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.

 

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

 

48 Comments

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

  1. Interesting stuff. Did you directly contact anyone affiliated with the NIPS labs to share these thoughts regarding their reporting practices?

    • Katie Stoll

      I have shared my thoughts with many folks in the labs. It is great to have The DNA Exchange to engage the genetic counseling community and to think about these issues.

  2. Lisa

    So what DO you say to the patient sitting in front of you who has a positive (or 99%) result for Down syndrome? Do you say the chance for Down syndrome is 99% or greater? Or do you say the risk is 33% or 40%? I understand the information presented here, but I have a hard time aligning this with the information presented on the reports. How can I feel confident in my counseling???

    • Jaime

      I don’t work in prenatal, but here is my suggestion…. I might skip the quantitative risk number and just say something qualitative. Perhaps something like, “This result is [highly] suggestive that the pregnancy has Down syndrome. This test is more accurate than the serum screen that you had, but the test is not perfect. You could consider a CVS/amnio for a more definitive diagnosis.”

      I think that this comment/question also speaks to the important role of pre-test counseling and the need to reinforce to patients what additional tests might be necessary should their test come back positive.

      I also agree with some of the other comments re: considering multiple overt ultrasound anomalies, especially for T18/T13. You’d want to counsel this patient with all of the information available to you.

  3. Maria

    This may be obvious to others, but how did you determine the number of total test positives? Also, wouldn’t it be better to determine PPV and NPV for each condition as opposed to lumping them all together? Wouldn’t the PPV be different for each condition?

  4. Perinate

    Ok, I agree that patients need pre- and post-test counseling and that it isn’t ‘diagnostic’, however this test is close.
    Remember, most of these tests (vast majority) will return ‘negative’. Based on your above assumptions, the NPV would be >99%. As such (assuming a normal sonogram), the patient will not elect amnio (decreasing iatrogenic fetal loss rate) and her anxiety will be lessened.
    You shouldn’t lump your positive results together, but break it out per specific aneuploidy (or at least for Downs). Trisomy 13 and 18 will likely have some other finding (abn NT or genetic sonogram), though Trisomy 21 may have a normal sonogram or one of those annoying subtle markers that usually end up worrying patients.
    If you look at a positive test result for only Trisomy 21, the majority of the time the test will be correct (again using your above values).
    This is far better than the current quad screening (81% sens, ref ACOG). Refering back to your example: a positive quad screen with then a “1:50 risk of Down syndrome” will occur far more often and is probably harder for a patient to grasp than what NIPT gives us.
    Major downside: price.

    • Katie Stoll

      I agree the high sensitivity and specificity with NIPS are better than analayte screening but I am concerned by the suggestion that NIPS is “close” to diagnostic. In the table above I break down the PPV for individual conditions using the sensitivity and specificity in the range of what has been reported by the labs. You can see that for a 35yo woman the chance that a NIPS screen that returns positive for DS is a true positive is 80%. And a positive result is much less likely to be a true positive for Trisomy 18 (a positive will be a true positive ~11% of the time) and Trisomy 13 (a positive is expected to be a true positive ~8% of the time). We must realize that this testing is being marketed directly to patients and primary OB providers and is taking place in the first trimester in places where MFM and genetic counseling services are not readily available. One could imagine that a 35 year old woman may get a “positive” NIPS result for Trisomy 18 or Trisomy 13 never having had a NT scan and well before the time of her fetal survey and may be compelled to make pregnancy decisions based on NIPS alone when led to believe that NIPS is nearly diagnostic test not realizing that the actual odds that the test is a false positive may be higher than the chance of a true positive. I believe the manner in which NIPS results are currently reported are difficult for both patients and providers to grasp.

