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.
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.
The DNA Exchange 
Interesting stuff. Did you directly contact anyone affiliated with the NIPS labs to share these thoughts regarding their reporting practices?
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.
Katie,
Would you allow your figure to be used in a publication? We would acknowledge you. I am a professor at the UW.
Mark Drangsholt
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???
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.
I am just dumbfounded that your giving advice on how to “counsel” patients when you just wrote an article about misleading advice, marketing, and messaging. If you do not work in prenatal, why would you be giving advice as to how to counsel? Lisa, if you need further support on how to counsel, speak with another genetic counselor that works for the laboratory offering the tests.
Sandy, I am not the author of the original post, so I am a bit confused as to your statement that I “wrote an article about misleading advice, marketing, and messaging.” However, I don’t think that a writing such an article should disqualify anyone from providing suggestions about how to present NIPT results to a patient, as your comment seems to suggest.
I agree with you that the fact that I’m not a prenatal GC is relevant, which is one of the reasons why I disclosed this when giving my suggestion. To clarify, I am a CGC and epidemiologist whose primary work is in a research setting at a large integrated healthcare system. I have counseled prenatal patients in the past, and I am familiar with the literature on NIPT, but I do not currently see patients.
I consider my comment to Lisa (and any other comment on this blog) as part of an ongoing, public dialogue. Lisa had a specific question about how to counsel a patient and seemed to be concerned about presenting accurate quantitative estimates, so I suggested a qualitative approach that might appeal to her (or it may not).
Since my suggestion may not be considered credible due to my lack of experience, I would encourage GCs with direct and recent experience in counseling NIPT-positive patients to share their approaches so that others can become more knowledgeable, more supportive counselors for their patients. If those ideas are not shared on this blog, then at conferences or with colleagues in clinic.
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?
Hi Maria – here is a link to the tables that illustrate the calculations for PPV and NPV in more detail for DS, T18, and T13 in a 35yo. The table in the post does separate out each condition – I just lumped them together in the text to highlight the possibility for any FP result in this population. https://docs.google.com/file/d/0B4Qk4jle8tsbT1FXcDJUaldMSGs/edit?pli=1
Hi Katie,
I’m also wondering about the total test positives, which appear to be assumptions in both the table above and the tables provided in your link. For example, it’s presented as a given that Trisomy 18 positives will be 449 of 100k tests; this represents a false positive rate of ~90%! If this is true, it’s the crux of why your lumped values for PPV come out so poorly.
Can you provide more detail as to where the numbers 498, 449, and 218 come in for total test positives for Trisomy 21, 18, and 13 respectively? What have I missed?
I also might point out, for the benefit of any women older than 35 reading this, that I would expect 35 yo women to be the worst case scenario for the test on the basis of it being the tested population with the lowest actual incidence of genetic issues. Bayes being Bayesian, a test grows more accurate in a population with higher incidences of a phenomenon being tested.
The false positive rate is calculated as the number of false positives divided by the sum of the number of false positives and the number of true negatives. So, I believe the false positive rate is less than 0.5 percent with the numbers provided.
Hi Keith,
Yes, these numbers are based on modeling using the incidence of T21, T18 and T13 at 16 weeks gestation at age 35yo of based on the reference cited. The specificity of the testing reported for each condition by each lab varies, and differences in test specificity have a significant effect on PPV calculations. The sensitivity and specificity used for these calculations were in a range of what was reported by the labs when this was originally written. This post was intended to illustrate the importance of the PPV when interpreting an NIPT result and such calculations would ideally be individualized using the prior probability of the condition in a specific patient along with the specific performance data of the lab who performed the test. Your point that “a test grows more accurate in a population with higher incidences of a phenomenon being tested” is one I was trying to emphasize as well.
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.
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.
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.
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.
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.
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.
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’.
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.
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.
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%.
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.”
“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.
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).
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.
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. 🙂
I found this article (Hum Reprod Update. 2013 Jul-Aug;19(4):318-29)) of interest.
