Tag Archives: noninvasive prenatal testing

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

Guest Post: NIPS And The Threat To Informed Decision Making

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.

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:

  1.  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).
  2. 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.
  3. 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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