  5. Vivian

    I always go back to the trusty Bayes! To help myself figure this out and to quickly figure out what the risk is for the patient sitting in front of me, I created an Excel spreadsheet using age-related-risks as the prior risk and then calculated the posterior risk using the numbers quote by the lab we are using. It’s fairly easy if you use Excel’s formula function and just drag and copy down the rows. It takes a little time to sit down and figure it out the first formula, but once it’s done, it’s a great tool and reference. Bottom line is, the PPV is highly dependent on the incidence. I did the same for NPV, and it is much less reliant on the incidence rate than the PPV. Using this schema, I can also adjust the risks based on other thing such as ultrasound findings. That’s just how I do it – I’d love to hear how others have been counseling patients re: their risks.

    • Lisa

      I do love me some Bayes! I first off think that the lab should be able to perform this calculation for us (and therefore produce results that are more representative of the actual risk, instead of 99% chance for DS). In the absence of this, I’m wondering if using the lab’s data is truly the best technique, vs. the above presented data (using population frequencies, etc). I calculated the PPV from the lab we use and it was surprisingly higher than what Katie presented. Katie also kindly pointed out that at least one lab skews their results by eliminating the cases of placental mosaicism. (speaking of which, it has occurred to me that the data presented above is likely an underestimate of positive cases, since pregnancies with placental mosaicism will be a true positive result, but not accurately reflect the status of the fetus therefore it’s considered a “false positive”?? Then do we consider all false positives to have placental mosaicism and monitor them as such??)

      I really enjoy this conversation. It has sparked debate among my colleagues and demonstrates the complexity of this “simple, nearly diagnostic” test. I feel like the honeymoon is over with NIPS and now we’re having to really evaluate how we use it as a counseling tool. And Katie’s point that this test is likely misused by well-intentioned providers is an important one.

  6. doesn’t the significance of a ‘positive’ result depend a lot on the lab? we haven’t really started up with NIPS yet but i think that MaterniT21 for instance reports just positive/negative results–so yes, you would have to go back and figure out positive predictive value..but Harmony, for instance, factors in the a priori age-related risk and includes that in their risk assessment. i think they also have a higher no call rate (5%) and report out a few “intermediate” results (rather than making a negative/positive call when info isn’t as clear), so i think their positive result is more likely to be a true positive–am i wrong? (of course, it could be confined placental mosaicism, vanishing twin, etc., etc.) – i’m not promoting harmony but that’s the one that we will be using just because they’re contracted with medicaid hmos. any feedback/thoughts?
    i have also heard of a handful of cases with false negative results. it would be nice if the false positives and false negative results from various labs could all be collected somewhere (without patient data) as is being done with BRCA mutations.

  7. NW WA doc

    I agree with the above comment regarding the utility of the test being when it comes back negative, allaying anxiety and reducing iatrogenic losses.

    Also, when does a test become ‘diagnostic’? Even amniocentesis and CVS (considered our ‘diagnostic’ tests) have false positives and false negatives.

  8. Dr. I.

    NW WA doc: I agree. If I have a patient complicated by fetal IUGR, clenched hands, and a heart defect, and the NIPT comes back c/w Trisomy 18, I would call the combination of the sono and test results ‘diagnostic’.

  9. Robert Resta

    While the Negative Predictive Value of NIPS is impressive it is also somewhat illusory. A 35 yo woman has less than a 0.5% chance of having a baby with Down Syndrome, so age alone as a screening tool has a negative predictive value of 99.5%. After a normal NIPS, she has a 99.9% chance of not having a baby with Down syndrome. Not exactly a great scientific achievement. Cognitively, most of us cannot distinguish between 99.5% and 99.9%. The very act of offering screening engenders anxiety for a low risk condition, and then we expect pregnant women to be grateful when a test tells them they are at low risk for the condition ? NIPS creates SPIN – Sane People Incredibly Neurotic.

    • NW WA doc

      That’s why it is more useful following an abnormal first or second trimester screen, after a patient has been told of their ‘positive’ test for Down syndrome (and what they hear is ‘my baby has Down syndrome’, despite counseling and reassurance). In my practice, NIPT has lessenned anxiety, not increased it.

