Author Archives: Katie Stoll

by Katie Stoll | September 4, 2018 · 3:10 PM

Expanded Carrier Sequencing: Would You Rather?

On summer road trips, my kids loves to play a game Would you rather? For instance, would you rather eat a bowl of spaghetti noodles without sauce or a bowl of spaghetti sauce without noodles? Would you rather have a unicorn horn or a squirrel tail?

In the spirit of summer road trips and the holiday weekend, I’d like to play a game of Would you rather? that only genetic counselors can appreciate.

This is a trade off we have to make with carrier screening.

Carrier screening programs intended for the general population as supported by the practice guidelines put forth by our professional societies tend to favor Option B. The reason being that more harm than good may result when providing information that is uncertain or ambiguous, especially in the context of reproductive decision making.

These days however, Option A is becoming increasingly common. Although at odds with society recommendations, which generally recommend a more targeted approach, the use of expanded carrier screening (ECS) panels that utilize sequencing are being more commonly accepted into practice with labs often claiming that more prenatal testing is better.

But is more really better?

In theory, it makes sense to offer screening that provides as much information as possible. However, we know that what makes sense in theory does not necessarily lead to good medical practice. And there are warning tales of screening programs that were initiated with good intention but led to unfortunate, unintended consequences.

Consider the early days of carrier screening for cystic fibrosis (CF) as an example. After years of careful study and deliberation, in 2002 experts from the American College of Medical Genetics together with American College of Obstetricians and Gynecologists published recommendations for use a panel of 25 mutations in the CFTR gene. However this initial panel was revised in 2004 when it became evident that one of the originally defined mutations, p.I148T (c.443TC) was in fact a benign polymorphism.

On a panel of just 25 mutations, in a well known gene, for a well defined condition, after years of critical expert evaluation, a mutation that was initially included on a panel as causative of disease was eventually determined not not be, only after being put into practice. It is likely that Option A was a reality for some families in the early days of CF carrier screening.

Now consider that with expanded carrier screening panels that increasingly perform whole exon sequencing, often of >100 genes, one can imagine that many of the mutations being called with carrier screening are not disease causing. I believe that Option A will become much more frequent with greater utilization of carrier screening panels that use sequencing.

And in addition to the possibility of incorrect variant classification, there is also a concern for increased false positive results as carrier screening expands. A reality with any screening test is that the rarer the condition, the more likely a positive result is a false positive result.

When questions arise regarding interpretation of variants on ECS panels, the labs often respond that they follow the ACMG Standards and Guidelines for Interpretation of Sequence Variants.

But here’s the thing, these guidelines were not developed for carrier screening in a healthy population. To quote the ACMG document: “The following approach to evaluating evidence for a variant is intended for interpretation of variants observed in patients with suspected inherited (primarily Mendelian) disorders in a clinical diagnostic laboratory setting.”

The authors of the ACMG Standards also warn: “Caution must be exercised when using these guidelines to evaluate variants in healthy or asymptomatic individuals or to interpret incidental findings unrelated to the primary indication for testing. In these cases the likelihood of any identified variant being pathogenic may be far less than when performing disease-targeted testing. As such, the required evidence to call a variant pathogenic should be higher, and extra caution should be exercised. In addition, the predicted penetrance of pathogenic variants found in the absence of a phenotype or family history may be far less than predicted based on historical data from patients ascertained as having disease.”

As genetic counselors we are trusted to advise patients of this information, and knowing that such information is used to make life changing reproductive decisions (i.e utilizing prenatal diagnosis, pregnancy termination, undergoing assisted reproductive technologies and preimplantation genetic diagnosis, or deciding not to have biological children) we know how important it is that the information we provide patients is unambiguous, accurate, and evidenced based.

However, we seem to be accepting the move to expanded carrier screening panels using sequencing rather than more targeted genotyping panels with little question about whether this is the right thing to do.

While many have accepted that expanded carrier screening with sequence analysis is the new normal, we should note that despite the marketing spin by the companies that this method of testing is superior, there are still no prospective studies that demonstrate clinical validity and utility of expanded carrier screening panels with sequencing. And guidance from our professional societies recommends a more limited approach to carrier screening.

While labs promote certain conditions included on their carrier screens as “recommended” by the ACMG and ACOG, they fail to acknowledge that those professional societies specifically advise against whole exon sequencing, and instead recommend a more targeted approach that evaluates, and reports on only well characterized mutations.

From the ACMG Position Statement on Prenatal/Preconception Carrier Screening (2013): “There must be validated clinical association between the mutation(s) detected and the severity of the disorder.” And more recently, from the ACOG Committee Opinion 691 on Carrier Screening for Genetic Conditions (2017): “Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening.”

Who should decide which test is best? The testing laboratories? The professional medical organizations? Patients?

It seems that for now, that the laboratories are steering this ship. Despite the lack of evidence proving benefit and many cautions against it, several labs have sunsetted genotyping panels and have moved exclusively to sequencing, for what seems to be an ever growing number of rare conditions. It is becoming increasingly difficult for clinicians to follow the guideline recommendations when ordering tests for patients and we seem to be quickly entering a time where Option B is not an option at all.

It should not come as a surprise that the labs are pushing this new expanded testing as there is an incentive for labs to use sequencing over genotyping from a business perspective.

Sequencing genes rather than using a defined mutation panel allows for labs to boast of a higher detection of carriers, thus provides bragging rights for their marketing materials. One lab highlights on their website that their test identifies “30% more pregnancies affected with cystic fibrosis or spinal muscular atrophy” when compared to the ACMG and ACOG recommended panel. What is omitted on their website is that for some of the mutations identified, we do not yet have definitive information about disease causation or phenotype. And thus we are asking patients to make reproductive decisions based on uncertain information.

Another compelling reason for the labs to expand to sequencing is that detecting more mutations in the patient begets more testing of their partners. And more testing is the name of the game with laboratories that aim to increase test sales. Understandably that is their goal as it should be, we need labs to sell test in order to stay in business and provide a needed service for patients and providers. That said, lab sales and profits should not be driving best practices for patient care.

While more may seem better in some situations, this notion should be especially scrutinized in the area of reproductive carrier screening. As the professionals that are trusted to interpret these tests results and help patients understand this information in the context of their own lives, we need evidence beyond modeled hypothetical disease risk to demonstrate that these expanded tests will truly benefit pregnancy outcomes. As has been discussed on the DNA Exchange in a prior post by Bob Resta, positive change to do best for our patients in this area will require work from multiple parties. Labs should put the brakes on with regards to marketing new tests and step back while independently funded research assesses the relative harms and benefits of testing. Governments need to fund such research. And clinicians need to critically evaluate the testing that is offered to patients, especially when unproven testing strategies are being introduced and promoted that may create more harm than good.

