The DNA Exchange

Tom Insel, director of the National Institute of Mental Health (NIMH), roiled the world of psychiatry in a blog post (how very 21^st 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?

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.

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 15^th, 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.