I Love Them, I Love Them Not….. Proposed Revised Medicare Guidelines For Coverage of BRCA Testing

Graphic by Emily Singh

Graphic by Emily Singh

The Centers For Medicare & Medicaid Services (CMS) has proposed a revised Local Coverage Determination (LCD) for BRCA* testing that is bound to make genetic counselors equal parts happy and  upset. Whether you are mad, glad, or confused, CMS is seeking input so you have the opportunity to applaud, chastise, or critique the proposed LCD as you see fit. The guidelines are too numerous to detail here, so I will highlight a few that are particularly relevant to the genetic counseling community. Please, please, please carefully read the guidelines yourselves.

The most radical change is that, as I read the LCD, it appears that genetic counselors are poised to become covered Medicare providers. In the section on coverage for multigene panels (itself a disappointment, vide infra), one of the criteria that must be met is “Pretest genetic counseling by a cancer genetics professional” defined as, among others, a Genetic Counselor certified by the American Board of Medical Genetics or the American Board of Genetic Counseling. Amen to that. This is a huge step forward for the genetic counseling profession and for patients covered by Medicare.  Note, though, that this “genetic counseling by a genetics professional” requirement is limited to patients who want multigene panel testing; it is not mentioned in the section on patients who undergo BRCA testing alone. Of course, patients who ask their providers about a multigene panel would need to be referred to genetics professionals. The LCD further points out that the Affordable Care Act mandates private insurers to provide no-out-of pocket cost coverage for genetic counseling and BRCA testing for eligible women.

The second major issue – and one that we should welcome but will undoubtedly  raises hackles among many genetic counselors – is that the coverage for genetic counseling excludes genetics professionals who are employed by a commercial laboratory. However, genetic counselors would be covered if  they “are employed by or contracted with a laboratory that is part of an Integrated Health System which routinely delivers health care services beyond just the laboratory itself.” In other words, a genetic counselor employed by, say, Ambry or GeneDx or Counsyl would not be covered but a genetic counselor who worked for, say, Baylor or the University of Washington would be covered. While we all want to deny that we would actually let conflict of interest color the care we provide, in fact conflict of interest could develop into a very serious threat to the integrity of the profession in the absence of clear-cut guidelines for lab-employed genetic counselors.

The third big change is that the new criteria include women who do not have a personal history of breast cancer but have a sufficiently concerning family history of cancer. Until now, only women diagnosed with breast or ovarian cancer were eligible for testing. The new criteria, based on NCCN guidelines, are quite broad, and besides breast and ovarian cancers some of the criteria also include pancreatic and prostate cancers. For example, as I interpret the LCD, testing would be covered for an unaffected woman if she has a first or second degree relative with breast cancer at any age and another relative with breast cancer diagnosed at 50 or younger; or if a first or second degree relative has breast cancer and there are two relatives diagnosed with pancreatic cancer or prostate cancer with Gleason score =7 (surely CMS means ≥ 7 ); or if a woman has a first or second degree relative with ovarian/fallopian tube/primary peritoneal cancer; or if a there is a first or second degree relative with pancreatic cancer or prostate cancer (Gleason score = 7) and there are two or more relatives with breast/ovarian/pancreatic/prostate cancer (Gleason = 7). In a further broadening of criteria, patients with pancreatic and prostate cancers would also be covered, provided they meet family history or ancestry criteria.

Critically, the guidelines for testing unaffected individuals specifically apply to unaffected adult women with a family history of cancer; there is no mention of  unaffected men. Thus, I assume that an unaffected male who otherwise meets family history criteria would not be covered. However, coverage is provided for men who have been diagnosed with breast cancer, and men who have been diagnosed with prostate/pancreatic cancer who meet family history criteria.

While I wholeheartedly support the expanded criteria, they are very, very complicated. It will require careful comparison of pedigrees with the new criteria; I suspect that many errors will unintentionally arise. Some patients who may have been told by their ordering provider that they might be covered will find out that in fact they don’t meet guidelines (hopefully through the careful checking by laboratories before testing is initiated). Other patients will be incorrectly told by the ordering provider that they are not eligible for coverage, resulting in an unfortunate lost opportunity for initiating cancer risk reduction strategies.

