Tag Archives: variants of uncertain significance

Is A Lab A Health Care Professional? An Update On “Everyone’s Worst Nightmare”

Two years ago I authored a blogpost, Everyone’s Worst Nightmare , about a family’s experience with genetic variant interpretation, communication (or lack of) by healthcare providers with families, and an outcome that couldn’t be more tragic – the death of a child. Here I am providing an update on the legal status of the lawsuit brought on behalf of the child by his mother. In my original posting, I did not identify the child’s syndrome or the specific court case. However, since then, the story has been picked up by a variety of media outlets (Turna Ray at GenomeWeb has done the best reporting on the details) and it now being a matter of public record, I have included some particulars here .

Briefly, the story began about 12 years ago when the child was experiencing multiple, intractable seizures and had a clinical picture consistent with Dravet syndrome. Unbeknownst to the parents, genetic testing was ordered and the child was found to carry a mutation in SCN1A, the gene linked to Dravet syndrome. The mutation was interpreted as a variant of uncertain significance, though at the time there was reason to believe that it could be pathogenic. Based on the genetic test result, it was felt that the child did not have Dravet syndrome and was kept on a sodium channel blocker, which unfortunately is contra-indicated for patients with this syndrome. Not long afterwards the child died of seizures at the age of two.

The patient did not find out that genetic testing had been performed until about 7 years after the test was ordered. Shortly after the mother learned of the test result and inquired into its meaning, the lab reclassified the variant as pathogenic.

In February 2016 the mother initiated a lawsuit on behalf of her deceased child in the fifth judicial circuit court in Richland County, South Carolina. The defendant’s lawyers requested that the case be dismissed on the grounds of restrictions imposed by the state’s statute of repose, i.e., a law that states legal action must be initiated within a certain period from the time the alleged offense occurred (it is similar to but slightly different from a statute of limitations). The defendants presented the argument that a genetic testing laboratory is a licensed health care provider and South Carolina has a 3 year statute of repose for lawsuits brought against licensed health care providers. Since the events took place a decade ago, the defendants asserted that the case should be dismissed. The plaintiff countered that, under South Carolina state law, a genetic testing lab that is separate from a hospital or a clinic cannot be considered a licensed health care provider and therefore the statute of repose did not apply. The plaintiff contended that this is a case of ordinary negligence, not medical malpractice, since the lab should not be considered a licensed health care provider and therefore the suit should be allowed to proceed.

The case was then sent to the US District Court in 2017 to rule on whether dismissal was warranted based on the defendant’s argument that the lab is a licensed health care provider and therefore the statue of repose applies. The federal judge then referred the case to the South Carolina Supreme Court to, as the legal lingo goes, certify the question of whether a lab can be considered a licensed health care provider under the specific provisions of South Carolina Code of Laws Section 38-79-410. Although we may have our individual opinions on this question, it is strictly a matter of law that varies by state. South Carolina law defines a licensed health care provider as “physicians and surgeons; directors, officers, and trustees of hospitals; nurses; oral surgeons; dentists; pharmacists; chiropractors; optometrists; podiatrists; hospitals; nursing homes; or any similar category of licensed health care providers.” (italics added)

The South Carolina Supreme Court heard the case on February 14th, 2018. For those of you who have never witnessed a state Supreme Court hearing, I recommend that you watch the ~40 minute video of the session. The court’s decision, which will be about whether the suit can proceed rather than determining liability, will depend on how it interprets whether a laboratory is a “similar category” to the health professionals listed in the state code. I thought that the five justices were insightful and asked thoughtful questions. As a side note, at about the 29-30 minute mark of the hearing, Justice Few gives a shout out to our genetics colleagues at the Greenwood Genetics Center.

The court does not have a set date on when they will issue an opinion; as the Supremes, they call that shot (the South Carolina Supreme Court’s motto is Nil ultra, which roughly translates as “Nothing is above us”). Typically, though, the time frame on a ruling is in weeks or months. If the court decides that the lab is not a healthcare provider, then the plaintiff’s suit will be allowed to continue, though I got the sense that the court felt that even if the ruling were in favor of the defendants that the plaintiff may still have alternate legal pathways to pursue a case. I will keep the good readers of The DNA Exchange posted on important developments in this case, which I suspect will continue to drag on for some time after the Supreme Court’s ruling.

With the rapid expansion of genetic testing in the clinical and consumer spaces, and the growing involvement of non-genetics professionals in ordering genetic testing, bad clinical outcome scenarios are likely to become more common. Critical questions about variant interpretation and legal liability aside, from a genetic counseling standpoint, this case highlights the importance of clear and ongoing communication with patients and their families about the limits and clinical interpretation of genetic testing. This can be extraordinarily difficult when a family is trying to cope with caring for a child with a life-threatening disease, but genetic counselors are trained to work precisely in those situations. Genetic testing may be simple to order and widely available but it benefits no one without good clinical care and counseling.