I agree, Dr. B. The review by Mersy et al http://www.ncbi.nlm.nih.gov/pubmed/23396607 is very interesting. There is an excellent table included in this paper that calculates the NPV and PPV at various Down syndrome incidences. Definitely worth a read for anybody interested in this topic.
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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?
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.
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
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.
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.
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
I stumbled upon this forum after searching for weeks. I am 43 and took the Panorama test on September 24, 2014. My doctor called when results were in (delivered the “BAD” news over the phone no less). I was told I had a 99% chance of our baby having Trisomy 18. I was not even told what Trisomy 18 was. What followed after the “BAD” news was, “I am sure where you stand on termination”. From the moment the results left her mouth I and my husband both had peace that all is well with our baby. I have not had further testing yet because I am in the process of switching doctors. I was never educated by the doctor in the least when it came to the Panorama test. I would not have done the test. My question is, is 99% positive 99 out of 100 chance? Do I have a 1% chance all is okay?? I am so confused at this point and need help understanding.
Thank you kindly.
To my knowledge, none of the currently available NIPS tests can predict a 99% (or >99%) chance that a pregnancy is affected with a chromosome condition. I know some companies report out high risk results as a “risk score” of >99% or >99/100. I find this to be confusing. Although the companies vary in how they report out a high risk result (“aneuploidy detected”; “positive”; >99%) they are all basically indicating an increased risk – but no studies to date support that any NIPS, test in and of itself, can provide a definitive, or even a 99% probability that a positive result is truly positive. I encourage you to meet with a genetic counselor to discuss your results in the context of your personal situation. Other factors such as ultrasound findings, the results of other screening tests, age related probabilities could all be factored in to provide a more personalized understanding of your risk. You can find a directory of genetic counselors in your area at nsgc.org
Dear Katie,
I am grateful for your reply. I will be seeing a new doctor on Tuesday and will post with an update. After getting all of my medical records from the previous doctor I found that the ultrasound detected nothing, all looked normal. After further reviewing the Panorama results it looked as though for my age the cutoff for being a low risk result was 1:46 and mine was 1:33 so it was a HIGH RISK for Trisomy 18. In all honesty, if the doctor would have said you have a 1:33 chance of Trisomy 18 I would not have been stressing for the first half of this pregnancy as I have been.
Melisa
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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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.
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.
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.
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.
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?
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
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. .
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….
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.
Katie,
This article has given my wife and I hope and we are thankful for that. We have been on a roller coaster that we just want off of at this point. Our quad screen results had a T21 risk of about 1-6700 so naturally we felt very good about our pregnancy as everything else is showing great growth. At our 20-week scan, the doctor was having trouble finding the nasal bone b/c our little girl would not cooperate.
He recommended the Harmony Test and quoted it as being 99% accurate and it would rule out any T21. We were nervous, but felt okay that the doctor was just playing it safe as even after he suggested we have this test he felt as if everything would be normal. After the results came back, it showed us as a high risk (>99%) that our little girl has T21. We are crushed, heartbroken, and sad for our little girl, but with so much conflicting information we don’t know what to believe. By definition, my wife should be characterized as low risk (Age 31 at conception) and a borderline soft marker at the 20-week scan. So how reliable can this test be in the low risk population? If the odds of T21 are .1%, does your PPV chart suggest that our positive result has a 50-50 shot of being wrong? And if her risk after the quad screen was 1/6700 (.015%), does that mean that a positive result is in the neighborhood of 15-20% accurate?
We had the amnio done and it went smoothly, but the waiting is killing us and we are expecting the worst, but I have more and more doubts about these NIPS test results in low risk pops…we are just praying for it to be a false positive as we have been devastated for the better part of 3 weeks now.
Thanks so much and I hope you get to read this!
-Adam
PS-I posted this down below but I thought I might get a better response if I tagged it under one of your posts.
How did this come out for you? I hope in your favor. We are in this position now and it is the worst thing I could imagine. I wish we never had the damn test!
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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?
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!
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.
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!