Another complication lies in the definition of “close blood relatives” which Medicare currently defines this as first, second, and third degree relatives. However, in the proposed LCD, various criteria apply sometimes to first and second degree relatives, and sometimes to third degree relatives. In other places, “close blood relative” is not defined. For example, under the first section titled “Personal History of Female Breast Cancer” the second criterion reads “Diagnosed at age 50 or younger with at least one close blood relative* with breast cancer at any age.” I may have missed it, but I could not find where the asterisked “close blood relative” was defined. Further complicating the matter are criteria that depend on Gleason scores for prostate cancer. Realistically, what patient is going to know Grandpa’s or Uncle Jack’s Gleason score, and if they died 20 years ago, how can the score be found? If a relative died of prostate cancer, there is a pretty good chance he had a high Gleason score but still definitive proof will be hard to unearth.

The fourth Big News Item is a limitation on coverage for multigene panels. Currently, I can get coverage for just about any multigene panel that included BRCA, as long as the patient met criteria for BRCA testing. The proposed guidelines, however, limit panel testing to situations where all of the genes on the panel are relevant to the patient’s personal and family history AND the individual meets NCCN guidelines for at least one other hereditary cancer syndrome such as Li-Fraumeni, Cowden, or Lynch. Thus, panels like Myriad’s myRisk, the University of Washington’s BROCA, or Gene Dx’s Comprehensive Cancer Panel would not be covered. Labs will need to do lots of rejiggering of their panels. For Myriad, the proposed guidelines would be an especially big hit since Myriad appears to be phasing out single gene testing and replacing all genetic testing with myRisk. Rubbing a little more salt into Myriad’s wound, the CMS guidelines state that BRCA CDx, the BRCA test intended for patients who are being considered for treatment with the PARP inhibitor Lynparza, will not be covered for patients who have already had BRCA testing.

No doubt this LCD will cause strong reactions, both pro and con. Genetic counselor input is critical. It is not a finalized document and we can play a key role in shaping the delivery of medical genetic services. The comment period is 6/17/2015 through 8/3/2015. Per the LCD, the Proposed Contact is Earl Berman, Attn Medical Review, Two Vantage Way, Nashville, TN 37228 or Earl.Berman@cgsadmin.com.

I may  have misinterpreted parts of the LCD so please call me out if I got something wrong. And share your thoughts about the proposed guidelines in the Comments section below.

* To get to the proposed LCD, click on the Accept button at the bottom of the link page, which will take you to the proposed guidelines.

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Guest Post: PPV Puffery? Sizing Up NIPT Statistics

by Katie Stoll and Heidi Lindh

Heidi and Katie are genetic counselors and both work with the newly established charitable nonprofit, the Genetic Support Foundation (twitter @GeneticSupport), geneticsupportfoundation.org.

The importance of the Positive Predictive value (PPV) in interpreting Noninvasive Prenatal Testing (NIPT) results is increasingly on the minds of providers as evidenced by frequent discussions, presentations, and publications on the topic. But what if, in an effort to make their lab look like the best lab, the NIPT PPV was overstated in marketing materials or even on test reports? And what if providers and patients believed this information without question or further investigation?

Until 2014, four labs (Sequenom, Verinata Health/Illumina, Ariosa and Natera) were the only companies in the United States that offered NIPT. Over the past year, we have seen a burgeoning of new labs offering their own branded NIPT tests. In some cases, the 4 original companies act as “pass-through” labs in which the testing is branded and advertised through a secondary lab however the sample is ultimately sent to the primary lab for analysis and interpretation. In other cases, referral labs have brought NIPT testing in-house, developing their own algorithms and reporting, such as the case for the InformaSeqTM test offered by LabCorp and Integrated Genetics. In a recently published marketing document, Illumina lists 16 laboratory “partners” that all offer a version of the Illumina NIPT. The other primary NIPT labs are also distributing their tests through other labs as well; Quest Diagnostics and the Mayo Clinic have been secondary labs for the Sequenom NIPT (Quest also has their own brand, the “Q-Natal Advanced”and Natera’s NIPT is available through GenPath and ARUP).

The growing number of laboratories that offer some version of NIPT presents a significant challenge for healthcare providers who are struggling to navigate the various testing options to determine what is in the best interest of their patients. The competitive commercial landscape and aggressive marketing of NIPT to both patients and providers can further confound clinical decision-making given the paucity of information available to providers that is not delivered with an angle aimed at selling the test.