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by Katie Stoll | May 10, 2018 · 1:39 PM

DTC: Direct to Children?

Last week Phil Rogers, of Chicago NBC News reported that he submitted a DNA sample from his dog, Baily, to the laboratory, Orig3n for analysis. This made headlines because a test report was issued on his dog for a test that was designed and marketed for humans. In follow-up to the story, Orig3n spokesperson, Karmen Conrad stated that, “…since October Orig3n has acquired a CLIA Certified laboratory and upon hearing about this issue has implemented controls to assure that nefarious samples such as this are rejected from further processing. We are sorry there was an error in reporting this one particular sample.”

I know firsthand that Phil’s experience was not an isolated case.* Last December, I submitted my dog Ginger’s DNA swab for the “Bloom Child Development” test, also by Orig3n, and I also received a completed test report. According to Orig3n’s website, “the Child Development DNA Test is a gene profile that will start you and your child on the path to lifelong discovery. From fitness to natural abilities for language and learning, the results help you get to know your child even better.”

Nothing was flagged as out of the ordinary with Ginger’s DNA. From the looks of her genetic test report, Ginger appears to be a pretty average kid in terms of her intellectual and athletic potential.

samginger

* Pictured on the left is Ginger. As you can see from the grey temples of my canine child, Ginger is safely over the requisite 13 years of age. On the right is my colleague’s dog, Sam, who also submitted a sample to Orig3n for the “Superhero” test. Sam also received a complete test report. According to Orig3n, Sam is likely to be good at endurance activities such as triathlons.

Genetic testing from the kitchen sink

This brings me to the second part of my experiment which proved to be much more troubling. It seemed plausible to me, given the homology between human and canine genetics, that the lab could have obtained results for at least some of the SNPs on their panel with Ginger’s sample. So, I decided to try the Bloom Childhood Development kit again, but this time I sent a blank. Using gloved hands, I carefully removed the swap from the sterile envelope and quickly ran it under the tap water of my kitchen sink, packaged it, and mailed it to the lab. In less than two weeks, I received a report for my imaginary tap water child. Like Ginger’s report, the results for the water sample was a 35-page report that varied at six of the 24 SNPs from Ginger’s results. But a much more disheartening difference between Ginger’s result and the water sample was that the report on the water sample was signed out by a DNA Laboratory Director, PhD Geneticist and fellow of a major American genetics organization.

This is worth repeating – a boarded geneticist signed out a report on a genetic test promising to predict the athletic and learning abilities of a child, from a sample of tap water.

Of the many tests offerings available through Orig3n, I chose the Bloom test in particular because I am deeply concerned that this test encourages parents to send in DNA samples from their children. I sent away for this test because I wanted to see for myself if there was a consent form or written information included with the test kit beyond what I could find online to caution consumers about the potential risks and limitations of this testing. Not surprisingly, there was nothing of the sort. Just instructions on how to obtain the sample and a simple postcard asking for a name, email and phone number.

Children are a target market for these tests

To me, the most disturbing part of the story is not doggie DNA but rather that children are the target for this and others tests like it, thereby compromising individual autonomy and privacy of genetic information. Regulatory gaps allow labs to boast of their CLIA Certification, which should provide some assurance of analytical validity, but may only serve to give an illusion of credibility. There are serious ethical concerns with this shift in “personal genomics” and allowing these unethical practices to go unchecked risks undermining the legitimacy of medical genetics.

Through social media, Amazon.com, and promotional events, companies are targeting parents of young children. Even Readers Digest gave the Bloom test a plug. This company encourages people to submit their children’s saliva sample to gain information about their health, “enlightenment” and fitness information. While their Terms of Service and Privacy Policy say the testing is not directed at kids under 13 years of age, the child pictured on the test kit box appears to be years away from double digits. The Orig3n twitter feed is full of cute pictures of preschool age children. And this Instagram post on the Orig3n sight with a mom blogger proudly swabbing her infant and toddler’s cheeks raised my genetic counselor anxiety through the roof.

Since genetic testing first became possible, the medical community has carefully deliberated the ethical ramifications of genetic testing in children and has recommended caution about how and for whom these tests should be used. Generally, it is held that a child’s autonomy and privacy should be protected when it comes to their genetic information. Unless the results could change medical management towards a better health outcome for the child, genetic testing of children is considered ill-advised. One can imagine the unintended consequences that may result from the use of these tests. It is not unfathomable that parents with great faith in the “science” of this technology may use results to determine how to allocate attention and resources in the family, investing more in one child or another based on the genetic results that may inaccurately suggest differences in intellectual or athletic promise among siblings. I believe that parents that are using these tests genuinely want all of the best for their children. They are seeking out these tests with the goal to give their kids the best possible advantage for their gifts and talents.

That being said, it is very difficult for me to imagine how such information could be beneficial to families and very easy for me to imagine the harms of growing up in a family guided by the results from a DTC test.

And what about privacy? It feels incredibly wrong to me that through no decision of their own, the DNA samples of many children are now in the hands of corporations to be bought and sold. We can only begin to imagine the possible unintended ramifications of this for the future, but only need to look as far as the recent Facebook news to get some ideas of what may be possible.

And while Orig3n may be the laboratory that is most direct in targeting children, it is not the only lab allowing for casual genetic testing of minors. Many people are sending in their kid’s samples to labs such as 23andMe, and in some cases inputting the raw data into 3^rd party applications that provide an output of information related to possible mutations in genes for adult onset disorders such as cancer susceptibility. Many of these results are false positives, but that is a story for another day.

Now genetic counselors are seeing patients for consultation on raw data of DTC tests that indicate the presence of mutations associated with Lynch syndrome and other genetic cancer susceptibility in young children. Historically, genetic counselors have taken great care in working with families to convey the potential implications of testing of children for adult onset conditions. Now, thanks to DTC testing, children everywhere are being tested for any number of genetic conditions, without counseling and without consent.

Gaps in regulation allow opportunistic genetic testing labs to operate and risk delegitimizing the field as a whole

This is not the first time that Orig3n has been in the news. Many may remember the planned “DNA Day” to be held at the Baltimore Raven’s game in 2017. Maryland shut this event down due to regulatory concerns, one of which was the fact that Orig3n was not CLIA Certified. The company remedied this problem late last year through their acquisition of Interleukin Genetics, a CLIA Certified laboratory that is now apparently the site where Orig3n processes their DNA samples. Many DTC labs tout their CLIA certified lab as a symbol of quality. It is one measure, but CMS’s oversight of labs under CLIA is quite limited. And from the tap water experiment, I am not so confident that CLIA certification provides much assurance of analytical validity.