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Everyone’s Worst Nightmare

The story that I tell here is, I know, a one-sided tale. It is also the source of pending litigation. A friend of a parent of the child reached out to me to ask me to share the story with the genetics community with the hope that some good could come out of a terrible experience, and did so with the approval of the parent’s lawyers. I obtained the details from publicly available records. I am not passing judgment on who was right, who was wrong, who did what, and who didn’t do what; the lawsuit will rule on that. I have had no involvement with the care of the patient or the subsequent legal wrangling, nor do I have any particular expertise about the disorder in question. For months I have struggled with whether the DNA Exchange is the appropriate venue for this, but ultimately decided that the family’s voice needs to be heard. I have largely anonymized the story because, really, specific names and diseases do not matter. What matters is that steps need to be taken to help ensure that other patients, families, providers, and laboratories do not repeat this sad tale.

The child was born about a decade ago, the product of an uncomplicated, happy, and desired pregnancy. At a few months of age, the child developed seizures after receiving a routine vaccination and went on to experience ongoing seizures of differing types. Various diagnoses were entertained particularly mitochondrial diseases and treatment included standard anti-seizure medications. A number of specialists were involved with the child’s care, including geneticists. Early on in the work-up genetic testing identified a mutation in a gene linked to a disorder that would explain the child’s seizures, a finding which the lab interpreted as a variant of unknown significance (VUS). Based on available literature at the time, there was some reason to believe that the variant might be a pathogenic mutation – it had been reported in affected patients –  but determining the clinical significance of a gene mutation is a problem that continues to plague genetic testing today.

Now here is where the story gets complicated and fuzzy, and to me where the tragedy starts to unfold. Apparently, the physician who ordered the test decided that the genetic test result was inadequate to help establish a definitive diagnosis, and pursued other diagnostic possibilities. As far as can be gleaned from the records, the genetic test results were not shared with the family although some of the treating physicians had considered the diagnosis on clinical grounds. The child continued to be treated with medications that, unfortunately, worsen the seizures for the condition that the child was ultimately diagnosed with – a condition caused by mutations in the gene in which the VUS was found. Sadly, the child died a few months shy of 3 years old from intractable seizures likely related to the contraindicated seizure medications.

The family did not find out about the genetic test results until about 7 years after the child died and only then after a parent requested the results. A few months later, the lab produced a revised report that reclassified the variant as a disease-associated mutation. Curiously, the report does not contain a revision date nor does it include the reasoning or data that led to the revised interpretation.

On one level, this story tells the genetics community nothing it did not already know – interpreting the clinical significance of a VUS is a terribly complicated and at times subjective affair. There is no single gold standard that can be used to determine clinical significance, which involves complex statistical, genetic, and biological analysis. Two equally capable labs can look at the same set of data and come up with diametrically opposite conclusions. Articles address the frequency of variants in genetic testing and differences in interpretation, along with providing an idea of the scope of the problem. But statistics are not stories. Stories convey the human impact of statistics and the urgency of the problem. As the saying goes, one death is a tragedy; a million deaths is a statistic (attributed to, of all people, Joseph Stalin).

Public databases such as ClinVar are starting to address this problem but they are still in their infancy. Indeed, a recent check of ClinVar revealed only one entry for the variant in question and the entry doesn’t even classify the variant. As human genome testing is ordered at exponentially increasing rates, the need for a uniform approach to genetic test interpretation and data-sharing is beyond pressingly critical. Restrictive gene patents and data hoarding may be good for business but they are not good for patient care. Lots of money will be made through genetic testing; some portion of those profits need to be channeled to funding well-curated freely available databases ( a database that is not well-curated is useless, and potentially harmful). Perhaps there could be tax breaks for labs that share data and government funding could favor research projects utilizing labs that share variant data.

But this story highlights other potential weaknesses in the genetic testing process. Parents and patients need to have pre-test genetic counseling so they are clearly informed when genetic testing is ordered. Results need to be explained to patients, even if they are uncertain. This is no mean feat, especially when a patient is going through an extensive work-up and many tests of all varieties are being ordered. Results have to be clearly available in medical records so all providers can have ready access to them, and patients should always have a copy of their test report made available to them along with an explanatory letter. A letter to the family summarizing the results could have prevented a lot of anguish for this family. There must be good mechanisms in place to regularly update test interpretations and for those updated interpretations to be communicated clearly and without delay to providers and patients. Patients should be encouraged to actively participate in seeking more information about their genetic test results and to enroll in centralized databases such as PROMPT. Maybe labs should allow a random sample of their report interpretations to be audited by an unbiased third party such as the College of American Pathologists to assure adherence to test interpretation guidelines. This could be a voluntary program but labs may be eager to participate as a selling point of their commitment to accuracy. Governments and insurers must allot the funds and resources for all this to take place.

The outcome here was the worst possible for everybody – most especially the patient and the patient’s family, but also no lab and no care provider ever wants something like this to happen to a patient. It haunts us all. If any good can come out of this, then this story will inspire us to work with greater urgency and cooperation to create workable solutions. Our patients deserve no less than the very best.

This posting is dedicated to the memory of the child whose all-too-short life is discussed here.

