  But this year, the annual handicapping of the Archon race (to sequence 100 genomes in 30 days or less, at a per-genome recurring cost of $1000 or less, to be decided once and for all in September 2013 and I don’t know about you but I am SO OVER IT) had to share the geek sports fan base with a new event: the Clarity Challenge.  In January 2012, Boston Children’s Hospital invited researchers around the world to analyze the DNA sequence data from 3 children with unknown genetic disorders.  Entrants were judged for their success in identifying genes or candidate genes for each child, and their ability to present their findings in a clear and accessible fashion.

The winner (Brigham and Women’s Hospital Division of Genetics – always nice for the crowd when the hometown team wins) was announced November 7 – PERHAPS YOU MISSED IT, as the press was inexplicably preoccupied with the U.S. presidential election, which occurred on November 6th.  Brigham’s team was praised for the clarity of its reports – a deciding factor, despite the fact that one of the runner-ups was actually the only team to identify putative deleterious mutations for all three kids.  More importantly, the competition highlighted the growing need for sophisticated and high quality analysis to complement the increasing quantity of sequence data.  The take-home from the Clarity Challenge is this: generating strings of A’s, C’s, T’s and G’s may be a technical tour de force, but only analysis will turn data into information, and provide clinical relevance.  For one child, the competition did result in a diagnosis after a 10-year medical odyssey – a success, but a qualified success, since the mutation for a muscle-wasting disease was identified by only 8 of 23 qualified groups participating.  Hailed as proof in principle of the power of DNA whole genome sequencing, the Clarity Challenge also illustrated the lack of universal standards for analysis (not to mention for handling tricky details like non-diagnostic findings unrelated to the presenting medical issue).

Mo’ data, mo’ problems, kids.  Having identified a serious issue that isn’t going away anytime soon, the Clarity Challenge is rumored to be gearing up for competition #2: the cancer genome analysis.  Great idea!  And guys — using a combination of computer simulations and a careful reading of the literature – in this case, the U.S. Constitution – I predict that the next presidential election will be held on November 8th, 2016.  PR protip: you might want to pick a different week to make any major announcements.

7. EU APPROVES A STEM CELL THERAPY FOR CLINICAL USE

glybera

Photo credit: Pharmafile.com

European Commission approval of Glybera, a stem cell therapy for familial lipoprotein lipase deficiency, marks a big step forward for the field, which had a tough year in 2011 when the first US trial of a stem cell therapy was shut down early as stem cell pioneer Geron withdrew to focus on experimental cancer therapies.  Poor stem cells!  It’s hard to be dumped for more lucrative therapeutics.  But researchers in stem cell therapy headed back to the gym – I mean the lab – and came back looking strong in 2012.  Reports suggest that a number of therapies have shown promise in clinical trials, including a publication in The Lancet describing a human embryonic stem cell therapy from Advanced Cell Technology that has showed early success treating retinal damage from macular degeneration.

6. TARGETED THERAPY: FDA APPROVES KALYDECO

vinylmation

Lots of reasons NOT to get excited about Kalydeco, the Vertex pharmaceuticals drug approved by the FDA in January 2012.  Sure the drug improves outcome measures for patients with cystic fibrosis (CF) – but only for those carrying the G551D mutation, a paltry 4% of individuals with CF in the United States today.  And what’s with the name?  It sounds like the Disney mascot for Epcot’s Visual Hallucinations Pavilion.

Photo credit: Drugs.com

Photo credit: Drugs.com

But Kalydeco, despite these limitations, is a leading indicator of growth for a whole category of targeted pharmaceuticals.  The Vertex product is the first approved drug to act by correcting the underlying genetic defect rather than ameliorating symptoms.
The strengths and the limitations of Kalydeco are its specificity; it restores the ability of the mutated CFTR protein produced by G551D to unlock the ion channel that is lost in CF.  Kalydeco, which represents the sort of therapeutic breakthrough everyone hoped would follow organically from a better understanding of disease pathophysiology, is a hopeful sign for all CF patients – a version aimed at the more common DeltaF508 mutation is reportedly in the works – and a hopeful sign for anyone who ever dreamed that we might someday talk about a “cure” for genetic disease.

5. TRANSLATIONAL MEDICINE MAKES GREAT STRIDES (IN ANIMAL STUDIES)

The new Francis Collins Initiative for Translational Medicine in Rodents got off to a flying start in 2012:

In Italy, researchers grew kidney-like “organoids” that performed many of the same functions as kidneys when transplanted – in rats.

A new drug tested by researchers at Washington State showed promise in treating Alzheimers Disease – in rats.

Scientists at the University of Michigan used gene therapy to develop a sense of smell to successfully treat congenital anosmia – in mice.