The lines between clinical and nonclinical labs are increasingly blurred. With lack of transparency in lab practices and enormous gaps in regulation, the ability to confidently assess lab quality is becoming impossibly difficult, even for genetics professionals. It is our responsibility, as part of the medical genetics community, to take a close and critical look at how genetic testing is developing, to shine a light on unethical practices, and push for regulatory standards that will better ensure integrity in the field of genetics. Our patients deserve nothing less.

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by Katie Stoll | March 26, 2018 · 12:50 PM

The Hidden Costs of “Free” Genetic Counseling

A Guest Post by Eleanor Griffith, MS, CGC

Eleanor is the founder of Grey Genetics, a telehealth genetic counseling and consulting company. Find Eleanor on twitter @elo81.

A lot of genetic testing companies are now offering genetic counseling along with genetic testing. That’s great, right? Great to see genetic testing companies hiring genetic counselors. Great for patients because it expands access to genetic counseling services to patients who wouldn’t otherwise receive genetic counseling.

Or actually, maybe not so great. Concerns related to conflicts of interest have been discussed on the DNA Exchange and elsewhere and are worth discussing further and at length. For starters, see here, here, and here.

But my gripe is that when a lab offers “free” genetic counseling—it’s not really free. The cost is just hidden, bundled into the cost of the test. Hiding the true cost of genetic counseling in turn diminishes the perceived value of genetic counseling services.

Genetic counselors providing “free” genetic counseling get paid for their work. And they should. But the amount that it actually costs to provide genetic counseling vs. the amount that it costs to run a genetic test is not transparent—not to the patient, not to the physician, and not to the insurance company—which may or may not cover “genetic counseling.” Or may or may not realize that they do, in fact, cover the cost of some sort of genetic counseling(-ish) services by covering the cost of the test.

From a business perspective, for genetic testing labs, “free genetic counseling” is a no-brainer. It’s a big selling point and increases the odds that a healthcare provider will keep sending tests to the laboratory that is able to meet the very real counseling needs of their practice. As long as laws and regulations allow it, I don’t see this changing.

If the recognized product is the genetic test, and the main (or only) source of revenue for genetic testing labs is insurance reimbursement or out-of-pocket payments from patients, then the salaries of genetic counselors working for genetic testing laboratories are basically being paid by insurers + patients. If you follow my logic, this means that insurers will cover and patients do in fact pay for the (hidden) cost of lab-based genetic counseling, bundled into the cost of genetic testing. But insurers often don’t cover the cost of independent genetic counseling. Conflict of interest aside, this strikes me as ridiculous.

Away from the morass of insurance, patients and consumers of healthcare are being trained to see price tags attached to direct-to-consumer genetic testing products of dubious value, while genetic counseling is “free with purchase!” Even for clinical genetic tests ordered through physicians, self-pay prices are becoming more accessible. The logic, of course, is that labs will have a high enough volume of tests to scale and still make as much or more of a profit from testing…. Genetic counseling, however, cannot scale in the same way. This is why widgets get cheaper and cheaper while the cost of most professional services that require advanced degrees and involve working with clients one-on-one—lawyers, doctors, psychologists, financial consultants—remains relatively high.

While building up my private practice, I work part-time for an agency offering “free” genetic counseling to patients who respond to a quiz on facebook. I love it and I hate it.

I love it because I speak with high-risk patients who have never been referred to genetic counseling in a traditional way—many of whom have never heard of the BRCA genes. Patients who are interested in going forward with testing receive a copy of my consult note (yep, and a test kit) to take to their healthcare provider. Those who decline testing still receive a consult note with a copy of their family history and are encouraged to share it with their healthcare provider. Their healthcare provider has the option of including my name on the test requisition form so that I can receive and review results with their patient. Initially, I’m scheduled for an hour with each patient. If the patient needs more time to gather family history or to speak with someone in the family who would be a more appropriate candidate for testing—no problem, I just schedule her for a second call. I’m connecting with patients who would otherwise never have known of the option of genetic testing, would never have guessed that their insurance would cover the cost of testing for them, and had no idea of the impact it could have on their medical management and the value it could provide to their family members.

I hate it because the agency of course has a relationship with a specific laboratory. That laboratory happens to be the laboratory that I would recommend above others for hereditary cancer testing. This makes me feel good about the quality of testing that patients actually end up having—but also means that my professed recommendation should be looked upon with skepticism. Although the modest amount I’m paid is not affected by whether or not a patient goes ahead with genetic testing, and although I’m not privy to the details of the arrangement between the agency I work for and the genetic testing laboratory—in reality, I’m obviously still being indirectly paid by the commercial testing laboratory. I’m just part of their operating costs.

I address patients’ questions about the costs of genetic testing, the likelihood that it will be covered by insurance. But there’s never a question as to how I’m getting paid, or why I’m getting paid. There’s no price tag assigned to the 30-90 minutes I spend talking with them. Sometimes patients are in a quiet place for our phone conversations. Sometimes they’re washing dishes, driving a car, picking kids up from school. After all, it’s a free call related to an impulse click on facebook. I have a Master’s Degree in Human Genetics, but my time costs them…. absolutely nothing. Or rather, the cost of my time is bundled into the cost of the agency’s services which is in turn paid by the laboratory which is in turn paid by insurers, which is in turn paid by my patients’ insurance premiums and/or taxes.

I feel less icky about this set-up than I had expected. (See the love paragraph.) Conflict of interest aside, however, this is a nasty bandage on a broken system in which the cost of genetic counseling is bundled along with the cost of testing rather than being recognized and billed for as a service provided by specialized medical professionals.

As uncomfortable as I feel getting indirectly paid by a laboratory, I feel equally but differently uncomfortable with charging patients for genetic counseling—which is exactly what I’m doing in private practice. The first patient who paid upfront and told me how valuable my time had been to her and how appreciative she was made it easier. But I still feel awkward asking patients to pay me. Most of us who have worked in hospitals have been similarly used to having the cost of our services swept up into other hospital costs and have not had to tell patients, “It will cost $X to see me.”

I think our time and services are worth $$$. Whether we work in industry, private practice, or for a hospital, I think we need to learn to be unapologetic about the fact that even if we love and find meaning in our jobs, we also work to make a living. The value of genetic counseling services should be accurately reflected in an associated cost. We’ve come a very short way from being a collection of mostly white, upper-middle class housewives who are happy to do volunteer work and don’t need to make an income. We need to take another step and get comfortable with transparently charging for the work we do.