Katie,
This article has given my wife and I hope and we are thankful for that. We have been on a roller coaster that we just want off of at this point. Our quad screen results had a T21 risk of about 1-6700 so naturally we felt very good about our pregnancy as everything else is showing great growth. At our 20-week scan, the doctor was having trouble finding the nasal bone b/c our little girl would not cooperate.
He recommended the Harmony Test and quoted it as being 99% accurate and it would rule out any T21. We were nervous, but felt okay that the doctor was just playing it safe as even after he suggested we have this test he felt as if everything would be normal. After the results came back, it showed us as a high risk (>99%) that our little girl has T21. We are crushed, heartbroken, and sad for our little girl, but with so much conflicting information we don’t know what to believe. By definition, my wife should be characterized as low risk (Age 31 at conception) and a borderline soft marker at the 20-week scan. So how reliable can this test be in the low risk population? If the odds of T21 are .1%, does your PPV chart suggest that our positive result has a 50-50 shot of being wrong? And if her risk after the quad screen was 1/6700 (.015%), does that mean that a positive result is in the neighborhood of 15-20% accurate?
We had the amnio done and it went smoothly, but the waiting is killing us and we are expecting the worst, but I have more and more doubts about these NIPS test results in low risk pops…we are just praying for it to be a false positive as we have been devastated for the better part of 3 weeks now.
Thanks so much and I hope you get to read this!
-Adam
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Katie, thank you so much for your article – both for the hope it has given me and for your effort to change the way these tests are discussed. I am 34 and had a good nuchal transparency ultrasound, no markers indicating anything wrong. I opted to take the MaterniT21 test anyway because of the way it was explained to me. My genetic counselor only told me that the test would check for Trisomies 21, 18 and 13 and that it was 99% accurate. I knew of the risk for false positives with traditional screens and told him that I was nervous about that, but he assured me this test is different. I received my results this week, and while they were negative for the thee more common abnormalities, they included an additional finding “suggestive” of deletion 22q. I didn’t even know they were testing for anything beyond the three mentioned trisomies, and my results didn’t include any other information (such as a 1 in xyz chance). I have schedule an amnio, but must wait two weeks until I am 16 weeks, then I will need to wait for those results to come in (two additional weeks for the full panel). It has only been 4 days since getting the results, and it has been agony. I can’t imagine waiting weeks or a month to know. And now I wonder if I should risk an amnio if the PPV is so low. But how do I make that decision without hard data (my personal risk, the PPV for this aspect of the test at this particular lab…)?
Although my doctor said that this is not definitive (and he only said that when giving me the results), neither he nor the genetic counselor explained PPV to me, or how that may relate to my results. I tried calling the lab, but they would not discuss my results or give me any information about how often deletion 22q is detected on the test. It is only through many hours of research that I have come to realize that this may not be a true positive. Your article explained it in a way to me that has given me hope. Given that deletion 22q occurs in about 1/4000 births, I am hopeful that the odds of this being a false positive are greater than it being a true positive. I need that hope to get through this period of waiting, even though I know it could end up either way. I am furious about how things were presented to me and think it is tragic that women are not given this understanding from the beginning. Even if they choose to consent to the test, they should know it’s limits.
I thought after this post I should update our result! I had my little girl three weeks ago now and it was a false positive for a deletion on chromosome 18. We did not do an amnio but just relied on ultrasounds to look for any abnormalities found associated with monosomy 18. I am not sure how accurate my next statement is but I was told the tests are seeing errors with deletions because the computer is having trouble knowing where a piece of a chromosome goes. I was told to think of it as filling baskets and certain sections of a chromosome are suppose to go into the basket for that chromosome determined by the computer. If part of the DNA looks too similar to another chromosomal DNA then it gets put into the incorrect basket leading one to not be as full creating a “deletion”. Guess, from what I understand, the deletions are pretty inaccurate at this time and they just started to report those this last winter and we are all in an experimental trial. Not sure if that helps you decide what to do but wanted to let you know what I learned so you can make the decision that’s best for your family with the limited information out there on microdeletions. The impression I got was part of my babies chromosme 18 must be similar to another chromosome and was put into the wrong basket. Our placenta was normal also…best of luck and try to enjoy your pregnancy and not worry about all these new 5-10% risks we are now given now due to too much testing/probing. 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 after making myself an expert on monosomy 18:). Congrats on your baby!
