Author Archives: MStrecker

by MStrecker | March 17, 2015 · 12:40 AM

Do You Want To Know A Secret? The Ethics of Reporting Non-Reportable Results

Gossip

I find myself increasingly unsettled by the manner in which some non-invasive prenatal screening (NIPS) laboratories are choosing to handle their non-reportable results. Imagine that your friend is pregnant with her second child. Her obstetrician speaks to her about NIPS, and she decides to proceed. The result comes back as non-reportable, and she is referred for genetic counseling to discuss the options of (1) doing nothing further, (2) repeating the NIPS, or (3) proceeding with prenatal diagnostic testing. In preparation for her visit, your friend’s genetic counselor calls the NIPS laboratory to follow up on the non-reportable result. The laboratory informs the genetic counselor that the data suggest a deletion on one of the chromosome 15s, but that since the test is not validated for this abnormality, it instead triggered a non-reportable result. And herein lies the conundrum. The laboratory has now disclosed information about a possible, unvalidated, incidental finding to the genetic counselor after issuing a clinical report stating that an interpretation of the data could not be given. And we wonder why the US Food & Drug Administration (FDA) has decided its time to start regulating laboratory developed tests…

The FDA and Laboratory Developed Testing

In July 2014, the US Food & Drug Administration (FDA) notified Congress of their intention to implement a risk-based regulatory framework for Laboratory Developed Tests (LDTs). The FDA defines an LDT as one that is developed, manufactured, and run within a single laboratory. LDTs vary in their level of technical complexity and in their level of associated “risk”, which is typically gauged by the severity of the anticipated or potential consequences of an erroneous result. (In 2012, the American College of Medical Genetics and Genomics (ACMG) released a policy statement to provide a specific framework for risk classification of inherited disorders.) The response to the FDA’s proposal to regulate LDTs by the medical community as a whole has been largely negative. In November 2014, the American Medical Association partnered with a number of professional societies, laboratories and laboratory directors and sent a letter to the FDA indicating that the proposed regulatory framework was in significant conflict with existing regulations, and that the FDA’s legal authority to regulate LDTs was in fact, questionable. There are certainly merits to the arguments on either side of the issue, however, my point is that the practice of reporting of incidental, analytically and clinically un-validated results as part of clinical care is just the sort of behavior that makes LDTs a legitimate target for the FDA.

Non-Reportable NIPS Results

In NIPS, a non-reportable result typically indicates that the laboratory is unable to make a determination regarding the risk of abnormalities for which the test was designed to detect, based on the data provided. There are a number of causes of non-reportable results, and patients are advised that this is a possibility prior to undergoing NIPS (hopefully). What I take issue with is the fact that a follow-up phone call from a clinician might mean being provided with some sort of quasi-result – an unvalidated, unsubstantiated result that lacks peer-reviewed evidence to support the interpretation of the data. To me, this is akin to providing a patient with results from testing that is still in the research & development stage, but treating it as though it were information from a clinically-validated test, upon which treatment decisions can be made. While several NIPS laboratories have policies regarding the ability to opt in/out of receiving additional information about certain microdeletion syndromes or trisomies commonly seen in pregnancy losses, I was unable to find any policies regarding how the discussion of non-reportable results are handled. Without clear, publically-available policies regarding what type of incidental and/or “investigational” information will or will not be reported, clinicians who decide to follow up on non-reportable NIPS results risk being put in the uncomfortable and ethically murky position of receiving an unvalidated result and having to decide whether it is most appropriate to withhold this information from the patient and simply inform her of the need to repeat the test, or to share the burden of this knowledge, hoping that the patient will fully understand the significance of a “result” that has been neither analytically nor clinically validated.

It’s Not a VOUS

For those of you who would argue that providing information about unvalidated finding is similar to encountering a variant of uncertain clinical significance (VOUS) on a prenatal microarray, I wholeheartedly disagree. A VOUS result on is one that is obtained on a platform with established analytic and clinical validity. With a VOUS result on microarray, it’s not the copy number variant call that is in question; it is the clinical significance of that copy number variant and how it may or may not impact clinical care that is in question. In contrast, if an NIPS laboratory provides information about a copy number change for which their platform has not been analytically validated, it is the result itself that is in question: is this accurate information or inaccurate information?

Discordant Results

In the nature of full disclosure, I find NIPS fascinating in part because I work in a clinical laboratory that performs prenatal diagnostic testing. Over the past couple of years, we have handled a significant number of discordant NIPS vs. CVS/amniocentesis results, particularly with respect to suspected microdeletions or partial monosomies. It is clear that we are gaining insight into some of the biological explanations for these discrepancies (vanishing twin; fetal, placental or maternal mosaicism; maternal neoplasm, etc.), however, we in our laboratory have observed that regions of homozygosity seem to be particularly troublesome for certain NIPS platforms, and may be prone to causing erroneous suspicions of a deletion or a partial monosomy.