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by Katie Stoll | February 2, 2018 · 9:25 AM

Growing Pains

With the rapid growth of the genetic testing industry, professional opportunities for genetic counselors have expanded rapidly. Not only are genetic counselors now working in nearly every area of healthcare, many are embracing new roles as laboratory specialists, clinical science liaisons, and in sales and marketing roles for genetic testing companies. Some are entrepreneurs founding their own companies and pioneering new models for access to genetic information. It’s not surprising to see genetic counselors embracing these new roles. Like the founders of our field, seeing opportunities in change and forging new trails in uncharted territory seems to be characteristic of genetic counselors.

But navigating new terrain isn’t often easy. As written by Alexandra Minna Stern in her historical account of the profession, ”the emergence of the genetic counselor as a bona fide professional was neither inevitable nor smooth.”

Do other genetic counselors feel that we are currently in the midst of a most turbulent and rocky stretch of our profession’s journey through time?

Although we have had graduates from Master’s level genetic counseling training programs for more than 40 years, as well as a growing body of evidence regarding the value we bring to patient care, we are still reaching for recognition as healthcare professionals. While we seem to be making progress towards this goal, we have yet to be recognized by Medicare and many commercial payers as healthcare providers. Additionally, in many states the quest for licensure remains an incredible challenge.

One of the biggest obstacles genetic counselors currently face is public perception of genetics and genetic testing. It seems that genetic discoveries that are part of evidenced based strategies to improve human health are increasingly being overshadowed by consumer genetic testing for entertainment. For example, screening for and treating familial hypercholesterolemia is considered to be a Tier 1 genomics application by the CDC given the level of evidence and potential to benefit public health. However it is estimated that less than 1% of the affected population in the US have been diagnosed.

On the other hand, consumer genetic tests are being increasingly utilized. Home DNA test kits through companies such as 23andMe and Ancestry.com were among the top selling holiday gifts this year. Consumer genomic testing claims to provide information about everything from personalized skin care recommendations, to what one’s ideal fitness regimen will work best, to what one’s hypothetical future children may look like. Some companies combine a mix of evidenced based health information with unproven claims related to entertainment and wellness information which leaves many in the field of genetics uncomfortable.

As genetic counselors, we are regarded as experts when it comes to genetic testing. So how should we respond to the flood of options in the direct to consumer space? How should we be talking about these tests with our patients? How should we be talking about these tests with other healthcare providers? These are crucial questions for our profession, but ones that genetic counselors don’t seem to seem to agree on.

Through the media, through our professional discussion forums, and in conversations at genetics conferences over the past couple of years, I have heard two predominant and conflicting messages regarding genetic counselors’ opinion on consumer genomic testing. Some are enthusiastic, and believe the use of such tests should be encouraged as an opportunity for to engage people in the area of genetics, and hopeful that such engagement in any genetic testing will lead to better adoption of genetics into healthcare. Some are concerned about the proliferation of these tests and believe that they may cause more harm than good by blurring the lines between medicine and entertainment, leading to misinformed health decisions, compromising privacy, and creating new and unanticipated conflict for psychosocial family dynamics.

Our field is small with only about 4,000 genetic counselors nationwide. We are all only separated by only a degree or two of separation. A tight-knit community. So it is not surprising that with our profession expanding in so many directions, that we are experiencing some tension and growing pains with these emerging issues.

Whether we believe that consumer genomics is something to be feared or embraced, these tests are out there, people are using them, and it is crucial that we adapt to be able to help the public, our patients, and each other navigate this new terrain.

Do you see consumer genomics as an area that we should encourage, participate in, and guide? Or should genetic counselors discourage the use of these tests, both on an individual patient level and in policy? How do you see us adapting to the brave new world of consumer genomics?

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by Katie Stoll | November 16, 2017 · 9:13 AM

The Routinization of Prenatal Testing and the Erosion of Patient Autonomy

As a long time admirer, reader and guest blogger, I am thrilled to have been invited to write as a regular contributor for the DNA Exchange. Some recent statements about prenatal testing in the news brought to mind my very first guest post on the DNA Exchange, Information Detoxification, published 5 years ago. So I am going to start this new chapter by going back where I began as a guest blogger, on the topic of the risks of routinizing prenatal genetic testing.

Last week, a genetic testing lab released a statement about their intention to use recent investments “with an eye toward making expanded carrier screening as routine as taking folic acid, noninvasive prenatal screening as routine as an ultrasound, and hereditary cancer screening as well-known as a pap smear.” While this vision is quite positive for the lab’s investors, it is concerning for the future of reproductive autonomy. The underlying goal that all pregnant women should have prenatal testing is not unique to this lab. In fact, there is increasing pressure towards expanding the use of these tests by many labs, likely representing the intense competition in the genetic testing business right now, driving the need to increase test uptake to the largest possible market.

I have mixed feelings about population screening for hereditary cancer, but the implications are completely different when considering prenatal carrier and cfDNA screening. Although prenatal testing is important to many, it is crucial that women and their partners be given the opportunity to make autonomous and informed decisions about whether or not to take these tests. The routinization of prenatal testing is problematic for several reasons: from a social and public policy standpoint, in regards to healthcare economics, and also for individual patient care.

Social and Public Policy

Advocating for reproductive autonomy and informed decisions around prenatal genetic tests was one of the first guiding principles of the genetic counseling profession. This is in part due to the fact that the start of the master’s degree trained genetic counselor coincided with social movements in women’s reproductive rights and also the emergence of the field of bioethics.

The prioritization of patient autonomy in reproductive genetics also arose from the rejection of eugenic ideology and practices that were common in the early part of the 20th century which sought to encourage reproductive of the fittest and to discourage (sometimes forcibly) reproduction among those deemed as defective or unfit.

This history supports concerns that the routinization of prenatal testing may effectively stigmatize those who have an increased chance to have a child with a genetic condition, thereby limiting reproductive freedom. This is especially troubling in the context of the current political and social climate with so many expressing racist, xenophobic, and ableist views, as well as increasing threats to health care security and social services.

Healthcare Costs

Issues regarding the cost of prenatal testing are complex and studies regarding the economic impact of expanding prenatal screening are needed. Such data analysis is complicated by the variability and a lack of transparency in the costs of these tests. While labs vary in their pricing, patients report receiving explanation of benefits representing that the amount billed to their insurance was many thousands of dollars – amounts that likely exceed the entire cost of the prenatal care in some cases.

Without peeling back all of the layers on this topic, there is one clear explanation for why routinization of prenatal testing does not make good financial sense. Given that the purpose of prenatal genetic testing is to inform personal reproductive decisions, in order for these tests to be of value, they must first be desired by the fully informed patient. No matter the price of a prenatal genetic test, it is a needless healthcare cost if the patient does not want it.

Patient Care

Should all patients be routinely counseled about their options for prenatal genetic testing? Absolutely. Practice guidelines for prenatal genetic testing support offering these tests to all women in the context of counseling that supports informed and value-consistent decisions. But this conflicts with the model that the testing labs seem to be promoting, which is to test everyone first and provide the information in follow-up, after testing has already been done. This undermines patient autonomy and can cause harm.