Researchers at UCSD debuted an RNA interference drug that reduced the severity of symptoms for Huntington’s disease – in mice …

And two groups (one in California; the other in Spain) demonstrated success using engineered zinc finger proteins to block production of the mutant huntingtin gene product – in mice.

A molecular embryologist in Brussels reestablished absent thyroid function through transplant of thyroid tissue engineered in the lab – in mice.

Blind mice see!  Vision restored after transplant of rod-cell precursors – mice (blind mice!).

Photo credit: Wired.com

Photo credit: Wired.com

Deaf gerbils hear!  Hearing restored using human embryonic stem cells to replace damaged auditory cells – in gerbils.

Diabetic mice cured!  Insulin dependency ended with transplant of pancreatic stem cells – in mice.

Truly, has there ever been a better time to be a rodent? 

 4. FETAL GENOME SEQUENCED THROUGH NON-INVASIVE PRENATAL TESTING

In an article published in Nature in July, 2012, researchers from Stanford announced  full genome sequencing done on fetal DNA drawn from the maternal blood stream – DNA, in other words, that could be obtained without invasive testing.  Several tests using non-invasive prenatal testing are already on the market, notably Sequenom’s MaterniT21 PLUS, the success of which drove a 68% increase in corporate revenue in the 3rd quarter of 2012 as compared to 2011 numbers.  Despite their commercial appeal, these beta versions of targeted non-invasive testing are still working out their kinks – amniocentesis or CVS are still needed as a follow-up to any positive MaterniT21 result – but the Stanford University researchers’ accomplishment drives home the potential of this technology to transform prenatal testing in the not-so-distant future.  Earlier, safer and more inclusive, this testing modality is likely to be a game changer that radically increases both the number of pregnant couples opting for testing, and the range of conditions included in a prenatal assessment.

3. BEHAVIOR ‘OMICS:  IN SEARCH OF A GENE FOR EVIL

On Friday, December 14th, Adam Lanza, a 20-year old loner described by former teachers as “intelligent, but nervous and fidgety,” took guns belonging to his mother and shot her four times in the head.  Then, for reasons we will never know, he took her car to the Sandy Hook Elementary School, shot his way through a locked door, and massacred 20 children and 6 adults and then himself with a systematic efficiency and precision that belied the random nature of the attack.  Sixteen of the children killed that day were 6 years old; the other four had already turned 7.

“Who would do this to our poor little babies?” asked Mrs. Feinstein, a Newtown teacher of 11 years.  For that question, no satisfactory answer would – or could – emerge.  Anecdotal reports of mental illness filtered out from people who had known Adam Lanza – he had a developmental disorder; he had autism; he was diagnosed with Aspergers.  Ten days after the attack, the Connecticut Medical Examiner sent a request to University of Connecticut scientists for help investigating Adam Lanza’s DNA.  “Geneticists Studying Connecticut Shooter’s DNA” ran the CNN headline on December 28th.  The article reported the consensus of the genetics community – no single genes existed that would be diagnostic for mental illness, and no single DNA sample could begin to establish variants or markers associated with violence – or any other behavior of a complex creature in a complex world.

DNA sequencing will shed no light on the painful question of why, but the use of sequencing in this context will color the public perception of genetics, with potentially dangerous consequences.  Ultimately, it is the headline that endures – the headline that suggests that some genetic quirk, some error in his code, some defect we can use to identify and root out the monsters among us — was the cause of this most horrific act.  It is far from the first headline of 2012 to imply genetic determinism (“Binge drinking gene’ discovered” proclaims the BBC; “As GOP convention begins, a look at how genes influence politics” trumpets the LA Times) but the Newtown tragedy illustrates most fully the potential for stigma and discrimination that accompany a reductive view of the relationship between genes and behavior.

 2. WHOLE EXOME SEQUENCING: AN INTERIM TECHNOLOGY GETS ITS MOMENT (BARELY)

 This was supposed to be about whole exome sequencing (WES) announcing its presence with authority in the clinical setting in 2012.  In May, David Goldstein et al published an article in the Journal of Medical Genetics documenting a high rate of success using WES to find diagnoses for patients with unexplained, apparently genetic conditions. Their exploratory studied considered a number of important, difficult issues: filtering of variants, variants of uncertain significance, communication of results to families, detection of carrier status and other non-diagnostic findings, obligations for re-contact.  Results were lauded as not only explanatory but in some cases “interesting” – the holy grail of academic research.