Thank you, Lisa! Congratulations on your little girl! I don’t understand how these companies get away with this. Not only are they essentially experimenting on us, as you said, but they are not transparent about the potential problems with validity or low PPV. I think it is criminal. I don’t know what we will decide about the amnio, but at this point I think that, no matter what we decide, I will spend my entire pregnancy wondering if we made the right decision.
Hi Sarah,
I’m a mother who has written and researched about these tests (I’m pregnant after having a child with Down syndrome, so was particularly interested in the NIPS option). I’ve written about it here: http://kimchilatkes.com/2014/10/16/materni21-harmony-and-verifi-myths-and-realities/
I just wanted to tell you that if you have had a negative NIPS experience, or feel that NIPS was incorrectly or misleadingly explained by the company’s marketing material, you can report it here: https://www.accessdata.fda.gov/scripts/medwatch/ (Prenatal tests fall under the “medical device” category.)
I’m so sorry that you’ve had such a negative experience, truly. I hope these next weeks pass quickly and you have some answers soon.
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Thanks to all who have shared their stories here in this comment thread. Here is a link to a follow-up piece about NIPS – largely inspired by some of the personal experiences shared here https://thednaexchange.com/2014/11/02/guest-post-nips-microdeletions-macro-questions/
Katie,
I align exactly with the 35 yr old woman in your example that has received a positive screening for trisomy 18. I did meet with a genetic counselor who has advised me to have an amnio, however my understanding (given so many stats stating 95%+ accuracy rate) was that I was simply confirming what the NIPT already told me by following up with the amnio.
I am in near disbelief at the explanation of the positive predictive value demonstration you have provided in your post, and the lack of this very important datapoint in any materials or discussions I have had as this unfolds for me in real life.
I understand that this screening is a huge advancement and appreciate the value in giving peace of mind to women. However, if the data you present is accurate I am appalled that (as a well educated women, though not in the medical field) I feel that I was duped by the companies providing these statistics.
As I await follow up, it seems to me the screen is extremely good at ruling out a chromosomal condition. However, given the poor PPV it should never be explained to someone in my position as being near diagnostic or simple and clear. Your title (convincing ourselves and patients) is fitting.
Regards
I received a >99/100 result for T13 from Panorama, with blood drawn at 10 weeks and a fetal fraction of 16.4%. This article helped me get through the long wait from week 12 when I got my Panorama results to week 17.5 when I got my amnio results back indicating my baby has totally normal chromosomes. Understanding the positive predictive values behind the Panorama test gave me a lot of hope that my baby would be healthy. Thank you for this article. I just wish that these NIPS companies would post these positive predictive values on their websites and in their brochures.
My maternal fetal medicine specialist office had no false positives when I first visited them around week 13, but when I went in for my anatomy scan at week 18 they told me that I was one of three T13 NIPS false positives in their office alone. This worries me that there are likely thousands of parents to be across the country going through the same stressful wait, many of whom do not understand the mathematics behind the real statistical values. I highly enourage genetic counselors, ob-gyns, and MFM specialists to advertise the positive predictive values to their patients who receive positive NIPS and not just the 99% accuracy rates.
Thanks for sharing your experience. I agree with you that healthcare providers need to really understand and communicate PPV information to their patients. Relying on “99% accuracy” can be misleading. And the PPV info should be discussed when a result returns positive but also in the pre-test counseling so that individuals can make the decision about whether or not to undergo these screening tests based on an accurate understanding of the benefits AND limitations of the tests. I think it is important to recognize that the company websites and brochures are marketing materials and aim to portray the product in the best possible light. Recently I have noticed PPV information reported in some lab marketing materials however the PPV information reported does not always seem to fit with what we see in medical research. Healthcare providers need to go beyond the glossy brochures and company websites to really understand test performance.