When an individual would use results to facilitate reproductive decisions, testing can be empowering. What is often overlooked in our well-intentioned goals to provide patients with knowledge however, is the potential harm and disempowerment that may result when testing information is not desired. Patients deserve the opportunity to make a choice about whether the information these tests provide is something they want to know or not.
It is imperative of genetic counselors to resist any suggestion that reproductive genetic testing should be routine. I hope that all of us, whether working in the clinic or the lab, will continue to advocate for reproductive autonomy for our patients and hold firm in the goal that all patients should have the opportunity to make informed choices regarding prenatal genetic tests prior to testing. How we move forward with this challenge in both practice and policy is a defining question for our profession.

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Tagged as Autonomy, carrier screening, noninvasive prenatal testing, prenatal testing

by Katie Stoll | May 4, 2015 · 12:24 PM

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 InformaSeq^TM 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 Verifi^TM 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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Tagged as NIPS, NIPT, noninvasive prenatal screening, noninvasive prenatal testing, positive predictive value, prenatal diagnosis, prenatal screening

by Katie Stoll | November 2, 2014 · 3:46 PM

Guest Post: NIPS: Microdeletions, Macro Questions

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetics.

At the recent National Society of Genetic Counselors Annual Education Conference in New Orleans, a presentation raised some important questions about noninvasive prenatal screening (NIPS). According to the speaker, a woman with a vanishing twin pregnancy underwent NIPS with an expanded microdeletion panel and the results showed findings “suggestive” of a chromosomal microdeletion syndrome.

The patient underwent amniocentesis with a SNP microarray and the results were normal. In a follow-up call with the NIPS lab, the genetic counselor learned that multiple copy number variants were observed (not originally reported) in the original sample. The lab suggested that these variants could be associated with a malignancy or fibroid tumor (and were of course unlikely to be associated with a microdeletion syndrome in the fetus).

As a result of this genetic counselor’s follow-up phone call and due diligence, the patient underwent an extensive work up for possible cancer, but no explanation was found. NIPS was repeated and this follow-up study was normal.

My first thought in hearing this case was – That poor woman! First a lost twin pregnancy, then concern for a severe condition in her baby, anxiety about the amnio, and worry that she may have Cancer. Although I am not a health economist, my second thought was – Holy Cow! How can our healthcare system afford all of the follow-up testing that may come downstream from these tests? NIPS is promoted as a test that will lessen the need for follow-up procedures such as amniocentesis, but will that remain true as the list of screened conditions increases?

In October 2013 Sequenom expanded their NIPS test to include screening for microdeletion syndromes and Natera followed suit in Spring 2014. Some new companies entering the NIPS market are also advertising screening for microdeletion syndromes.

The addition of microdeletions is a brilliant business strategy for expanding the testing market to include all pregnant women. Even though microdeletions are rare, their incidence—unlike that of Down syndrome –is not linked to maternal age. Women who are currently not offered NIPS because they are not included in the high-risk categories proposed by the American College of Obstetricians and Gynecologists (ACOG) guidelines could now be given a reason to undergo NIPS—even though the predictive ability of the NIPS for rare conditions is less than impressive.

Women who elect the test because of an interest in Down syndrome or because they are eager to learn fetal gender may unknowingly be screened for rare microdeletion syndromes which they know little to nothing about. To add to the complexity, a maternal microdeletion condition may be an incidental finding. In a poster presented at the NSGC meeting this year, Sequenom presented a series of 22q11 deletions detected with their MaterniT21 PLUS test. Included in this report were two mothers who were themselves incidentally diagnosed with 22q11 deletion syndrome. Based on the consent form on the Sequenom website it seems unlikely that these women had any idea such a result may occur.

Where is the evidence to support this expanded screening?

These tests are being performed despite there being no published clinical validation studies. There have been some case reports and proof of concept studies; however given that this testing has been commercially available for over a year now, there is shockingly little published about cell free DNA screening for microdeletions. An abstract from a poster presentation at the ACOG annual meeting in April 2014 evaluated 6 samples (or is it 7? – it is not clear from the abstract) from pregnancies known to be affected with microdeletions and 8 simulated samples. They conclude, “This is the most comprehensive, accurate validation of noninvasive microdeletion detection hitherto… This approach will enable accurate, noninvasive, prenatal population screening for these severe disorders.”

Proof of concept is one thing; proof of clinical validity is another. If we value evidence-based medicine, a sample of six (or seven) affected pregnancies is a long way from being a basis for population screening. Whether population-wide screening for extremely rare disorders is worth paying for is, of course, a question in itself.

But in the unregulated environment of laboratory-developed tests, we adopt first and report out results later. Accompanying this process is a lack of transparency – labs performing NIPS with microdeletions have not made performance statistics publicly available and thus patients and providers have no way of determining the accuracy of microdeletion NIPS. In a webinar hosted by Sequenom , the presenters were asked about the positive predictive value (PPV) of Sequenom’s screen for microdeletions. One speaker replied, “We have calculated them. However, what we would like is essentially to wait a little bit to give you more clinically relevant results. Because so much depends on the fetal fraction of the sample and so on and so forth, so we feel that the more appropriate number to release is after we have done 50,000 samples, how many have we found, how many have we reported back, how many were confirmed, how many were in line with the clinical picture.”

Shouldn’t the accuracy of the test be publicly known before it is run clinically on 50,000 women?

Labs have given us only a glimpse of their performance statistics. I was previously provided information from Natera regarding estimated PPVs for the microdeletions on their panel, but I cannot locate this information anywhere in the public forum. The table I was provided stated a 1/19 PPV (5.3%) for 22q11 with a Fetal Fraction >6% and dropping much lower (to 1/45) with decreased fetal fraction (interesting thread here of multiple women with a 1/19 chance of 22q11 on their NIPS result).

In a letter to the editor, former CMO of Sequenom Allan Bombard and colleagues reported that they had evaluated 264 samples from pregnancies with known microdeletion and microduplications or “enriched genomic mixtures” and report a 100% sensitivity and 99.3% specificity. Applying these statistics to 22q11.2 deletion syndrome (the most common microdeletion syndrome on the panel with an incidence of 1 in 4,000) indicates a PPV of about 0.036 or 3.6% . The overall PPV would be expected to be lower given the very low incidence of the other microdeletions on the panel. At the NSGC meeting this year, Sequenom presented some preliminary data from a series of 120,726 samples screened from October 2013 – July 2014 with test performance that exceeds those estimates. Although they did not have complete follow-up data for positive and negative results, a press release from the company following the NSGC meeting reports “high positive predictive values (estimated combined PPV ranged from 62% to 94%)”.