  10. Jaime

    Thank you for this post. I’d also suggest folks read through to the recent NEJM perspective piece on this topic: http://www.nejm.org/doi/full/10.1056/NEJMp1304843. It clearly talks about the issues with predictive value and prevalence/incidence of disease. NIPT/NIPS has only been validated in high-risk populations. Until similar studies are done in the general population, you can’t assume the same performance characteristics.

    Another good example of an screening test with extremely high sensitivity/specificity but variable predictive value is the ELISA test for HIV. If you use this test in a population of IV drug users, the PPV approaches 100%. If you use the same test in a population of blood donors, the PPV drops to roughly 50%.

    • Katie Stoll

      Thanks for sharing the link to this article, Jamie. Excellent timing with this discussion! From the Morain et al paper – “…cfDNA-testing companies have not reported information about their tests’ positive predictive value (PPV), and there is reason to question the tests’ performance on this measure. Arguably, PPV is more important than sensitivity and specificity to patients undergoing testing: it indicates the probability that a positive test result indicates a true fetal aneuploidy. Thus, PPV should be discussed in study reports and marketing materials but isn’t.”

      • NW WA doc

        “NIPT/NIPS has only been validated in high-risk populations”– not true. At least one major study (w/in last year) involves a low-risk population with similar sens/spec, with more coming.

    • Jaime

      Yes, NW WA doc is correct. One of the NIPT/NIPS tests has published findings based on a study that included broader population of pregnant women regardless of a priori risk. However, as this post and the NEJM editorial point out, we really need PPV/NPV and not just Se/Sp, and that requires a different type of validation study design. Honestly, I would need to revisit all of the NIPT/NIPS publications to refresh my memory about which reported PPV/NPV and did so using a study design that permits reliable calculations of these measures. But when I speak of validation, I think of PPV/NPV as well as Se/Sp.

      Also, in my mis-statement above, I generalized all of these tests as a whole, which speaks to another issue: in general, we consider NIPT/NIPS tests as a single “test class,” so to speak. So, if you think about the body of direct evidence for these tests, you’ve got perhaps 8-10 validation studies of some kind. However, that’s really 1-3 studies for each of the 4 commercially available tests, and those studies have differing levels of rigor. I think we need to think about how we are lumping and/or splitting these tests — a blanket blessing for all tests in this class may or may not be warranted.

      Another issues is that, to my knowledge, all of the studies thus far have been industry-sponsored. Have they partnered with reputable academic sites and physicians? Yes, and that’s great. And it’s understandable — if a company is going to spend millions of dollars developing these tests, they should have a role in the initial studies. But when the CEO/CMO of the company that processed the sample is a co-author on the study, one has to raise an eyebrow. If we’ve learned anything from the pharmaceutical industry, it’s that industry-sponsored studies are more likely to demonstrate a benefit, and the magnitude of benefit is likely to be greater than in non-industry-sponsored studies. That’s not to say that these tests shouldn’t be used or aren’t valid, but that they should be treated with additional respect/caution/restraint until truly independent validity and utility studies are available.

      In any event, I have no doubt that NIPT/NIPS will *eventually* be shown to be a valid, reliable *screening* test for the general population (either as a class or for individual products). Even if they aren’t diagnostic, their performance should be notably better than our current serum screens. But we don’t have those studies yet and expanding use beyond what we have published evidence for is a disservice to our patients.

      P.S. For those who are interested in reading more about how one can assess the validity and utility of screening and diagnostic tests, I would suggest starting with the ACCE model (http://www.cdc.gov/genomics/gtesting/ACCE/index.htm) and QUADAS-2 (http://www.bris.ac.uk/quadas/quadas-2/ and http://annals.org/article.aspx?articleid=474994).

      • Katie Stoll

        Jaime, thanks for your many excellent points. And thanks for including the links regarding ACCE and QUADAS-2 – they are great tools for providing structure for thinking about the NIPS studies analytically.