This story was supposed to be about WES, having its moment as the field transitions from targeted gene testing to whole genome analysis.  But everywhere I looked there it was, whole genome sequencing (WGS), hanging around the gym, saying “ooh, ooh coach – put me in!  put me in!”  Was 2012 the year of WES?  Well, yes! … but it was also the year when WGS with a 50-hour turn-around time was introduced for use in neonatal emergencies – and immediately declared standard of care for the neonatal intensive care unit at Children’s Mercy Hospital in Kansas City MO, where the pilot study was done.  And it was the year when the 1000 Genomes Project published data drawn from the WGS of over 1000 participants (thus the name), giving us what Genome Web Daily described as data that “made it possible to identify almost all of the variants found in as few as 1 percent of the population.”  Congratulations, WES!  Your moment has come.  Just don’t blink.

1. ENCODE: IDENTIFYING THE UNKNOWN UNKNOWNS

Remember “junk DNA”?  Me neither.  I am almost certain that none of us ever believed in the preposterous idea that the 98% of the human genome not coding for genes is a vast trash heap of discarded genes and chromo-babble.  A giant sea of artifacts and nonsense, meticulously copied by each dividing cell – surely this model defies everything we understand about the parsimony of the natural world?  For this reason alone biologists as a group instinctively knew the notion to be false.  At least, that is how I recall it.  As Lizzie Bennett says in Pride and Prejudice, “in cases such as these, a good memory is unpardonable.”

In September 2012, an international consortium of researchers organized by the NHGRI and wrangled by “cat-herder-in-chief” Ewan Birney of the European Bioinformatics Institute produced the first edition of the Encyclopedia of DNA Elements (ENCODE), in the unprecedented form of 30 articles published simultaneously in 3 cooperating journals: Nature, Genome Biology and Genome Research.  The combined publications constituted a first peek into the mysteries of the 98%, examining the expression and modification of non-coding DNA on a cell- and tissue-specific basis, identifying sequences receptive to chemical modification,  promoters of gene transcription, and all manner of transcriptionally active DNA signatures whose significance – if they have a significance – remains entirely speculative.  All together, it is an ambitious cataloguing of what Eric Green at NHGRI described as elements “involved in the complex molecular choreography required for converting genetic information into living cells and organisms.”

What is the take-home message of ENCODE?  That “not translated into protein” is not the same as “unused.”  In fact, the combined studies suggested that 80% of those shadowy untranslated regions were in fact transcribed into RNA – with a quarter of those RNA elements having known functional relevance.  As for the rest — well, some of it is regulatory – for instance, ENCODE documented a vast number of switches, used to turn genes on or off.  But for much of the genomic activity documented by ENCODE, all that one can say is that it exists.  Does it have functional implications for individuals?  The jury is out (and bickering).

The are so many reasons why ENCODE is the top genetics story of 2012.  It is on-trend as a BIG DATA story, producing raw DNA sequence data that required more than 300 total years of computer time to analyze – an illustration of the increased need for analytic skills that will follow as the celebrated technical achievements of the past decade become, in a flash, merely the norm.  The searchable ENCODE database is a model of open access – another 2012 hot topic.  And the project demonstrates that, despite a certain amount of clamor to the contrary, the most significant work in genetics today is a giant research project and several steps removed from clinical application.

In the dark years before the Human Genome Project, inebriated geneticists offered up back-of-the-cocktail-napkin approximations about the number of genes we carry, and every one of them was wrong.  Eighty thousand?  One hundred thousand?  Nope.  The final tally was more like 22,000 genes – and so unless we are prepared to declare ourselves less complicated than a water flea (31,000 genes), this can only mean one thing: that the architecture of human complexity is not derived solely from the blueprint laid out in our genes.  ENCODE, as a search for answers beyond the coding regions of our genomes, is a natural extension of the HGP, a first attempt to move beyond answers that lie solely in the exome.

For me, here is what makes ENCODE the genetics story of the year: it is both a beginning and an end.  The publication of ENCODE is a commencement ceremony for the HGP age – a moment in time when you come to the end of something and realize it is only the beginning of a greater journey.  The information it contains, while vast, is a mere sprinkling of breadcrumbs for others to follow.  But the trail it leaves shows us what we do not know.  Unknown unknowns are true ignorance – the sort of ignorance that leads us into a belief like “junk DNA.”  ENCODE is a great next step – the elucidation of what we do not know.  To a geneticist with exome data, like a man with a hammer, everything looks like a gene.  For ten years we have been hitting those nails hard.  ENCODE is a look beyond, to a wider array of targets, a wonderful acknowledgement of how much we do not know.

And that, ladies and gentlemen, is genetics in 2012!  Let me know what I’ve missed….