My point is, there is a good deal of data to suggest that NIPS is really excellent at screening for trisomy 21, and quite good at screening for trisomy 13 and trisomy 18 (although there is a whole separate discussion to be had on the positive predictive value of NIPS based on the incidence of the disorder it is intended to detect. See Katie Stoll’s previous post for an excellent discussion of that topic.) What I am concerned with is the practice of selectively reporting potential, but unvalidated abnormalities. As a genetic counselor, I much prefer that my patients have accurate information from a diagnostic test, rather than relying on a screening test, no matter how good of a screen it is. However, if I have a patient who is keen to avoid “invasive” testing, I would probably struggle with whether or not to tell her about an incidental finding of unclear validity, knowing that this information it may unduly influence her decision about whether or not to undergo diagnostic testing. Quite frankly, the onus should be on the laboratory NOT to disclose unvalidated results following an “official” interpretation of a result as non-reportable.

Fetal Aneuploidy or Maternal Malignancy?

Recently, the reporting of incidental, unvalidated results on NIPS received significant media attention when it came to light that NIPS results may serve as a marker for unrecognized maternal malignancies. BuzzFeed published an article detailing how an obstetrician who had ordered NIPS on one of his patients was shocked to learn that the laboratory suspected his patient may have cancer based on the results of her NIPS. While serendipitous discoveries such as this can lead to major improvements in diagnostic testing, it is not clear at which point this unvalidated information should be disclosed to the clinician. In this particular situation, it turned out well for the patient, who did, indeed, have cancer. However, if the information had been erroneous, and she did not have cancer, things could have taken a very different course. I think as clinicians, most of us recognize that incidental findings are a part of medicine. But this should be even more reason to determine how best to handle unanticipated results before they occur. Clear policies regarding what types of incidental findings can be/will be reported need to be put into place, and patients should be made aware of these possibilities as part of the informed consent process.

What Is the Solution?

I am all for making NIPS the best screening tool it can possibly be. I support prospective clinical trials to evaluate the tests’ performance and to determine what other abnormalities can reliably be detected. However, the reporting of analytically un-validated results, needs to stop. I understand the temptation to allow exciting preliminary data bleed over into clinical care, but when it comes down to it, we must commit ourselves to providing conscientious, responsible care. To me, this means rigorously validating and replicating results across heterogeneous populations before applying that information to the practice of medicine.

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by MStrecker | July 18, 2012 · 10:49 AM

Conflict of Interest and Practice Guidelines: A Call to Arms

ON THE LEVEL

I admit that I started out with the intention of writing a point/counter-point piece to Bob’s post on conflict of interest. As a laboratory genetic counselor and a member of the NSGC Practice Guidelines Committee, I figured if anyone should step up, it should be me. So I started doing my background research. First, I decided that perhaps Bob just couldn’t find the Conflict of Interest Policy on the NSGC website. I was determined to find it, right there, hidden in plain sight. But, no such luck. It’s not there. There is not even a mention of it on the page with our Code of Ethics link. OK, score one for Team Resta.

So what about our “sister” organizations like ACMG and ASHG? What do they do? I went to the ACMG website and after searching for several minutes, I couldn’t find anything there, either. OK, so we weren’t the only ones who did not have a conflict of interest policy posted on our website. Team Strecker, makin’ a move. How about ASHG? (At this point I was thinking, well, if ACMG didn’t have anything, I bet ASHG won’t either.) Wrong. In fact, waaaaaaay wrong. ASHG has a link to their Conflict of Interest & Disclosure Statement, prominently displayed under their Bylaws, which provides clear definitions regarding what constitutes a conflict of interest, how both real and potential conflicts of interest are handled, and to whom the policy applies. Yeah, I admit it; I was impressed.

TAKING A GOOD, HONEST LOOK AT OURSELVES

Next I decided to tackle Bob’s recommendation that we base NSGC’s conflict of interest policy for the development of practice guidelines on the Institute of Medicine’s (IOM) Committee on Conflict of Interest in Medical Research, Education and Practice recommendations. “It would not be that difficult to implement,” he tells us. All I could think was “Sure, easy for you to say.” But then I realized, that maybe, just maybe, Mr. Know-It-Almost-All Resta might just be right. Section 7 specifically addresses conflicts of interest with respect to developing practice guidelines. I’ll summarize it for you:

1) Don’t accept industry funding for the development of guidelines.

No problemo!! I can tell you that on my watch, no one has ever offered money to help us get practice guidelines written. In fact, I almost laughed when I first read this one, because I feel like any of us would have the good sense to see the wolf dressed up in granny’s clothing here (My, what big stacks of cash you have, grandma!).

But then I reminded myself that when it comes to ethics, credibility, and money, we must assume nothing.

2) Exclude individuals with conflicts of interest from guideline development panels.

I have mixed feelings about this one because I’m not sure whether we are talking about individuals with (i) true conflicts of interest (in which case, I agree and they should have the good sense to recuse themselves) or (ii) the potential-for-the-perception-of-a-possible-conflict-of-interest.

