Tag Archives: noninvasive prenatal diagnosis

NIPS SPIN

Advertising is the art of making whole lies out of half truths. ~Edgar A. Shoaff

Every few years a new screening technology comes zooming down the prenatal pike, sometimes arriving more quickly than we might like. First there was maternal age, with the magical age of 35 as the cut-off. Low maternal serum AFP arrived in the 1980s and the OB community embraced it virtually overnight when ACOG’s Committee on Professional Liability issued a statement that practitioners could be held legally liable if they had not offered this screen to a patient who had given birth to a child with Down syndrome. This was followed in short order by the Triple Screen, The Quad Screen, nuchal thickening, Integrated Screening, etc., each one a statistical notch above its predecessor. The latest iteration – cell-free fetal DNA or Non-Invasive Prenatal Screening (NIPS)  – stands head and shoulders above the rest. Two of our colleagues have already discussed the limitations and strengths of NIPS here on The DNA Exchange.*

NIPS is big, as in global big. One lab makes its brochure available in more 20 languages, from Afrikaans to Xhosa (the pregnancy gods must be crazy, dropping pamphlets out of The Cloud). Tens of millions of women around the world are likely to undergo NIPS in the near future. And pregnant women are a “renewable resource” –  a whole new batch pops up every day and many women will have two, three, or more children. Competition for market share among labs is stiff and there is little incentive to dissuade women from undergoing prenatal screening. It’s not that labs coerce women to undergo screening, advocate eugenic agendas, or run roughshod over personal autonomy. All labs would support a woman’s right to decline prenatal screening and Lord knows they stay away from the abortion discussion. But if enough women decline, then there is no incentive to offer the screen. The companies have something to sell and will spin their product to attract customers.

Which brings me to the subtly misleading implications of the name Non-Invasive Prenatal Screening. Sure, NIPS is non-invasive. But so is ultrasound, AFP, HCG, etc. All of these screening tests are non-invasive and therefore do not carry a direct risk of fetal loss. NIPS  is no different from the rest in that sense. It is superior to other screens in terms of having a very low first positive rates, high positive predictive value, and high sensitivity. But NIPS is still an alternative to other screening tests, not to amniocentesis or CVS.

Yet the websites of companies that offer NIPS communicate a different message that subtly suggests that NIPS is in fact an alternative to amniocentesis/CVS instead of an alternative to, say, the Integrated Screen:

First we thought the PC was a calculator. Then we found out how to turn numbers into letters with ASCII – and we thought it was a typewriter. Then we discovered graphics, and we thought it was a television. With the World Wide Web, we’ve realized it’s a brochure. ~Douglas Adams

The suggestion that NIPS is a diagnostic test is further reinforced by reassuring text in large, appealing fonts – Comprehensive, Accurate, Trustworthy, and, my personal favorite, No Confusion. Such wording conflates screening tests with diagnostic tests. Who could resist a test that boasts to be >99% accurate, especially when combined with images of smiling, beautiful parents and babies so cute that you wish your touch screen would allow you to hug them? It is easy to see why parents might be confused and some genetic counselors feel that 75% of their patients may think that NIPS is diagnostic. Yes, the labs also offer comparison to other screens, information about the conditions being screened for, links to disability focused websites, and acknowledge the role of diagnostic testing. But information does not sell products; images and impressions do.

http://en.wikipedia.org/wiki/The_Treachery_of_Images

The Treachery of Images by René Magritte

NIPS is a pretty good screening tool that can help patients decide if they want to proceed to diagnostic testing such as amniocentesis or CVS. However, the first step in the process of considering any testing should be a soul-searching and difficult discussion between parents and with their care providers about views on disability, parenthood, expectations for their children, and beliefs about pregnancy termination (I can’t prove it, but I am pretty sure that discussion is not taking place anywhere near as frequently as it should). For parents who feel it is important to know the chromosomal status of their baby, the next step is to outline the pros and cons of screening tests, emphasizing that a screen only provides a probability that a child may have a particular chromosomal disorder. The risk estimate provided by the screening test may help parents decide if they wish to undergo diagnostic testing.

One might counter that labs are commercial entities engaging in good old American advertising, which everybody knows is not exactly a strictly honest business. But prenatal screening is not like trying to sell Coke vs. Pepsi or Ford vs. Toyota or Chia Pet vs., well, whatever it is that Chia Pets are in competition with. We are talking about babies, our deepest hopes and dreams, and the core values that define our humanity. This demands a higher standard and this is where genetic counselors need to work with their laboratory employers to elevate the discussion.

 


* Missing from much of the professional  discussion about NIPS has been the viewpoint of people with disabilities, their families, and their advocates. As Rachel Adams points out, the Down syndrome community in particular might feel particularly targeted by a test named Maternit21 – but that thorny topic is for another day.

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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:

“Definite, informative results.”

“Positive or negative results.  Never maybe.”

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

By Katie Stoll, MS

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.

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.

Sensitivity Graph

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.

  1. 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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