[Follow me on twitter: @laurahercher]

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by | November 29, 2012 · 11:10 AM

To Improve Care for Your High Risk HBOC Patients, You Don’t Need the Supreme Court: It Is All in Your Hands — and In Your Files

What happens in 2015 when the essential Myriad patents on BRCA 1 and 2 expire? 

Think about it a while.   What are you imagining?  Lower costs, better tests, quicker turn-around times?  A single panel covering all breast cancer susceptibility genes?  An end to unhappy conversations with patients trying to explain why the process can’t be simpler and cheaper?

While you mull over your utopian fantasies of a patent-free universe, keep this in mind: Myriad has been thinking about it for a while now.  After all, BRACAnalysis remains close to 90% of their total revenue, so it’s probably on the minds of Myriad executives.  It certainly was on their minds at Goldman Sachs when they listed Myriad Genetics as a sell in February 2011. 

Does Myriad have a plan?  It sure looks like it.  In 2006, Myriad ceased to publish BRCA variant information, and ended their relationship with the open-access Breast Cancer Information Core (BIC) database.  Since then, they have assembled a private repository of genotype-phenotype information that seems to be a central component of its strategy for future earnings.  How central?  Well, Dan Vorhaus et al at the Genomics Law Report speculated back in 2011 that a strategy of relying on their “vast—and currently proprietary—database of BRCA test data, including VUS data” was behind the company’s decision not to even bother fighting patent infringement in Europe, citing Myriad CEO Peter Meldrum’s emphasis on “other competitive factors” as an alternate strategy for competitive advantage.

Forget about the ACLU lawsuit, and next-gen sequencing and all the other changes you have read about that may affect genetic testing going forward.  Get the DNA sequence data wherever you want, and however you want, and as cheaply as you can, but as long as Myriad has sole control of the information needed to provide analysis, no other company will be able to challenge them on a competitive basis.

 Is this fair?  Well, it is an end run around the philosophical basis of patent protection, which is meant to provide a 20 year window of unfettered commercial use in return for a free and open sharing of information to stimulate further innovation.  But it is not illegal.  Myriad controls their database, and can’t be compelled to share.  They own the database – but NOT the information.  The information is out there – in report after report after report, languishing in the files of thousands of clinical cancer specialists.  In other words, YOU HAVE IT.

 So now, some exciting news.  Dr. Robert Nussbaum at UCSF is spearheading an effort to collect BRCA 1 and 2 variant data in ClinVar, an accessible archive of anonymized genotype/phenotype information hosted by the National Center for Biotechnology Information (NCBI).  While the goals of ClinVar are very broad – to aggregate information about sequence variation and its relationship to human health – Dr. Nussbaum’s goal are quite specific: to assemble a list of BRCA 1 and 2 variants found since 2005, along with information classifying them as benign, pathogenic, or unknown. 

 But THIS ONLY WORKS AS A COLLABORATIVE EFFORT.  Dr. Nussbaum has contacted 600 clinicians involved in clinical care of HBOC patients (so far, 26 centers have contributed over 3000 BRCA 1/2 variants).  With their cooperation and yours, ClinVar could amass a database to rival that of Myriad, ushering in an era of genuine access to unrestricted, competitively priced information for our patients.  How great is that? 

 To get involved, contact Dawn Lee, a genetic counselor at Partners Center for Personalized Genetic Medicine who is working with Dr. Nussbaum.  Here is her contact information:

Dawn Lee

DLEE30@PARTNERS.ORG

617-768-8548

You can get all the important specifics from Dawn, but for those of you who are interested, I’ve made a stab at some FAQ’s:

 WHAT EXACTLY IS BEING COLLECTED?

This project is limited to collecting information on the variant, identifying it using cDNA and/or genomic numbering, and its classification in a 3-tier scale as benign, pathogenic/deleterious or unknown (some reports use a 5-tier scale including possibly benign and possibly pathogenic, which is also good).  The goal is to capture each variant one time per family.

 IS THIS OK?  ISN’T IT A HIPAA VIOLATION?

Great question!  HIPAA does not place any restrictions on the disclosure of information that is de-identified.  For this reason, no names or other identifiers will be collected, including familial information or the name of the facility where the patient was seen.  Does this mean that the clinician who orders the test has the right to use it in this way?  “Ownership of Information’ issues are governed by state laws, and you can check out your state regulations in this 50-state survey of state laws governing the  collection, storage and use of human tissue specimens by the National Cancer Institute but – spoiler alert – Dr. Nussbaum thinks the answer is yes, in all states.

DO WE NEED IRB APPROVAL?

Poor IRB’s!  Everybody hates them so much.  Don’t you think that is hurtful to their feelings?  Sure, lots of people are doing this data collection without IRB approval.  Those people are following Federal Regulation 46.101(4) from the Office for Human Research Protections, which specifies as exempt: “Research involving the collection or study of existing data,documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.”  But does anyone ask the IRB how this makes them feel? 