NIPT Statistics in Marketing Materials

We have noted that multiple labs offering testing have promoted extraordinarily high positive predictive values (PPVs) in their marketing materials distributed over the past year and on their websites ^ and on laboratory test reports. These tables include information regarding PPV frequently reference data from the Illumina platform and VerifiTM methodology and a study by Futch et al. as the source.

 

Performance Data Presented in Marketing Brochures for NIPT
Condition PPV NPV Sensitivity Specificity
T21 0.994 0.999 >99.9% 99.8%
T18 0.910 0.999 97.4% 99.6%
T13 0.843 0.999 87.5% >99.9%

These figures (or slight variations thereof) have been observed in the marketing materials for multiple laboratories offering NIPT. These specific statistics were reproduced from an InformaSeq brochure and sample test reports available online

 

The PPVs reported in this table – being widely distributed on test reports and as educational information for providers – have NOT been demonstrated by the referenced study by Futch et al. or any published NIPT studies of which we are aware.

Of course, the PPV of a screening test depends on the prevalence of the condition in the population being screened. Using the sensitivity and specificity of testing accompanying these predictive value data in the same brochure, one could only derive PPV of >99% if the prevalence of Down syndrome in the screened population was 25% or 1 in 4 pregnancies, far higher than the a priori risk for the vast majority of women undergoing prenatal screening.

PPV = (sensitivity x prevalence) / ((sensitivity x prevalence) + (1 – specificity)(1 – prevalence))

.994 = (.999x.25)/((.999x.25) + (1-.998)(1-.25)

In contrast, if we utilize performance statistics provided by the laboratories, we calculate a PPV of 33% in a population with a prevalence of 1 in 1,000 (which is similar to the prevalence for women in their 20’s) and a PPV of 83% in a population with a prevalence of 1 in 100 (which is similar to the prevalence in women age 40).

The Futch Factor

The study by Futch and colleagues that is frequently cited in marketing materials for NIPT does not demonstrate the high PPVs that are referenced, although we suspect that these statistics were arrived at through a series of assumptions about the Futch data that we will attempt to outline.

This study reported that in a cohort of 5,974 pregnant women tested, there were 155 positive calls for T21, 66 positive calls for trisomy 18, and 19 positive calls for trisomy 13. In this published report, only a fraction of the positive NIPT results had confirmation of the fetal karyotype, 52/155 cases of Down syndrome (33.5%); 13/66 cases of trisomy 18 (19.7%); and 7/19 cases of trisomy 13 (53.8%). There was 1 case of Trisomy 21 that had a normal NIPT result (false negative result), however negative test results were not methodically followed-up, so the true false negative rate for the screened conditions is unknown.

In analyzing the data presented by Futch et al, for marketing materials to derive PPVs of >99% for Down syndrome, 91% for trisomy 18 and 84% for trisomy 13 would require that all of the positive calls WITHOUT follow-up by karyotype confirmation were true positives.

 

Outcomes data from Futch et al, 2013 and projected PPVs based on category inclusion or exclusion as true positive.
T21 T18 T13
NIPT Positive 155 66 19
Confirmed (karyotype or birth outcome) 52 13 7
Discordant (Unexplained NIPT results that do not match karyotype from a source or birth outcome) 1 6 3
No information (laboratory did not obtain any information on outcomes) 22 12 0
Pregnancy loss (miscarriage , demise or termination without karyotype) 7 5 2
Unconfirmed (no karyotype or birth outcome known but history of clinical findings suspicious of aneuploidy such as ultrasound findings or high-risk biochemical screening results ) 73 30 7
Total Positive NIPTs where follow-up karyotype not confirmed 102 47 9
High End PPV* 99.4 90.1 84.2
Low end PPV** 33.5 19.7 36.8

*High end PPV- It appears that marketing material PPVs are considering all categories, including confirmed, no information, pregnancy loss, and unconfirmed to be TRUE positives in determination of PPVs.

**Low end PPV- calculated considering all cases, which were not discordant to be false positive results. A minority of positive NIPT results were confirmed with birth outcome or fetal karyotype information.