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Do I Really Have To Tell Them? Duty To Recontact And Variants of Unknown Significance

Duty to recontact (DTR) is one of those principles that on Mondays, Wednesdays, and Fridays I feel should be an unquestioned standard of care. On Tuesdays, Thursdays, and Saturdays, the practical part of me prefers to sweep it under the ethical rug (on Sundays, I give it a break and enjoy a wee bevvy of single malt Scotch). The devil lies in the details of time, effort, unremunerated cost, and frustration involved with trying to notify patients of significant re-interpretations of test results or the availability of new testing technologies. A recent systematic review of DTR by Ellen Otten and her Netherlandish colleagues concluded that, broadly speaking, patients value being recontacted whereas clinicians feel that DTR is desirable but impractical.

I was surprised to learn that the American College of Medical Genetics is the only professional organization that has issued a formal statement in support of DTR, initially in 1999, with an update in 2013 specifically addressing clinical exome sequencing and clinical genome sequencing (Readers, please let me know if I am mistaken). I am not aware of case-law or legislation that mandates DTR, but I would feel awfully uncomfortable if a law suit were brought against me for failure to recontact a patient. It is hard to ignore something that carries the label “duty.”

In a previous posting I suggested that  labs should refrain from reporting variants of unknown significance (VUS) because VUS should virtually never be used to guide clinical practice, and that labs should track VUS and alert clinicians to significant reclassifications. That blogpost generated interesting discussion on all sides of the issue. Collaborative databases such as ClinVar and PROMPT may help sort out the clinical relevance of human genetic variation, and to some extent relieve individual labs of part of the burden of dealing with VUS. But these efforts will only further the importance of clear and reasonable DTR guidelines. We are in this to improve the lives of our patients, and if advances in genetic knowledge are not used to help clinical care, then we have a  failure on our hands.

As a first step, let me offer some suggestions toward establishing reasonable DTR guidelines:

  1. The primary – but not exclusive – responsibility of monitoring and reclassifying variants should lie with the original testing laboratory or whichever corporate entity might one day buy out the lab.  However, transparent sharing and curating of data among labs – such as with PROMPT and ClinVar – is critical and should be supported by government funding and built into the cost of testing. Classifying variants is enormously complex and the final word requires more than just a few smart people at a single lab rendering their opinions.VUS scale
  2. Labs should make good faith efforts to contact ordering clinicians – not patients – when a variant is reclassified. The clinician is responsible for integrating the test results into patient care. If the clinician is not reachable or no longer affiliated with the same institution or practice, then the original ordering facility should be notified. If efforts to re-contact clinical personnel fail, labs might then consider contacting patients directly, though this could be left up to individual lab policy. If all attempts to recontact fail, well so be it, but should be fully documented. If clinicians do not want to take on the responsibility of DTR, then, quite frankly, they should not engage in the practice of ordering genetic testing and should refer their patients to geneticists or other clinicians who are willing to assume this task.
  3. DTR should be limited to situations where the reclassification of a VUS has direct clinical impact. Thus, there should be no DTR if a VUS is “down-graded” to a polymorphism or a benign allele. In my experience, the vast majority of VUS are down-graded. Alerting patients to every variant and then notifying them months or years later that the VUS was clinically irrelevant is not the best use of resources and manpower. However, DTR becomes critical if a VUS is “up-graded” to Suspected Pathogenic or Pathogenic, or – the more painful phone call to make – if a Suspected or Pathogenic allele is “down-graded” to a polymorphism (“Uh, that salpingo-oopphorectomy and mastectomy, well, maybe they weren’t so necessary after all.”).
  4. There should a “statute of limitations” on how many years out from the testing date that DTR would apply. My daughter suggested 7 years from the time of the original interpretation; she tells me that this is consistent with the length of time that care providers are legally required to keep patient records. I might be persuaded in favor of five years, in light of the mobility of clinicians and patients, the inevitable business cycle of lab acquisitions/mergers/closures, and advances in genetic testing that will rapidly make today’s cutting edge techniques look as elegantly primitive as Clovis point technology.

    iClovis

    iClovis

  5. When undergoing genetic testing, patients should fill out a form with their contact information. Patients should be actively involved in their medical care and this brings with it an obligation for patients to inform clinicians of contact information, along with details of who and how to contact if the patient becomes deceased, mentally incompetent, or otherwise unreachable.  Ideally clinics would contact patients every two years or so to update contact information. While this is theoretically straight-forward with electronic medical records (EMR), most EMR are far less flexible and surprisingly less able to allow such seemingly straight-forward database functions. Getting your IS department to extract individualized reports, mail merges, and data analysis from the EMR is almost as difficult getting the US Congress to pass meaningful legislation. And, to add another layer to participation in their own care, patients should be permitted viewing access to online VUS databases, which should be made user-friendly. It may not be what every patient wants, but it should be available for those who wish to pursue it. In this area, we could learn a lot from direct to consumer genetic testing labs, which are light years ahead of us in designing easy to use, highly informative, up to date websites and creating on-line communities.

Some of you will support a few of these proposals and think that others are about as good an idea as Discount Colonoscopy. But if we don’t do something then nothing will ever get done. What are your thoughts?

 

Once again, thanks to Emily Singh for doing the hard work on the graphics (really, isn’t iClovis très cool?).

 

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

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

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

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

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

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

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

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

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

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

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

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

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