IS THIS GOING TO BE A HUGE PAIN IN THE ASS?

First of all, if you have the reports in electronic form, it should be pretty straightforward.  If you have them on paper, you have to make de-identified copies, which means masking the names in two places (Dr. Nussbaum suggests post-it notes).  Dawn reports that there is a small stipend available for paying someone (contact her) – I suggest genetic counseling students (if you are in the NY area, contact me).  And – wait this is exciting! – the next 20 centers to provide >200 variants will receive an Ipad mini. 

 WHY NOT COLLECT MORE PHENOTYPIC INFORMATION?

Why indeed?  Why not report age of onset or bilaterality?  And if you are going to do that, you might as well check for hormone status.  It’s like that child’s book, “If You Give a Mouse a Cookie.”  If you give a researcher laterality, he is going to want oncogene status.  If you give her oncogene status, she is going to want response to treatment data.  The limited goals of this project make it easier for more people to participate (see IS THIS GOING TO BE A HUGE PAIN IN THE ASS?, above), and thus  to advance the primary goal.

 

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by | November 5, 2012 · 1:55 PM

Time Magazine is Raising Questions about Genetic Testing for Minors– Do Genetic Counselors Have Any Answers to Give Them?

On October 25th, Time Magazine ran an article about genetic testing of children with the provocative title, “What Your Doctor Isn’t Telling You About Your DNA.”  The piece begins by describing a dilemma in the cytogenomics lab at Children’ s Hospital of Philadelphia: a mutation for early-onset dementia is picked up through what the article describes as ‘genome analysis’ (it was microarray, actually) of a sick baby.  The doctors at CHOP, absent any notion of the family’s  preferences, decide that it is not in their best interest to have this information forced upon them – a choice that has drawn the ire of a number of prominent voices in the blogosphere.  “Nice to know that two physicians in Philadelphia not only have medical degrees, but specialize in mind-reading”, says Razib Khan in a post for Discover Magazine.

 Bam!  That noise you hear is the sound of a thousand genetic counselors smacking their foreheads in unison.  Really?  Why are they struggling with this after the fact?  Where was the pre-test counseling?  This was a particularly surprising story for me coming out of CHOP, given that on the same day the Time article was published, University of Pennsylvania genetic counselor Barbara Bernhardt was in Boston at the NSGC meeting describing the NIH-funded work being done at CHOP to document the wishes of families whose kids go through WGS.  So how did this situation happen?  Well, it turns out that clinical microarray testing, genomic or otherwise, does not require informed consent and no guidelines exist for microarray when it comes to return of incidental findings.  As other research coming out of CHOP has shown, physicians who order microarray vary widely in how they handle both the discussions with family members and the return of incidental findings.  For the record, in this case, there was no genetic counselor involved. 

 Would genetic counseling have changed the outcome?  Maybe.  Perhaps the lab personnel at CHOP would be sleeping a little better at night.  But it is important to note that counseling in and of itself is NOT a panacea.  Making sure that families get counseling is only a first step in the process, and the second step – the harder step — is figuring out what those counselors ought to say.  Having spent the past many months chairing the NSGC task force on genetic testing of minors* (too many months; it doesn’t speak well for my stewardship, frankly!) I can tell you with some authority no one can offer you any simple answers.

 The starting point for many genetic counselors is the familiar NSGC position that stresses deferring genetic testing of minors when feasible, in order to preserve the child’s right to decide for him or herself as an adult.  However, even this conditional commitment is far from universal; in the Time piece, Misha Angrist of Duke’s Institute for Genome Sciences and Policy responds: “We think that premise is nonsense…Parents should be given access to this information that’s derived from their bodies and their children’s bodies. This information is for everyone. It’s scary because we have chosen to make it scary. We exacerbate it by treating it like the bogeyman.”  Now I have some sympathy with this position – quite a lot, actually – but I do have to say that for me the prospect of mid-life dementia is pretty scary.  Jus’ saying.

 What I don’t like is the idea of inserting myself as an arbiter of parents’ decisions on behalf of their children, because I don’t think anyone knows my children as well as I do, and I imagine others feel the same.  On the other hand, genetic counselors have had a lot of experience with patients who have the kneejerk reaction ‘I want to know everything,’ and then change their mind when prompted to think through specific scenarios.  So I appreciate what Razib Khan means when he says, “this sort of fiat paternalism on the part of the medical community is frankly going to make enemies of exactly the sort of engaged high-information patients who can be their allies in staving off public hysteria about vaccination and the like.”  But – but – our practice guidelines and our instructions to students have to be relevant to the low-information parent as well, the one less inclined to information gathering – perhaps because some of them are aware that they lack the means, whether that’s financial or personal, to turn warnings about the future into prevention.  Sure, it is very satisfying to turn lemons into lemonade – but if you can’t afford the sugar, it just leaves a sour taste in your mouth.