 

Given that Futch et al. did not have confirmed fetal karyotype or birth outcome follow-up for the majority of positive calls, it seems at best unlikely, and at worst impossible, that all of these positive NIPT results were correctly called, rendering claims of such high PPVs in the marketing materials based on this assumption to be unfounded. On the other end of the spectrum, if the PPV was calculated to include the not-karyotyped/no-birth outcome information pregnancies as false positive, the assumed PPVs would be 33.5% for Down syndrome, 19.7% for trisomy 18 and 36.8% for trisomy 13. Since the study does not report follow-up karyotype for the majority of positive test results, the true PPV for these NIPTs test likely lies somewhere in-between the high end PPV and low end PPV, perhaps closer to the 40-45% (for T18 and T21) previously reported in another Illumina sponsored study.

While the PPV of NIPT for Down syndrome, trisomy 18 and trisomy 13 exceeds that of traditional biochemical screening, no studies have demonstrated test performance as high as those presented in many of the PPV/NPV tables that are being provided to healthcare providers in marketing materials and, in some cases, on test reports.

A Call For Truth In Advertising And In Test Reporting

Honest communication about test performance metrics must be available to providers so that they can provide accurate counseling to patients making critical decisions about their pregnancies. While most labs do state that NIPTs are screening tests and that confirmatory testing of positive results is recommended, it is not surprising that providers and patients are having difficulty appreciating the possibility of false positive results when the laboratories are incorrectly reporting positive predictive values that exceed 99%. The consequences of relying on lab-developed materials rather than a careful analysis of the available literature are significant. There are reports of patients terminating pregnancies based on NIPT results alone. It is not surprising that some women choose not to pursue diagnostic testing to confirm abnormal NIPT results given the very high stated predictive value.

It is imperative that we recognize not only the potential benefits of these new technologies but also their risks and limitations. Testing companies are primarily responsible to their shareholders and investors, so information provided by companies about their products is largely aimed at increasing test uptake. Professional societies need to call for independent data and federal funds need to be made available to support independent research related to NIPT. Policies and best practices cannot arise from the industry-influenced studies that are currently available. While some regulatory oversight of marketing materials will likely be necessary, we urge the laboratories to consider their marketing approach and how it is affecting patients and providers. If laboratories want to truly partner with patients and providers, they need to provide accurate and straight-forward information to limit provider liability and likewise, help patients avoid making life-changing decisions based on inaccurate and/or confusing information related to test performance. As a medical profession can we come together and make this change without regulatory oversight? Now that would be a medical breakthrough.

^ – Notably, Counsyl has also recently produced a table that provides more accurate estimates of their NIPT predictive values

 

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Great Expectorations – A NextGenetic Counseling Model?

One of the few things we can all agree on is that there are few things we can all agree on. – Quote attributed to Yours Truly.

Genetic counselors have an uncanny knack for being in the right historical time and place. We have combined this historical luck with an almost naive courage in taking professional risks and parlayed them into a phenomenal growth rate for the profession. As soon as any new genetic testing technology was barely in the womb – amniocentesis, CVS, maternal serum screening, hereditary cancer testing, cardiac genetics, whole exome/genome sequencing – genetic counselors were there to gestate it and deliver it into medical practice.  We have frequently re-invented ourselves to meet the needs created by new technologies – cardiac counselors, neurogenetic counselors, oncogenetic counselors, whole exome counselors, lab counselors. But one area where we may have stumbled a bit is direct to consumer (DTC) genetic testing. How do genetic counselors fit into a service that wants to bypass genetic counseling and that so far has been of dubious clinical value?

In our e-tail world where you can purchase just about anything online, some version of genetic testing/counseling that bypasses the traditional clinician-in-the-clinic model seems inevitable. Indeed, Color Genomics, a biotech start-up backed by players in the genetics and tech communities, is now offering what is essentially a hybrid of the traditional genetic counseling paradigm with DTC testing for hereditary breast cancer risk assessment. Tests are ordered and interpreted by a physician “either your own or one designated by Color.” Patients request a test kit directly from the lab, provide a saliva sample and then mail the kit back to the lab. The 19 gene panel includes BRCA1/2 along with the usual list of genetic suspects – PALB2, CHEK2, etc. The same tests that we offer to patients in our clinics for thousands of dollars along with the hassles of dealing with insurers and the complexities of scheduling and paying for a genetic counseling appointment can now be had with a spit sample provided from the convenience of your home. No muss, no fuss, never needs ironing – and at the shockingly low cost of $249.