The limited information available suggests PPVs for microdeletion syndromes fall within a broad range of <3% – >90%. Published peer-reviewed studies are needed to help clarify the PPV associated with this testing so that healthcare providers and patients can make informed decisions about utilizing and interpreting this testing.

About a year and a half ago I published a piece on the DNA Exchange that discussed the importance of PPV in interpreting NIPS results. This was written for an audience of genetic counselors, but the posting is being increasingly used as a venue for patients to share their stories and seek information about their test results. Many patients report considerable anxiety – “the waiting is killing us…we have been devastated for the better part of 3 weeks now” – and some express regret for undergoing this testing at all, “I too wish I would of just done the typical old fashion test so nothing was in the back of my mind and hours of my life would be given back…” Recently, a woman remarked that she did not consent to additional testing for microdeletions and indicates her frustration with not being able to find information about the PPV for this test, “Not only are they essentially experimenting on us…they are not transparent about the potential problems with validity or low PPV.”

As genetic counselors, we are implicated in these companies’ approach. We should be demanding better evidence before leading our patients towards testing that could create this kind of distress. We need to be asking good questions, and we should demand good answers. If we cannot figure out how reliable a screening test is from a thorough review of the literature, I think we really need to ask ourselves if we should be offering it in a clinical setting.

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Tagged as cell-free fetal DNA, cffDNA, microdeletions, NIPS, noninvasive prenatal screening, prenatal diagnosis

by Katie Stoll | December 9, 2013 · 10:33 PM

Guest Post: Adrienne Asch – Reflections from a Genetic Counselor

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetic counseling.

We recently said good-bye to Adrienne Asch, a thoughtful and powerful voice in bioethics, disability, and reproductive rights. Adrienne passed away at her home in New York on November 19, 2013, surrounded by the love of many friends and family.

Adrienne touched my life deeply in the brief time I knew her and I am grateful to have had a connection with her. Her perspective has significantly shaped the way I view the genetic counseling profession and my role within it.

Adrienne was an accomplished scholar and an incredible person. Several beautiful tributes speak of character and her accomplishments, and these only give us a glimpse of her impressive body of work. See the The New York Times, as well as blogs related to philosophy, feminism, and bioethics for more about Adrienne.

Many genetic counselors are aware of Adrienne’s focus on the intersection of disability rights with reproductive technologies. She was supportive of abortion rights, but questioned the implications of prenatal diagnosis and selection for disability rights, for individual parent expectations, and for humanity. She asked the question, if individuals with disabilities are not welcomed into family life, how can we expect inclusion in schools, in the work place, in society?

In her scholarly work, Adrienne spoke frequently about the parent-child relationship, and I had often wondered about her personal experiences as a child in this relationship. I came across the transcript of a fantastic interview with Adrienne conducted by Anna Kirkland at the University of Michigan, in 2006. I was delighted to find these insights into Adrienne’s own family life and it is heartening to realize that Adrienne’s views on this topic were in part shaped by her own childhood experiences of being supported to be true to herself:

“My parents taught me to think for myself and to be comfortable with who I was, even if people around me weren’t entirely comfortable with who I was either as a leftwing type or somebody who loved classical music, or someone who was Jewish, or someone who was blind. So they just taught me to be myself.”

At one point the interviewer asking Adrienne if she had ever had the opportunity to address genetic counseling students. Adrienne has been an outspoken critic of prenatal diagnosis and this has made her quite a controversial figure among genetic counselors.

Anna: I’d be interested to know, have you ever had the opportunity to address a group of genetic counseling students or…or…

Adrienne: Yes. I have.

Anna: Yeah. How did that go?

Adrienne: Not well.

Anna: [laughs] What [laughs]…what did you say to them?

Adrienne: The same kind of thing I’m saying to you. But it challenges…I mean, maybe that I haven’t said it gently and kindly enough and I’m trying to do that. I have sympathy for how difficult it is to do this work. But I have no sympathy for people telling me that parents aren’t interested in this information or it’s not appropriate to give them the kinds of information that I’m describing. I think in fact that’s what genuine information is.

Recently, I had a chance to work closely with Adrienne when she helped to conceptualize a symposium for the National Society of Genetic Counselors Annual Education Conference, Reaching for Common Ground: Prenatal Genetic Counseling and Disability Equality. Although Adrienne’s health prevented her from traveling to Los Angeles for the meeting, she was determined to hear all of the presentations live and to participate in the conversation. We achieved this through the technological miracles of cell phones, speakers and microphones for the entire 6 hour conference and this allowed her to both listen and contribute to the conversation.

In early October, she recorded a video for this conference and the National Society of Genetic Counselors has kindly allowed me to share it here. I encourage you all to take the time to listen to Adrienne’s final address to genetic counselors. I think she finds the balance she was striving for in being sympathetic to the difficulties inherent in the work of genetic counseling and remaining strong in her challenge to our profession to be more than genetic educators.

In genetic counseling, you have an enormously important role to play in helping prospective parents’ to think about the meaning for themselves of the genetic impairments or prenatally diagnosable impairments that they might discover in a fetus or an embryo. And the role that you have to play is not genetics education alone. It is genuine counseling. It is counseling with a genetic component. But it is dialogic counseling. It is not merely reciting facts about laws and services and family support for people with Down syndrome. It’s not reciting how wonderful it is and how loving the children are…It’s not reciting how terrible it is and how bad group homes might be. It’s asking parents to think about the goals they have for their family life and how a child with characteristics that they can know in advanced will affect the achievement of those goals… The other reason you have a big job is that you are not given much time in which to do it. And all of the institutional forces work against that kind of conversation. But I am urging that genetic counselors take their respective places as counselors to really help prospective parents think through what they want for their family life. How a particular characteristic or impairment will affect that…

…Just as life is made up of many experiences that are shareable, you don’t need to have particular characteristics in common to share a life and to share experiences. And you as a genetic counselor have an opportunity to communicate that to prospective parents. And ask prospective parents to think about what they want in their family’s lives. And whether a child with a particular characteristic you can name in advanced will make the achievement of those goals any harder or any less possible.

That’s a job of real counseling. It’s not a job of imposing your values. It can be as nondirective as you like but it is a job of asking questions maybe questions parents don’t want to be asked but that’s often true of any counseling. No therapist worth his or her salt merely smiles and nods and says, “Ahah!”, and says, “I see what you mean”. Therapy and counseling are about asking people to reflect and think twice or three times about the views and the values they are bringing to their lives. You don’t have three years or 3 months or sometimes even 3 weeks to do that with the people in front of you. But in the 45 minutes to an hour that you have, or if you’re lucky, more than that, you have a chance to communicate the joys of parenthood, the problems of parenthood, and the ways in which a child with any set of characteristics may or may not fulfill the goals that a parent has.”