 And so it comes around again to careful informed consent – which is a problem in and of itself, because everything comes round to informed consent, and we can’t just keep making it longer and longer.  For one thing, it will be an obstacle to clinical use of next-gen testing, since we don’t have that many counselors and if we did, who would compensate them for a consent process that lasts multiple hours?  And what about the poor parents?  Rationally, we have no choice but to design a consent that you can get through in something like half an hour, after which one can expect to encounter only blank faces and autonomic head-bobs from glassy-eyed participants. 

 So, after laying before all of you the Herculean task of imagining an all-inclusive and yet remarkably concise process of pre-test counseling, I guess the least I can do is offer something concrete.  In that spirit, five guidelines for the use of DNA sequencing in minors:

 1. Optimally, pre-test counseling should be a cooperative affair between lab and clinical counselors.  In general, I would suggest that the lab offer a framework for how to approach informed consent, since they have the most experience with testing.  However, the process of informed consent and specific decisions about how to proceed should come from the clinical side, since they have a relationship with the patient.  This is a psycho-social thing, but mostly it is a medical thing, since you cannot stress enough the importance of taking phenotype and family history into account in deciding how to use genetic information.  In the case of the baby at CHOP, would it make a difference if the parents were thinking of having another child?  What if one of the parents was showing signs of dementia? (note: people tend to think about information flowing downwards through the family tree, but it goes back up too, like xylem and phloem!). 

 2. Best practices protect a family’s right to know – AND a family’s right not to know.  I know it can be hard for hard-wired information gatherers to accept, but some people feel just as strongly about not knowing as they do about knowing.  I don’t care if you respect it in your heart so long as you incorporate it into your informed consent procedures.  And to be fair, preventive medicine may not seem like the holy grail to people who are struggling to afford healthy food and dental cleanings.  So try not to judge.

 3. For all that we talk about preserving the child’s right to decide (a worthy goal, all other things being equal), the most important reason to avoid giving out predictive information is that fact that it might be wrong!  Standards for what qualifies as clinically valid information had better be REALLY HIGH, because, so far, our track record as astrologers of the interior stars is not so hot.  Now, what people tend to assume is that it will get better but keep in mind that it will also get worse – when your information is built on tests that were done on people with a certain phenotype or a family history and then you move on to getting genetic information on people without that context, inevitably you are going to find the exceptions – the ones who would never have come to medical attention because they stayed healthy.  It happened with sickle cell anemia and cystic fibrosis, and it will happen with everything else.  Did you know James Watson has Cockayne syndrome?  Yup.

 Back in the day, my embryology teacher had a policy of taking off only some points if you missed an answer – and more points if you wrote down something incorrect.  When you are wrong, she pointed out, your best guess has dangerous implications in the clinical setting.  Words to the wise.

 4. Watch out for cascading liabilities.  Doing WGS on a child cannot make a clinician liable for every genetically-primed event that occurs in their lifetime.  I think it is important to draw a very clear distinction between the right to contact – the right to follow up with a patient when you have significant information that was not anticipated or not available at the time of testing – and the duty to re-contact, which places that burden on the lab, researcher or clinician – turning it into a legally-binding obligation.  The endless, boundless expectation of re-contact is a nightmare for genetics and every informed consent must make these limits clear in advance to all participants.

 5. And my sincere nod to anti-paternalism: parents know their children best.  They need a chance to think these issues through with someone familiar with how these choices may play out (Even high-information parents.  Especially high information parents).  But remember, they need to be counseled – not converted. 

 *NOTE: While I am currently serving as chair of the NSGC Task Force on Genetic Testing of Minors, the opinions expressed here (as always) are mine, and mine alone.

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by | October 23, 2012 · 3:02 PM

‘We Need to Talk About our Eggs’ – Yes or No?

There is an intersting opinion piece in the NYT this week titled We Need to Talk About our Eggs. The author argues that it is the responsibility of the medical community to bring up the discussion about fertility with women, before it is too late for them. Is she right?

Cast your vote and/or share your thoughts, below.

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by | October 5, 2012 · 11:46 AM

Whole Genome Sequencing Is the Future of Genetics, BUT the ‘$1000 Genome’ is a Bait and Switch

Let’s STOP talking about the $1000 genome!  Please.