  11. Jaime

    Another thought re: thinking about these tests as “close to diagnostic.” Perhaps this viewpoint comes from the history/evolution as these tests. Originally, the goal was to have a non-invasive diagnostic test that could supplant CVS/amnio and therefore eliminate the unintended miscarriage of a wanted pregnancy. However, as the data started to roll out, it looked good, but “not quite diagnostic,” which was our original reference point.

    But maybe we need to start thinking about these tests relative to serum screening instead of relative to CVS/amnio. So, instead of “close to diagnostic,” they could be thought of as “much more accurate than serum screening” or as “a highly accurate advanced screening test.” I dunno. Just throwing that out there. :)

  12. Dr B

    I found this article (Hum Reprod Update. 2013 Jul-Aug;19(4):318-29)) of interest.

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  14. Pingback: Not exactly a great scientific achievement: prenatal screening for Down syndrome in young mothers — Down Syndrome Prenatal Testing

  15. Lina

    I hope you will excuse this question from a non-professional who is interested in this field. Also, please excuse my grammar mistakes; English is not my native language.
    How can these tests have specificity and sensitivity at around 99% but still have such a large number of false positives? Is it because of the characteristics of the patient group?

    • Jaime

      This is a great question and you correctly answered your own question — it’s really about the characteristics of the patient group, most importantly how common the condition is in the patient group. The graph at the beginning of this post with the 4 different curves is one way of demonstrating this. The 4 lines represent variations in how common the condition is in the population — from a low of 0.01% to a high of 1.00%.

      Generally speaking, sensitivity and specificity are characteristics of the test itself and are static measures of test accuracy.*** However, the *predictive value* of the test (which impacts how many false positive and false negative results you have) is a function of the test itself AND how common the condition is in the population (usually referred to as prevalence or incidence).

      Sensitivity and specificity are very important and are critical measures for the laboratory folks who develop tests for diagnosis or screening of medical conditions. However, for folks who work with patients in clinical practice, positive and negative predictive value (PPV and NPV) are more important because they directly relate to patient care. PPV and NPV help answer questions like, “My patient has a positive test for Condition X. What is the chance that the patient REALLY has the condition?”

      This publicly available article titled “Understanding diagnostic tests 1: sensitivity, specificity and predictive values” might be helpful to you: http://alondra.udea.edu.co/moodle/pluginfile.php/14029/mod_resource/content/0/DIAGNOSTICO/Understanding_diagnostic_tests_1_sensitivity_specificity_and_predictive_values.pdf. It is geared towards clinicians, but is still relatively accessible to lay-people. Table 2 in this article is especially helpful — it shows how the predictive value changes even when the sensitivity and specificity remain the same. It’s similar to the graph in this post, but in table form with “hard” numbers.

      ***There are exceptions to this, such as tests that have different sensitivity and specificity in men vs. women, but the static nature of sensitivity and specificity are true as a general rule.

      • Donna Blumenthal

        Sorry so late. I just woke up. I asked why PPV wasn’t reported at the very first NIPT lecture I attended. they said it’s because the prevalence of Down syndrome is unknown that early in pregnancy. I don’t know why I bought that. But then i thought about the different incidence of Down syndrome at time of amnio compared to incidence at delivery and i realized that since NIPS can be performed at any week of pregnancy after 10 or so weeks, the PPV would have to be calculated based on the incidence of Down syndrome at that gestational week. Is that what they were thinking? this is how i conceive of the statistics: Sensitivity answers the question, “if my baby has Down syndrome, what is the chance the test will be positive?”. Specificity: if my baby is unaffected, what is the chance my test will be negative?” PPV: if my test is positive, what is the chance my baby has Down s

      • Lina

        Thank you for your helpful reply and the link. I think I understand it a little beter now. It’s still quite sad, though – I was hoping that NIPS/D could be a good way to expand a reliable diagnostic tool into the wider population. I guess we’ll have to wait some more for that.