Part of our fundamental core professional values as genetic counselors is to be non-directive in our counseling – not to decide the morally ‘right’ path for pour patients. We strive to support individuals to choose the path that they decide is right for them. Our responsibility as genetic counselors is to do our best to make certain that the decisions people make are as informed as possible.

What Adrienne helped to crystallize for me is that part of ensuring informed decisions requires inquiry into of the prospective parent’s expectations, hopes and dreams. It may also call for us to challenge misconceptions about how life with a disability is imagined and this may need to begin first with examining our own misconceptions and biases.

Adrienne certainly dismantled my preconceptions about life and limitations for someone who has been blind since shortly after birth. Although too short, her life was undeniably rich and full and her contributions were many. I imagine there are many DNA Exchange readers who have some interesting reflections about Adrienne of their own. I hope you will share them here.

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Tagged as Adrienne Asch, bioethics, disability rights, Genetic counseling, prenatal diagnosis

by Katie Stoll | November 4, 2013 · 10:25 PM

Guest Post: NIPS And The Threat To Informed Decision Making

by Katie Stoll

A few months ago, I reached out to the DNA Exchange readership and called for more truth in advertising by the Noninvasive Prenatal Screening companies regarding the accuracy of test results. I recently returned from the National Society of Genetic Counselors meeting where I had the opportunity to survey the marketing and patient materials from labs offering NIPS and to learn about the experiences of my fellow genetic counselors with these new tests.

Not surprisingly, in this dynamic and rapidly evolving field, all of the companies have updated their materials. Some brochures proudly acknowledge how quickly this testing is being integrated into clinical use. It feels like we are being patted on the back for adopting this new test quickly and without question.

I remain very concerned about the misleading claims in the marketing materials aimed at providers and in the patient directed brochures. It is easy to see how the language of the brochures could lead healthcare providers and patients to conclude that these tests are diagnostic or near-diagnostic. These quotes from the materials illustrate my point:

v “Definite, informative results.”

v “Positive or negative results. Never maybe.”

v “No confusion. Just simple, clear results.”

To my knowledge, there are no new large studies to dispel my concerns about the positive predictive value of NIPS. Depending on the prior probability, a significant portion of positive results may be false positives– especially with rarer conditions such as Trisomy 18 and Trisomy 13. And because these technologies have been rapidly integrated into clinical practice based on limited research, we do not have robust outcome data to see how false positive and false negative data are playing out in clinical practice.

Since most NIPS testing is done outside of a clinical research protocol, the labs that choose to put resources into follow-up are at the mercy of the providers to share that outcomes information. Even in the best scenarios, voluntarily reported outcome data are not likely to tell the whole story. I spoke with a testing company representative regarding a poster presented at ACMG last year which based its false positive and false negative results on ad hoc feedback. When I inquired about the meaning of ad hoc feedback, it was explained to me that the company didn’t have the resources to track outcomes so were relying on providers to let them know if the testing results were incorrect. Of course, if a patient terminates her pregnancy based on a false positive test result, nobody will know that the NIPS result was incorrect.

Don’t think a patient would terminate based on NIPS alone? We all hope that women who receive adequate counseling about the limitations of the testing would confirm results with a diagnostic test, but this is not always the case. At a presentation during the recent NSGC Annual Education Conference, one lab referenced preliminary data showing some patients are terminating pregnancies without first getting diagnostic testing, and in the absence of ultrasound findings. While this tracking has some limitations, this lab should be applauded for investing resources in tracking outcomes data and for sharing these data with genetic counselors. Hopefully we will see it published soon and other labs will follow suit.

This situation of patients making reproductive decisions based only on NIPS results may be particularly problematic in communities that don’t have ready access to genetic counseling and/or maternal fetal medicine services.

Imagine this scenario: a 35-year-old woman living in small town, USA who has limited access to abortion services beyond the first trimester, receives a positive result for Trisomy 13. Based on positive predictive values calculations, there is an 8% chance that her “positive” result is a true positive. But, the patient – and her doctor – may think the probability is much higher, maybe even close to 100%, based on the reporting practices of the labs, which may say “Aneuploidy detected” or “Positive” for Trisomy 13. This does not support informed reproductive decisions.

This patient has 3 options:

Wait for an appointment at a high risk referral center, at some distance from her home to undergo diagnostic testing. This may limit her reproductive options by delaying time to diagnosis (the later a pregnancy termination occurs, the more expensive it is, and pregnancy termination outside of the first trimester is often not available in many smaller communities).
Seek out pregnancy termination options in her local community based on the NIPS results alone – knowing that she is up against a gestational age ticking clock.
Decline further testing and continue the pregnancy.

If the patient feels that she would not want to continue a pregnancy given a Trisomy 13 diagnosis, and she understands the limitations of the testing, I would imagine that she likely would feel it was worth the wait and the travel for diagnostic testing. However, given the emphasis on the accuracy of NIPS based on the lab reports, and the misconception by OB providers that this testing is “nearly diagnostic”, it is easy to imagine a scenario where she may elect to have a termination based on NIPS alone.

Based on an aggregate of data from the NIPS companies from the first quarter of 2013, one health economist estimates that NIPS is utilized by 40% of the high-risk population in the US, and this number is growing rapidly. So while the patients you see in your genetic counseling practice may be very informed about the limitations of the testing given your expert counsel, this statistic suggests that most NIPS is probably taking place outside of our offices.

We must continue the conversation about how NIPS is marketed and used in prenatal care. While the advantages to a more sensitive screening test are obvious (e.g. fewer women needing to undergo diagnostic testing), we must recognize the largely undisclosed limitations and dangers. Without adequate counseling, patients are being harmed by the misleading claims about the accuracy

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Tagged as Down syndrome screening, informed consent, NIPS, NIPS accuracy, NIPT, noninvasive prenatal diagnosis, noninvasive prenatal screening, noninvasive prenatal testing, prenatal diagnosis, prenatal screening

by Katie Stoll | July 11, 2013 · 10:27 PM

Guest Post: NIPS Is Not Diagnostic – Convincing Our Patients And Convincing Ourselves

By Katie Stoll, MS

A couple of years ago we were just beginning to learn about a new prenatal testing technology termed Noninvasive Prenatal Diagnosis. It was soon relabeled as Noninvasive Prenatal Testing, and now the American College of Medical Genetics and Genomics recommends this be taken one step further by terming it Noninvasive Prenatal Screening (NIPS) to highlight the limitations of this new technology.