Unless you’ve been living under a rock since 2001, you’ve been hearing about the $1000 genome for years.  The inevitable, the holy grail, the game-changer – the ultimate goal post as proclaimed by an entire chorus of Chicken Little genomicists crying, ‘The cost of sequencing is falling!  The cost of sequencing is falling!’  And it’s true! Not only has the cost of sequencing dropped faster than Facebook stock on IPO day, but the product has improved at the same time, in speed, accuracy and coverage.  Will it be transformational?  It already is. 

The early references to the ‘$1000 genome’ were purely aspirational, tossed out in stark contrast to cost of the newly-completed 2.7 billion dollar genome generated by the Human Genome Project.  But the emergence of the $1000 genome as a meme began in earnest in 2005, when the Craig Venter Foundation offered $500,000 to whoever got there first, an incentive that has since evolved into the $10,000,000 Archon X Prize (100 human genomes/30 days/98% accuracy), to be contested in September, 2013.

But all that money aside (seriously, that’s a lot of zeroes!), the phrase, the ‘$1000 genome’ represents much more than a measure of technological prowess.  As George Church describes it, “The ‘$1,000 genome’ has become shorthand for the promise of DNA-sequencing capability made so affordable that individuals might think the once-in-a-lifetime expenditure to have a full personal genome sequence read to a disk for doctors to reference is worthwhile.”  Which is exactly why, as the technical parameters of the challenge have grown clearer and more explicit, the bandying about of the term has grown more and more misleading.

HERE is what the ‘$1000 genome’ DOES NOT MEAN: that getting your DNA sequenced will cost $1000.  This may be self-evident to all the genomics experts competing to win the Archon X prize, but it is anything but obvious to everyone else.   The $1000 figure covers only renewables – those things like reagents and chips that are consumed in the process of sequencing.  It does not include the cost of the sequencer or the cost of the tech who runs the sequencer.  It does not cover overhead or profits.  And most of all, it does not cover the costs associated with interpretation, without which a DNA sequence is merely an endless stream of A’s, C’s, T’s and G’s. 

Sequencing as a “once-in-a-lifetime expenditure”?  More caveats!  Integrated sequencing and interpretive processes make it difficult to re-examine old data, and with both our knowledge base and our sequence quality improving by leaps and bounds, lab experts have assured me that re-sequencing would make more sense than working with data that is even a few years old.  So the whole sequencing-at-birth idea?  Not so much – at least, not yet.

Finally, while the magic of sequencing may lie in the technology that makes it possible, the value of sequencing lies in our ability to translate that technological virtuosity into improved health.  A number of exciting early reports demonstrate the potential health benefits; unfortunately, most of them fail to acknowledge all the ways in which these early adopters do not represent the general public.  A highly-publicized article in Cell in spring 2012 described the experience of Michael Snyder, a molecular geneticist from Stanford who experimented on himself using genetic sequencing followed by a serially repeated, battery of tests designed to monitor his health and biochemistry.  When his genetic sequence showed a variant associated with an elevated risk for type II diabetes, Dr. Snyder added a close monitoring of his blood glucose and other markers for diabetes — a testing regimen unprecedented for someone without risk factors for the disease.  Lo and behold, following an attack of respiratory virus, Dr. Snyder’s blood glucose levels rose to a level consistent with type II diabetes!  The doctor improved his diet and increased his level of exercise, and six months later his blood glucose levels were normal.

Was this, as suggested, a miracle of preventative medicine?  It’s a little hard to know from a sample of one.  Because aggressive monitoring is not done for individuals with no signs or symptoms of diabetes, we don’t know much about the likelihood of transient high blood glucose.  But one thing is indisputable: like the Personal Genome Project participants and other high profile subjects of whole genome sequencing, Dr. Snyder had available to him levels of expertise and medical care that are not in any way typical.  For much of America, paying for routine medical care is a challenge, and paying for acute or chronic medical care the most likely cause of personal bankruptcy.  And even people with money to spare don’t usually get a sit-down with George Church to discuss their most disturbing sequence variants.

Whoever wins the Archon X Prize next year: I salute you.  The $1000 genome is an enormous technical achievement and you deserve every penny!  But let’s not confuse people about what it means.  Let’s not confuse the $1000 genome with the $10,000 interpretation or the $25,000 follow-up.  The meme that represents the future of genetics should not be a bait-and-switch. 

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by | June 26, 2012 · 3:15 PM

23andMe Reveals a Snippet of it’s own DNA

You have got to feel sorry for 23andMe.