For many patients, the hardest part of genetic testing is actually making it into our offices. It takes a big emotional investment to make an appointment that might involve psychologically sensitive and scary information, several rounds of phone tag with the scheduler, figuring out an appointment time that fits into in busy family/work schedules, determining insurance coverage, and then having to deal with multiple appointments at institutions that require additional visits for a blood draw and for results disclosure. Not uncommonly, my patients’ medical records often indicate that the referring provider had recommended genetic counseling many times over several years. Nobody comes to see us until they are absolutely ready to do make the commitment to do so. The Color Genomics model, by comparison, makes the traditional approach look positively byzantine.

Sure, we want assurances from Color Genomics on technical details of the test such as depth of coverage, ability to detect the widest possible range of mutations,  follow-up on variants, etc. And we might question the success potential  of a business model that offers a test at one tenth or less  than what most competitors are charging. But this is a medically and financially savvy group, and I am willing to bet that they thoroughly addressed these issues before they launched this product. We can probably expect to see similar genetic testing start-ups in other areas of genetic testing.

With an estimated turn-around time of 6-12 weeks, this test is not for cancer patients looking to make a surgical decision in a few weeks. And, interestingly, $249 is more than many of my patients typically pay for BRCA or multigene panels. Because most of my patients – especially those who are being treated for cancer – have already met their deductibles, their out-of-pocket costs for genetic testing are minimal, assuming they meet their insurers’ criteria for coverage for genetic testing. For now, at least, Color Genomics might appeal to patients who have large out-of-pocket expenses, or those who do not want to go through the “hassle” of face-to-face genetic counseling, or lack insurance coverage for genetic testing/counseling, or who do not meet their insurers’ criteria for coverage for genetic testing, or patients whose insurers don’t cover multigene panels. More to the business point, Color Genomics’ mission is Democratizing access to high-quality genetic information, consistent with the recommendations of Dr. Mary-Claire King, one of the company’s advisors, for all women to undergo genetic testing for hereditary cancer risk assessment (me, I am not a big fan of universal screening for anything, but that’s probably just one more area where I am in the decided minority, and I wince at the use of the word “democratizing”). Of course, if insurers get wind of this inexpensive pricing and require samples be sent to low cost labs, then there will be even less of an incentive for patients to go through the traditional genetic counseling/testing model (currently Color Genomics does not bill insurers).

I can hear the protests about the problems that will arise when genetic counselors are not involved face-to-face in pre-test genetic counseling. The wrong relative will be tested, inaccurate interpretations by patients and care providers, increased patient anxiety, inappropriate under- or over-utilization of high risk screening and surgery. But we largely have only ourselves to blame. With a few exceptions and some small case series, the genetic counseling community has done little research to prove that meeting with a genetic counselor prior to genetic testing makes for comparatively better health or psychosocial outcomes. And, at least for now, the early studies on DTC testing have so far concluded that most of our concerns about patient anxiety, inaccurate test interpretation, etc. are mostly unfounded (yes, I know we all have a story to tell that suggests otherwise but for now they are only stories).

But whether we like it or not, one form or another of this new genetic counseling/testing model is probably here to stay. In fact, I will venture the prediction that most genetic testing for cancer and other common conditions will eventually go around rather than through clinic-based genetic counselors. It is convenient for patients, saves money (until we can prove otherwise), and may be every bit as good as we are in educating patients. Private labs, unlike most clinics and hospitals, have the great good sense to invest the resources in developing highly readable websites that include explanations, information, and graphics to help patients better understand their results (personally, I think that lab-provided education can subtly bias the information to make disease risks seem higher and interventions more beneficial, but that is a topic for another day).