  16. Again this article pointed out the lack of education in statistics and genetic testing among the public and sometimes even the creator of the genetic tests. I am glad that this genetic counselor wrote this article and is trying to make the public understand that the statistics we obtain from those tests are not always diagnostic. The soon-to-be parents need to be aware of this for sure.

  17. Tamsin

    Hello Katie
    I realise that I am replying to this after the conversation has perhaps closed so I really hope you receive my message. I’d like to thank you very much for your article as it was what gave me the most hope when I recently received a high risk (88%) result for Trisomy 18 on the Panorama test. Although my 12 week scan and blood test had come back with excellent results, 1 in 9173 for T18, my obstetrician and fertility doctor both responded that,while I should confirm with an amnio, things certainly looked pretty bad for me. At this stage I was 13 weeks pregnant and completely devastated. To cut a long story short , I went back for another scan the next day and the radiologist told me that my scan showed a beautiful baby and he didn’t think the Panorama result was right. I had am amnio on December 23 (just before 16 weeks) and again when doing an ultrasound, they said the baby looked excellent in all areas examined (eg head, brain, spine, four chamber view of heart etc etc – all double checked as potential markers for T18). I have just received the final result which, along with the FISH result, was all normal. The radiologists have said the Panorama test was a false positive. While I, and my family, have been through an indescribably terrible ordeal, having to contemplate the worst outcome very seriously, I just feel so lucky that I have been told this is a false positive. I really just wanted to share my story, to thank you for your research and your article, and to give other people in my situation hope. I also really think Panorama and other companies must change their marketing material as it is currently very misleading. The only reason I did the test was because I’m 36 and thought it would give me peace of mind (this is a big part of how the test is promoted), but obviously for me it had the opposite effect creating complete devastation.
    Thank you

  18. Katie Stoll

    Hi Tamsin,
    Thanks for your comment and for sharing your personal and very powerful story here. I am so sorry to know that you have been through so much distress through this testing process. I think speaking up about your experience as you have done here will help to challenge misconceptions about the testing and will hopefully encourage more thought in how information about this testing is marketed to healthcare providers and to patients. Thanks so much again for sharing your experience here.
    -Katie

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  20. Brenda

    My experience was the opposite of Tamsin. At my 20 week ultrasound, the doctor saw a couple of markers for Trisomy 18. We didn’t want to do invasive testing like the amnio, so our doctor suggested we do the Harmony test. She assured us that it was over 99% accurate. I did the screening and it came back negative with a 0.01% risk of having Trisomy 13, 18 or 21. So of course, we trusted those results. Last month we buried our baby. He was born with full Trisomy 18. Obviously we were in shock. How could a screening that is promoted as being so accurate with NO published reports of false negatives be so wrong? What’s the point of even doing a screening if the results can’t be trusted and you have to do invasive testing anyways? I could never recommend the Harmony test to anyone.

  21. Katie Stoll

    Brenda, I am so sorry to hear about the passing of your son. Thank you for sharing your story. I share your concern that the possibility of false negative or false positive test results is trivialized in the discussion of NIPT. Have you found the Trisomy 18 Foundation? http://www.trisomy18.org/ There is a great community of support there.