As currently reported by labs, NIPS presents new challenges for genetic counselors. Of particular importance is figuring out how to convey to patients and healthcare providers why relying on sensitivity and specificity alone may lead to misinterpreted results. In the absence of positive and negative predictive values there may be a tendency to assume that the high sensitivity and specificity reported with NIPS means that these tests are more powerful – more diagnostic – than they actually are.

It is imperative that we understand both what the terms mean and how they relate to a person’s likelihood of having a condition. Sensitivity measures the true positive rate – the proportion of actual positives which are correctly identified as such (e.g., the percentage of fetuses with Down syndrome (DS) who have a positive test result). Specificity measures the true negative rate – the proportion of actual negatives which are correctly identified as such (e.g., the percentage of fetuses who do not have Down syndrome who have a negative NIPS result for DS).

A test can have both a high sensitivity and specificity without being a good predictor of whether the condition is actually present. The likelihood that a positive test is a true positive result also depends on the incidence of the condition.

Genetic counselors are used to thinking about aneuploidy screening in terms of PPV, as this is generally the format for reporting maternal analyte screening such as Integrated , Quad screens, etc. Analyte screening takes into account the prior probability based on maternal age and provides a PPV as the end result. For instance, an analyte screen result may be reported as Positive with a 1 in 50 chance of Down syndrome. The PPV with analyte screening lets us know how many patients with a “positive” test will actually have a pregnancy affected with the condition and reporting results this way makes it clear that this is a screening test.

Can we apply the same interpretation to NIPS results? Some labs provide a “risk score” which appears similar to what we see with analyte screening, but I am told by the labs that the vast majority will be reported as either >99% chance or <.01% chance. Some labs do not report a risk score, instead giving essentially a positive or negative result. But does this mean that greater than 99% of women who receive a >99% or a positive result are actually carrying a fetus with Down syndrome or other chromosome condition?

Given that women 35 year and older are a population targeted for NIPS let me work out the expected NIPS results given the approximate sensitivities and specificities reported for a hypothetical population of 100,000 thirty-five-year old women (while I cannot tell you the specific number of women age 35 who give birth per year, CDC data suggests that for the past several years about 400,000 – 500,000 women in the age 35-39 have given birth each year in the United States – so 100,00 births annually by 35-year-old mothers is probably in the ball park of the national trend.

The performance data vary significantly from lab to lab – for the purpose of this illustration, I am using sensitivity and specificity in the range of what has been reported. The data below are based on the chance of Trisomy 21, 18 and 13 at the time of amniocentesis for a woman 35 at time of EDD¹.

	Down Syndrome	Trisomy 18	Trisomy 13
Incidence	1/250	1 / 2000	1 / 5000
Affected Fetuses	400	50	20
Sensitivity	99.5%	98.0%	90.0%
Specificity	99.9%	99.6%	99.8%
Total test positives	498	449	218
True test positives	398	49	18
False positives	100	400	200
Positive Predictive Value	80%	11%	8%

If we add all of the positive results together in a population of 100,000 thirty-five-year old women we see that 1165 (1.2%) have positive test results for Trisomy 21, Trisomy 18 or Trisomy 13. Note, though, that only 465 of these results will be true positives. This indicates that the majority of the time (greater than 60% using these statistics), a positive result on NIPS for a 35-year-old woman will be a false positive – and this doesn’t even include calculations for sex chromosome aneuploidy which some NIPS labs also screen for.

Notably, the negative predictive value for NIPS is very high indicating that a negative test result is a true negative >99% of the time. But how do we reconcile that for many women, the chance of a false positive with NIPS may be higher than the chance of a true positive result when that seems to be contradicted by way the labs are reporting the results?

In trying to explain the chance of a false positive result to patients with a “positive” test report in hand, I have found that I am met with disbelief. I can understand why – if a test says there is a>99% chance of Down syndrome and the lab says the test has >99% sensitivity and >99% specificity, how could this test be wrong?

While genetic counselors understand the limitations, the reporting practices of the labs place us in a position in which we have to work hard to convince our patients that NIPS is only a screening test.

Currently four labs offer NIPS in the U.S. and all have different strengths and weaknesses in their reporting practices. All could be improved by making the limitations of this technology more obvious. In some cases the language used in the reports gives the appearance that NIPS is diagnostic. For example, one company’s report suggests that the healthcare provider should advise for “additional diagnostic testing”. The labs vary in whether the need for genetic counseling following a positive result is recommended. Additionally there is variability in the transparency of how the performance data are derived.

Given that the performance statistics vary significantly, we need to be sure to take these details into account when considering PPV. I encourage genetic counselors and other healthcare providers to critically look at how the performance data are derived. The sample sizes on which these numbers are based are often quite small and the confidence intervals can be broad. I was surprised to see in the fine print of one report that the performance data “excludes cases with evidence of fetal and/or placental mosaicism.” Given that mosaicism is a known cause of false positive results and because mosaicism cannot be definitively determined through NIPS, it doesn’t seem accurate that these cases should be excluded from calculations of test performance.

The pitfalls of interpreting NIPS results is a challenge we need to address because NIPS is increasingly taking place without the involvement of genetic counselors in pretest or post-test counseling. There is real concern that patients are making pregnancy decisions based on screening tests with the misunderstanding that NIPS is diagnostic.

I write this as call to the NIPS labs to change their reporting practices to better emphasize the screening nature of this technology. Providing some positive predictive value estimates would be tremendously helpful as we try to make sense of NIPS results for our patients. While it may be difficult to provide individualized risk assessment, a general table of how prior probability impacts individual test performance would be beneficial for interpretation. Furthermore, eliminating language from the reports that suggests these tests are diagnostic and giving more transparency to ways in which performance data are calculated would also be welcome changes.

As genetic counselors, we strive to ensure informed decision-making for the clients we see. Key to informed decision-making is an understanding of the limitations of this evolving technology. As fellow patient advocates, I hope the genetic counseling community will join me in requesting increased accountability and responsible reporting on the part of the labs regarding NIPS.

I would like to acknowledge Evan Stoll, retired GAO data analyst for his contributions to this piece.

Please Note: Authors who contribute to The DNA Exchange cannot offer medical advice. Many commenters have raised interesting and thoughtful questions about NIPS. If you have undergone NIPS and have questions, you should meet with a certified genetic counselor. To locate a genetic counselor, go to the Find A Genetic Counselor section of the website of The National Society of Genetic Counselors.

Hook EB. Prevalence, risks and recurrence. In: Brock DJH, Rodeck CH, Ferguson-Smith MA, editors. Prenatal Diagnosis and Screening. Edinburgh: Churchill Livingston, 1992.

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Tagged as NIPD, NIPS, NIPT, noninvasive prenatal diagnosis, noninvasive prenatal screening, prenatal diagnosis, prenatal testing

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