So maybe it is time for genetic counselors to again re-invent ourselves. Perhaps the classic model of pre-test counseling is mired in twentieth century ethical and technological paradigms. New employment opportunities and roles for genetic counselors in labs will develop and labs may eventually become the primary employers of genetic counselors. We will have to reconsider how genetic testing is arranged and managed in our clinics. And most critically, we will need to develop an ethical framework for delivering these services. Opportunities for conscious and unconscious conflicts of interest abound in all areas of genetic counseling, but perhaps most conspicuously in laboratory employment. Will we be swallowed by the business community and its emphasis on profits à la Milton Friedman, the influential economist? Will we become consciously or unconsciously less critical of the downsides and limits of genetic testing when profits and salaries depend on testing volumes? What are ethical and unethical behaviors for genetic counselors in these settings? Will psychosocial issues fall by the wayside? Frankly addressing these questions will make us uncomfortable, but no one ever said that genetic counseling would be an easy profession.

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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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THE TIDE HAS COME IN AND THE LINE IN THE SAND IS GONE: DECISION TIME ON HUMAN GERMLINE ENGINEERING

For decades we have speculated about what it might mean to be able to change the genes of an embryo. Not to be able to treat disease, or to prevent disease, or even to generate extra embryos in order to pick the best of the litter, but to get in there, to insert ourselves into the process by adding variation that nature in its evolutionary wisdom, has not made available. Germline engineering, it is called by some. Tampering with humanity, by others. Playing God.

The language betrays an unease that is both non-specific and widespread. The stakes are enormous. If we can alter a child’s DNA to make the child smarter, stronger, less susceptible to cancer or heart disease, why would we not do it? There are a multitude of answers, but perhaps the most compelling one is this: we don’t know what we don’t know. A generation raised on nuclear fears does not trust the intentions of man; a generation facing the fallout of climate change has no faith in humanity’s ability to foresee long-term consequences.

Let’s spill a little ink on some of the other qualms as well. Expensive genetic technology will exacerbate inequality in a world where the haves and the have-nots are increasingly at odds. It will make life harder for those who are not helped, the ultimate children left behind. It will enshrine the prejudices of those who control the technology. “What do you see?” I ask my students. “Taller,” they say. “Smarter.” “Blond hair and blue eyes.”

“Heterosexual,” says one boy, with a sad shrug.

Anxieties about the personal and social costs of tampering with humanity are as old as Icarus, who flew too close to the sun on his homemade wings. Inchoate fears have accompanied every step forward in genetics. We want better children, “ said Leon Kass, in a Washington Post editorial in 2003, “but not by turning procreation into manufacture or by altering their brains to give them an edge over their peers. We want to perform better in the activities of life–but not by becoming mere creatures of our chemists or by turning ourselves into tools designed to win and achieve in inhuman ways.” Evidence from polls suggests that society agrees with him in theory, but does that mean individuals would be willing to forego perceived advantages for their own children? Does it mean that they should?

In response to threats real and perceived, genetics has lived for decades with germline engineering as our line in the sand. Gene therapy for the individual, but no changes to DNA that will be passed along to successive generations. Frankly, this was an easy point to concede, when no credible means of accomplishing the goal safely was in view. But out there, in the absence of regulation, in the unconstrained global marketplace, in the power of what might someday be possible, the question lurked, not answered, just deferred.

Last month, twin editorials in Nature and Science served notice that the time has come to make some hard decisions. Things long envisioned as a part of our future are suddenly edging into the present, thanks to the stunning success of the CRISPR/Cas9 system of DNA editing.   A recent article by Antonio Regalado in the MIT Technology Review posits that we are teetering on the cusp of successful human germline alteration, and that in fact we may already be there (the article says that papers claiming successful embryo modification have been submitted to journals, but no evidence is in print — yet). In response, a veritable who’s-who of the genetics world (including Jennifer Doudna, a co-inventor of CRISPR) have called for a time out – a moratorium on human germline research while the world considers whether or not the technology – and the technologists – are ready for prime time.

Although the array of voices joining in this chorus are impressive, don’t overestimate this show of unanimity. The arguments in favor of a pause are diverse, and don’t represent the same long-term goals. There are three major types of arguments made against proceeding with germline manipulation, often conflated, and it is important to sort them out. The first line of argument concerns safety alone. Some signatories, such as Harvard’s George Church, see the ‘pause’ as simply an acknowledgment that safety and efficacy data are not yet available. Others are anxious to avoid the threat of a public outcry that could complicate the use of CRISPR/Cas9 for less controversial uses.