    • Jo

      I too want to share my story with you in the hope it encourages you to carrying on with your great work. I do want to say that even though this is awful I do feel lucky to have great medical care-I just want people to know the human side too so please forgive the length of post. We were told at our 12 week combined scan that our baby had a 1 in 4 chance of having DS, low risk for T18 and T13. The process is; arrive at the hospital, have bloods taken, wait, then have a long and very detailed scan (lucky for this as we are at Kings London) the scan was great, everything ok, this is our 2nd baby and it was very similar to that of our first – jokes with the sonographer and back to the waiting area with pictures of our baby. At that point the normal chat begins about now we can tell people and general joy that everything is ok. Then you are called back in to talk through blood results (just like with our first) I knew instantly something was wrong as the atmosphere had changed entirely and there were a lot more practitioners in the room-we were told my blood results had increased the risk of DS to 1 in 4. It knocked us sideways, I was so unprepared after such a great scan. Further testing options were explained to us including the option of the Harmony test. We asked how long for results and we were told 2 weeks for Harmony and 10 days for the CVS – on that basis I chose Harmony due to the no risk to the baby factor and they could fo it straight away. The results came back last Friday (11 day agonising wait) as high risk for DS. It is only at this stage that I discover if I did want to go on and terminate I have to have the CVS anyway, even though the results data sheet make it pretty clear it’s highly unlikely to be incorrect and I’m prepared for that. So I had the CVS on Monday and I’m told that the results about DS will be ready on Friday-a much shorter timescale than I was told 2 weeks prior-I understand that the full results take 2 weeks but for DS, which is the only condition the baby is (at this stage) high risk for. So now I have another 3 days and 4 nights to get through carrying my baby and waiting before we are allowed to proceed with a termination if that’s what we choose. I have never experienced stress like this and without doubt the waiting knowing what the outcome is highly likely to be has made this pretty unbearable. I wish I’d understood better the full wait if the results were high risk. I am now 15 weeks and 3 days. I can’t begin proceedings for a termination until 16 weeks plus. I wish I hadn’t been offered the Harmony test. I wish I had gone straight to CVS as by mid last week this most hideous experience would be decided and I could start my long journey of grieving. It is an unbearably isolated situation to be in. I’ve read the stats on how many women terminate once DS is diagnosed but I can’t seem to find any. We carry this terrible decision silently and the drawn out process as made it so much harder.

      • DM

        Hello Jo
        I found myself in a similar situation. According to my first trimester screening my chance of carrying a baby with Down syndrome was 1 in 70. The ultrasound results were excellent, but the blood test results were really really bad (extremely low papp-a at 0,14 MoM). Thanks to my doctor’s lazy scheduling and the lab’s delay in producing the results, I missed the deadline for a CVS. I opted for the NIP test (Prena Test, the European version of the MaterniT21) and it came back positive. I had an amnio to confirm and I ended up terminating the pregnancy at 22 weeks 6 days. So the successive testing did delay what in the end became inevitable. I know it will sound weird, but I did not really mind how drawn out the process was. I was not looking forward to a second trimester abortion (which is basically an induced miscarriage) and the more it looked like this was where I was headed the less I worried about when my results would come in.

        Before having the termination I had what here in Belgium they call an “echo affective”. This is a 3-d ultrasound you have for emotional (“affective”) reasons, not medical ones. I told the doctor who performed it that the baby had Down and I noticed she was curious about whether she could spot it on the screen. She said only the ears seemed to be positioned a bit low, nothing else would have seemed suspicious.

        This would have been my second child too, I found that having a child at home waiting for me helped me get over my hospital experience. Having the baby despite the Down diagnosis was not really an option for me. If it had been a surpise diagnosis at delivery I would have found the strength to cope but I couldn’t knowingly go down that road.

      • Katie Stoll

        Jo and DM, thank you for sharing your stories here. Oftentimes in the US genetic counselors are able to provide support and information and connect families who have similar experiences with one another. Perhaps there are genetic counseling services that could provide this support and information where you live?

  22. Mr.Li

    Katie Stoll:
    How seriously should I take NIPT test positive in 21 trisomy?
    My wife (gestational age 15w) and I, both Taiwanese(in Asia, ethnic Chinese) in 32 years old without genetic history, are in an agonizing wait for the forthcoming amniocentesis next week as a confirmatory check of trisomy 21, of which we were informed last week by a qualified NIFT institution claiming the new sreening method, NIPT, to be a test with the accuracy of 99% sensitivity and specificity as well as very low false-positive rate, with no relevant information of positive predictive value(PPV) published.
    Please kindly advise to me. Best regards.
    a worrisome husband

    • Katie Stoll

      Mr. Li, Thank you for sharing your story. As discussed NIPS is a screening test and the diagnostic testing of amniocentesis should be able to provide you clarification. I hope there are genetic counselors or other healthcare providers that can provide you additional information and support with regards to your specific situation. .