Ha!  What a funny thing for me to say.  Genetic counselors don’t feel sorry for 23andMe.  After all, they offer a service of which many of us are deeply distrustful, suspecting that for all the data they provide, all the fact-filled blurbs and fancy graphics, their outpouring of information often serves to obscure rather than to illuminate the more significant truth: that most of the time, these reports are not a valid or reliable source on which to base decisions about your health and well-being.  That their message promotes a kind of mantra of genetic determinism that complicates our job, since it creates expectations that cannot be fulfilled.  That their credibility and media presence have less to do with scientific bona fides than an intimate relationship between their founder Anne Wojcicki and Google’s Sergei Brin, which gives 23andMe access to both some very deep pockets and the reflected glory of an association with the epitome of technological wizardry.

And now they are doing research, and they don’t even have to bother with an IRB.  It’s so unfair.

But really, you should feel sorry for 23andMe.  I’m serious.

It’s not easy being them.  Think about it this way: the entire premise of the 23andMe sales pitch is that they can offer you valuable information.  Valuable how?  Well, presumably because it will SAVE YOUR LIFE, or something to that effect.  “Personalize your healthcare,” they say on the website.  “Prepare for serious diseases.”  However, at the same time, 23andMe can not say that any of this valuable information is diagnostic.  They have to be careful not even to imply that it is diagnostic, because offering diagnostic information constitutes a medical test, and medical tests are subject to a much more rigorous degree of government regulation.  If you were a company, would you care to invite a greater degree of scrutiny from the FDA?  No, you would not.

It’s a fine line they walk.  You’d have to be clear-headed and on your game to walk a line like that.  I bet those guys in corporate communications at 23andMe have to stay stone cold sober all the time.  You know that show Mad Men?  The opposite of that.

Now, a tough job gets even tougher.  Last month, 23andMe announced their first-ever patent, awarded for a method of determining an individual’s risk for Parkinson’s disease, a finding drawn from a study of 5,000+ PD patients who were offered the 23andMe genome screen virtually for free – what the company refers to as “the largest Parkinson’s community for genetic research in the world.”  This was a big day for the company, since the patent represents not only a new potential line of revenue but proof in principle for their strategy of crowd-sourced genetic research.  Given their outsider status, 23andMe was probably prepared for a certain level of pushback from the standard-bearers of academic research.  What they may not have expected was that their big day would be marred by an insurrection in the ranks – but to their apparent surprise, the announcement drew outraged responses from many 23andMe research participants. 

It turns out that many in the “Parkinson’s community” felt betrayed by the patent application, perceiving it as an unexpected move to monetize on the part of the company they believed was only interested in a cure – after all, Sergei Brin himself has revealed that he has a genetic risk for PD.  While the press releases from 23andMe emphasize the importance of the patent as not a money-maker but an inducement for other companies to use this information to develop treatments – “the patent will be important for a biotech or pharmaceutical company to pursue drug development” – the majority of the voices making themselves heard seem to find this a dubious distinction.  Admittedly, it defies logic to assume that a commercial entity would file for a patent merely so someone else could (eventually) make a profit, and in fact if we are looking for evidence of capitalistic intent, we can find it conveniently staring out at us from the informed consent that all 23andMe customers are required to sign: “If 23andMe develops intellectual property and/or commercializes products or services, directly or indirectly, based on the results of this study, you will not receive any compensation.”

So why did so many research participants feel deceived by a naked expression of commercial intent?  Well, it turns out that, once again, hard cold facts spelled out in black and white, however clearly stated, were less convincing than a fundamentally different message that was never articulated but merely implied, insinuated, forcefully and emotionally conveyed by the fundamental nature of the language used.  “Join us” they said.  “Everyone can help.”  23andMe research is billed as a community effort, “powering research breakthroughs.”  It’s like a research Wiki.   “I had assumed that 23andMe was against patenting genes and felt in total cahoots all along with you guys,” said one research participant. “If I’d known you might go that route with my data, I’m not sure I would have answered any surveys.”

Okay, so as insurrections go, this one is a bit of a tempest in a test tube.  Should we care?  Is it a problem if a small number of people who didn’t read the fine print feel misused?  C’MON PEOPLE.  You haven’t been abused.  You haven’t been robbed.  You did not sacrifice flesh or blood — just a little spit.  But the objections of the 23andMe crowd should be noted by all companies (or researchers) who want to make use of the DNA and altruism of willing donors.  It’s a very fine line you draw for yourself when you unpack those chromosomes: hard to walk, easy to trip over.  If you tell people that the genomic revolution is all about their health, and it turns out to be more about your profits, once-willing participants may be more inclined to spit at you than spit for you.  If 23andMe plans to make data mining an integral part of their revenue stream – and this patent is one pretty clear indication of their intent – then they will have to find a way to convince their target audience that this is a chimera of a company, a capitalist beast with the loving heart of a non-profit enterprise.

 

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