Essentially everyone agrees that if it isn’t safe enough you can’t ethically proceed, although defining ‘safe enough’ could be contentious.

A second set of arguments reflects concerns that some practices, though perhaps not dangerous themselves, will lead us in the direction of something more fraught. These slippery slope arguments are consistently employed in appeals to a popular audience, in part because they help make complicated issues accessible, and in part because they allow those making the argument free rein to speculate on the most click-worthy of potential scenarios. “The technology could be used to create, say, a unicorn, or a pig with wings..” suggests a Daily Beast article entitled, New DNA Tech: Creating Unicorns and Curing Cancer For Real?

For realz. And you wonder why I don’t care for slippery slope arguments.

And then there are those who are concerned about the potential negative consequences of the technology itself. Those voices too are a part of the quorum calling for a moratorium.   One Science co-author, stem cell researcher George Q. Daley, told the New York Times that the ability to modify our germline “raises enormous peril for humanity.” The Times quotes lead author and Nobel Laureate David Baltimore as saying “I personally think we are just not smart enough — and won’t be for a very long time — to feel comfortable about the consequences of changing heredity, even in a single individual.”

So presuming the world agrees to a pause – and presuming what Baltimore calls our “moral authority” is a thing in science, because it sure as hell isn’t in other spheres of would-be influence – what are we to do with the downtime? Editorials across the board call for a public discussion, so let’s start right here. I’ll go first. Four points:

  1. The tide has come in and the line in the sand is gone.

I don’t say that flippantly, because I understand the allure of a line. A line means you don’t have to think everything through every time. It suggests someone has an answer. It says some things are right, and some things are wrong, and somebody has gone to the trouble of figuring out which are which. But sad to say, it isn’t so. We don’t know. There’s too much at stake to arbitrarily rule out whole fields of research based on the need to avoid existential distress.

All the slopes on which we practice are slippery. Subtleties matter. Details matter. We are going to have to figure these things out case by case. Accept this and move on.

  1. Change has its price, and the good comes along with the bad.

Articulating a risk, or describing a negative consequence, is not adequate evidence in and of itself that something is bad and we should not do it. Vaccinations and IVF do have negative consequences for some individuals. There are risks. Those risks are well outweighed by the benefits. This is inarguable (do you hear me, Internet? Inarguable). Conversely, the fact that a subset of humanity can be helped by some practice is not in itself an argument that it must be allowed to move forward. There are times when individual’s best interests have to take a back seat to the needs of society. In China, where sex selection is rampant, the number of women ‘missing’ in the past 25 years is equal to the entire female population of the United States. Ask them how that’s working out.

Our debates are filled with people talking at one another, one side telling us why we should be afraid, and the other pointing out that it is a terrible thing to stand in the way of progress when people are in pain. The thing is, they are both right. Don’t imagine that there is some secret formula that will allow us to have the benefits of new technology and not experience any negative consequences.

  1. Realistically, we don’t have the option to stop moving forward.

When the cave people discovered fire, do you think perhaps one of them pointed out the danger? I mean, this stuff burns. Our great-great grandchildren will live in a different century. We may have something to say about what that world looks like, but we will not have the option of handing them a world that looks like ours, and neither did our ancestors.

  1. Consensus, not government regulation, will govern practice.

 Sticking out your hand and saying no is not a useful response. Suggesting regulation without acknowledging who will be doing the regulating is not a useful response. In the end, in a world where all the players can vote with their feet, consensus and not regulation will dictate behavior once the whistle blows and the timeout is over.

What do you think? Please join the conversation.

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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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Guest Post: Starting a discussion on severity and the merits of carrier screening

By Gabriel Lazarin, MS, CGC

Gabriel is the Director of Genetic Counselors at Counsyl, a laboratory that offers expanded carrier screening.

Discussions about carrier screening inevitably center around disease severity. Is the disease severe enough that it is worth offering screening? Who defines severity and then who decides whether that category of disease severity merits population screening?

These questions are easily recognized, but subjectively answered. Both sides of a complicated equation must be balanced. Physicians and public health officials desire screening protocols that address pressing medical concerns knowing that any screening program comes with costs, financial and otherwise. Parents-to-be have an interest in knowing what daily challenges they may face. Unsurprisingly, these sometimes competing interests result in conflicting perspectives on disease severity.