For example, I take issue with unconditionally excluding laboratory genetic counselors from co-authoring guidelines simply because their laboratory offers a test for the condition about which the practice guideline is being written. Obviously we want the reputation of the NSGC and its practice guidelines to be above reproach, but we also need to be pragmatic. The expertise of laboratory genetic counselors should not be marginalized. Let’s use our judgment with this one, and if the magnitude of the conflict of interest is deemed significant, then it is fair to provide an option for participating as an advisor, rather than an author.

3) If there is difficulty identifying authors without any conflicts of interest, involve the public in an attempt to identify experts without any conflicts of interest.

I like this one. A lot. You know why? Because the public (and by public here, I really mean the NSGC membership) is no longer involved in any aspect of the Practice Guidelines process. Topics for upcoming practice guidelines are not provided or voted on by the membership. The fact is, as a volunteer-driven organization, we are entirely reliant upon the gracious volunteer efforts of our colleagues. So with no trace of disrespect whatsoever, you know what they say about beggars and choosers. The thing is, this method of ascertainment leaves me feeling like we’re in some sort of secret society. Apart from the Practice Guideline Committee members, the NSGC Board of Directors and the authors themselves, I’m not sure that anyone else even knows what practice guidelines the NSGC is working on for 2012-2013. (And they certainly don’t know our secret handshake. Kidding!)

In fact, most of the time, members don’t even know a practice guideline is in the works until it is made available for Membership Review. Oh wait, we don’t even have that anymore. This March, the Practice Guidelines Committee received feedback from the NSGC Board that guidelines were taking too long to complete, and in order to help “streamline the process” the NSGC Board determined that practice guidelines would no longer undergo Membership Review. This was none too popular with the Committee, but we were informed that the Board’s decision was final. So, this IOM recommendation got me to thinking that perhaps we could institute an open call to the NSGC membership once a practice guideline proposal has been accepted in order to allow interested individuals with relevant expertise the opportunity to volunteer as co-authors. This would allow us to identify as many conflict-of-interest-free potential co-authors and expert reviewers as possible, and although it wouldn’t be the same as re-instituting member review, it would be a step in the right direction.

4) If exclusion of authors with conflicts of interests is not feasible, the number of authors with potential conflicts of interest must comprise a minority of the author group.

Whew. Done and done. We are good here – our policy already states this.

5) The chair of the guideline committee should have no conflicts of interest.

I am with Bob here – we need to revise our current Conflict of Interest Policy to reflect this. At present, our policy for practice guidelines authors states that “a conflict of interest does not exclude an individual from being appointed lead author if doing so is anticipated to improve the overall quality of the guideline.” It is a very well-intentioned statement, but in order to garner respect for our profession, our society and our practice guidelines, we have to toe the line on this one and make it clear that lead authors cannot have any relevant conflicts of interest.

6) Individuals with a potential conflict of interest should not be included in voting for the acceptance of a practice guideline.

Woohoo! Got that one! Oh wait, maybe not. Dang it! The reality is that the Practice Guideline Committee members with potential conflicts of interest have always recused themselves from voting on practice guideline proposals and final drafts of guidelines, but after re-reading our Conflict of Interest Policy, I realized that we don’t actually say that we do this in the document, and we need to.

DIVULGING OUR FINANACIAL AFFILIATIONS

So we have clearly established that Bob might, in fact be right about that whole IOM thing not being all that difficult to implement. But what about his challenge to make our corporate income sources publically available? I don’t have a problem with Bob’s suggestion to make a list of our corporate sponsors available, but rather than providing them with free advertising on our site, perhaps it could be made available on request. In addition, I would like to once again direct your attention to our colleagues at ASHG and their “Guidelines for Corporate Sponsorship” in which they delineate the steps that are taken to prevent concerns about undue financial influence on the society by outside sponsors. I think a similar policy would be a great addition to the NSGC website. Being upfront about our sources of income helps demonstrate that it is important to us to be free from undue external pressure and lends credibility to our professional society.

BRING IT!

I’ll close with the quote that appears on the title page of the IOM’s recommendations regarding conflict of interest:

“Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe

You see, Pom-Poms Resta, you sit comfortably on the sidelines, telling us that it is not your intention to actually DO anything about the issues you bring up; all the while, taunting the rest of us to “Buh-ring it!”. OK. You know what have to say about that? In the immortal words of Priscilla in “Not Another Teen Movie” (Columbia, 2001) let me just say– “Oh it’s already been buh-roughten!”. (Insert sassy Z snap here for emphasis.)

I have contacted the NSGC Practice Guidelines Committee’s Board liaison to propose a volunteer taskforce dedicated to strengthening our Conflict of Interest Policy and fortifying our efforts toward transparency in our corporate sponsorship ties.

So, the only question remaining is “Who is willing to get all Goethe on this issue with me?”