  23. Lisa

    Just wanted to share my result because from what I am learning….it’s rare, unheard of. I am currently 15 weeks and was told, by vertifi, we had monosomy 18. Could be a ring. Guess the ratio of chromosomes was 3:4. I contacted the company asking for a PPV for our situation and they emailed me back, first stating they just tried calling me which is not true…was home all day and I never gave them my phone number. They told me they to not test for that but will be when they get clinical trials set up in the future. It was actually the biggest BS email I have ever read.
    Guess my concern is that they are reporting results that have no trials set up for sensitivity. We were told our fetus is at risk, 10%. It’s always in the back of your mind, knowing the risk is small but yet your told it’s possible for something that they claim they do not test for? Not sure I agree with them giving results, positive yet they write and chromosome ratios for data they do not seem to have a handle on. Just wanted to complain….

    • Katie Stoll

      Lisa, Thanks for sharing this. Sounds like it has been a confusing journey. I hope you have been able to connect with a geneticist or genetic counselor to provide more information and to make a follow-up plan.

  24. Pingback: NIPS SPIN | The DNA Exchange

  25. Melissa Schinella

    I just received a positive diagnosis from the NIPT test for Down syndrome. I am 22 weeks. Termination has never been and option for us. We opted out of genetic testing early because my risk was so low. I am only 26 years old. This is my second child. We did have some very small markers in our ultrasound bit nothing that made it super obvious. I went in fully expecting a negative test to come back. I was told by the genetic counselor and doctor there was a 99% chance my baby has downs. We opted out of the amino due to the risks. So we will just have to wait until the baby is born. But it seems that false positives are more possible than I realized. I know the test is still highly accurate and more than likely my baby does in fact have DS. But I have also read that the younger your are your risk of false positives increase. Is this true of what you have read in your research?

    • Mr.Li

      Dear Melissa Schinella:
      Facing with the decision of whether to undergo
      amniocentesis is a miserable torture, the experience of which my wife and I
      have had (the message I left 3/30 on this page).
      The Z-score of NIPT to my wife is more than 2 but less than 3
      (3 is a standard num generally accepted by qualified NIPT laboratory in calculating the risk of trisomy ) ,
      so we decided to take amniocentesis as a confirmation. The consequence is exhilarating- no trisomy 21.
      I recommand you ponder questions as follows before making your final decision on whether or not undergo
      amniocentesis: Does fetel with trisomy 21 alter the the decision on delivery?
      What will you and your spouse do if you have to raise a kid with trisomy 21?
      Remember seek help and professional consultation form your doctor!
      Good Luck!

  26. Concerned parent

    I am a physician and my 29 year old wife recently underwent the panorama test at ten weeks gestation. It came back positive for turners. Looking over the published data on sensitivity and specificity, I remembered the one lecture that we received in medical school on statistical analysis of test results. I am certainly going through my own denial, but very much appreciate your article and helping me recall the integral importance of disease prevalence to the validity of any test….particularly a screening test. Thankfully for us, it is irrelevant to our decision making process, and we won’t even consider the amino because of the increased risk… but are non the less terrified. However, I do realize that this is a very personal decision, and some chromosomal anomalies are much more devastating. I hope more people come across this fundamental analysis of test results, and take a close look at its validity and the implications associated with a positive test result.

  27. aa707

    With the focus on positive predictive value of these noninvasive tests, Im now wondering what the positive predictive values are for CVS and amnio. Do you have literature on those numbers? I feel like I need to know what I would do if I had a positive noninvasive test in order to figure out if I want to do the noninvasive test at all!

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