The focus on severity has increased as carrier screening panels have expanded the list of potential diseases for which a person may be screened. Despite the lack of consensus on definition of the word, severity is nonetheless cited in literature and referenced in conversations about carrier screening. In the ACMG’s statement on expanded carrier screening, the first criterion for consideration is, “Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having prenatal diagnosis…” Setting aside for the moment the stipulation that prenatal diagnosis should be considered (I, and many prenatal GCs, have many times encountered the patient that changes decisions once a hypothetical scenario becomes real), a paraphrase is that a disease should be severe enough so as to be “worth” screening.

The ACMG statement references severity again, saying, “The inclusion of disorders…associated with a mild phenotype should be optional…” A physician offering the test (and the laboratory supplying it) can reasonably question which specific disorders have a “mild” phenotype. Is hearing loss a mild phenotype, and who has the authority to make that decision? The recent joint statement on expanded carrier screening notably excludes commentary on severity, which further highlights the difficulties of its use in panel design. 

In December, PLoS ONE published a study conducted by myself and others at Counsyl that is a first attempt at defining severity. ACMG provided the backbone of this approach: severity was one characteristic assessed when developing a universal newborn screening panel recommendation. Nearly 300 people participated in this significant endeavor, including at least 3 experts for every disease. While successful, replicating that process — laboratories have been updating their screening panels at least once a year — is prohibitively labor-intensive. We aimed for a process that was easily replicated and did not require convening experts of rare diseases.

Our results validate an algorithm that incorporates easily identifiable characteristics such as shortened lifespan or sensory impairment, and places that disease into one of four categories (also derived from ACMG): mild, moderate, severe, and profound. This avails the following advantages: more consistency among laboratories for selection and presentation of screening panels, and a common vocabulary among providers for describing diseases (like the singular language offered by a tumor staging system). Furthermore, the survey was completed in just under 6 minutes on average, making it much more practical for frequent use.

The study population included GCs and physicians, the majority working in reproductive settings. We intentionally did not attempt to identify experts on the diseases surveyed. Instead, commonly known diseases (e.g., cystic fibrosis) and lesser-known diseases (Bardet-Biedl syndrome) were concurrently assessed. All were evaluated in a consistent manner, indicating that familiarity does not affect severity categorization. In addition, the algorithm is completed by identification of disease characteristics not disease names. Even if an evaluator was not familiar with homocystinuria per se, she would certainly understand a list of its characteristics, such as intellectual disability and shortened life expectancy.

So, what’s next? A status check on current expanded screening offerings seems reasonable – Counsyl GCs applied the algorithm to 63 diseases that are common to three commonly-used commercial panels and determined that 25 have profound severity (e.g., Herlitz junctional epidermolysis bullosa, Tay-Sachs disease and metachromatic leukodystrophy) and 38 are severe (cystic fibrosis, ataxia telangiectasia, primary hyperoxaluria). All being in the two most impactful categories, many providers would likely agree on their inclusions.

However, another reasonable next step is to identify and reconcile differences that might be discovered by surveying the reproductive-age patient population. We, the medical community, also need to determine the desired aims of a screening program and apply those aims with consistency and objectivity. It could very well be that expectant parents and obstetricians agree with the ACMG’s statement that interest in prenatal diagnosis should be an influencing factor in a screening panel (what patients want has historically been an absent consideration in constructing guidelines).

But what about those who are not yet pregnant? Without the pressures of pregnancy, is it reasonable to allow the opportunity to consider a wider range of diseases? Obstetricians and GCs are more accepting of pre-pregnancy expanded screening. In pregnant women, decision-making can be influenced by interests in reducing stress and delaying information until after birth in order to reduce anxiety. A carrier screening protocol should serve the interests of pregnant and non-pregnant women, perhaps utilizing different severity thresholds for each scenario.

Through this study and blog post, I hope to open the conversation about what diseases should be screened, who should be screened for them and when that screening should happen. Without a standardized, objective vernacular, these discussions are colored by personal beliefs (which may not align with patient beliefs) and assumptive interpretations of important criteria. This is but a first step that needs to involve all stakeholders – providers, patients and professional societies. By first developing this standard language, we can begin this important discussion.

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