I am sharing a link to a story in the Boston Globe on the topic of NIPT that may be of interest to many of you on this comment thread. https://www.bostonglobe.com/metro/2014/12/14/oversold-and-unregulated-flawed-prenatal-tests-leading-abortions-healthy-fetuses/aKFAOCP5N0Kr8S1HirL7EN/story.html#comments
Also, I encourage you to participate in this online Live Chat on the topic from 2-3 EST tomorrow 12/15: http://necir.org/2014/12/12/prenatal-web-chat/
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Thank you for starting this discussion here, it gives expecting mothers like myself hope that my baby will live! What unbearable emotional stress a positive screening result is for trisomy 13, which we had at 15 weeks (we are 19 weeks now). We had the NIPS testing because I am over 35, our 16 week ultrasound showed no markers for trisomy 13 yet. The collateral damage of this screening test far outweighs any good it can do for expectant mothers. Our genetic counselor told us there is a 92% FALSE positive rate, here’s to hoping we are lucky enough to fit in that category.
Update…we are now about 30 weeks and no markers have shown up in ultrasounds for Trisomy 13. We still do not want to risk having an amniocentesis but have hope that we have a false positive since the baby’s growth is great so far and looks perfect.
My baby boy Lincoln is now two months old and is perfect, no trisomy 13, it was a false positive and such a long emotional wait since we didn’t do an amnio. Hardest thing was letting go of the fear and choosing to love. Positive thoughts out to those dealing with these situations!
We are in the agonizing position now of waiting to have an amnio to very a positive T18 screen from Verifi. I am so glad I found this as it provides some hope and the doctors did not. I am 35 and our NT measurement was 3.9, clean family history. Do you think that NT measurements are reflected here, and do you have any explanation as for how these false positives happen in the first place? Thank you!
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Thank you so much for this article.
I am reading about it on behalf of a friend of mine who has recently received a Harmony test result of ‘>99% risk for T18’. They claim a detection rate of 99% and a false positive rate of 0.1%. I am a molecular geneticist but some of these concepts still escape me. Can you please clarify something for me – are those figures the sensitivity and specificity rate? if not, how is that ‘false positive rate’ calculated??
I’ve been looking at their website and they do acknowledge (if you really look for it and know what you are looking for!) that the PPV for T18 is around 65%
thanks
I’ve had the same result >99 trisomy 18. My degree is in Maths and I am stunned at the lack of clarity in Harmony literature. Perhaps not helped by having no sleep at all due to the horrendous upset. What I would also like to point out is that I’ve not been asked to follow up on any further results. So if I was a false positive, which they would have me believe is 99% unlikely they would never know.
Generally, the detection rate is the same as sensitivity and the specificity could be calculated by 1- FPR. To calculate the PPV though, you also need to know the prevalence of the condition in the population being screened – so in the case of T18 it depends on maternal age, any ultrasound findings, biochemical screening results, etc. The PPV of the test would be expected to be higher in women who begin at a “higher-risk”. You may find some useful information in this fact sheet developed by the National Society of Genetic Counselors http://nsgc.org/page/abnormal-non-invasive-prenatal-testing-results . It could also be helpful for your friend to meet with a genetic counselor to sort through all of these variables if she hasn’t already done so. A directory of genetic counselors can be found at: http://www.nsgc.org/
Thank you so much for your reply. The link to the NSGC page is really useful.
So the way that the PPV value is affected by the maternal age is through the prevalence, ie higher prevalence at older age, therefore higher PPV, therefore more chances that a positive is a true positive, correct?
She is 40, would you have an estimated PPV?
also what is still not clear to me is how is the false positive rate reported by the lab calculated?
thanks again
Ana, I would encourage your friend to seek a consultation with a genetic counselor and/or MFM specialists who should be able to put all relevant factors related to your friend’s personal situation into context for the interpretation of her NIPS results.
Thanks Katie, she is doing that anyway, I guess I am just very anxious for her!
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As the author of this post, I would like to share a new resource that may provide useful information related to many of the questions asked in this comment thread. Check out the animated video and website content at Genetic Support Foundation’s website: https://www.geneticsupportfoundation.org/genetics-and-you/pregnancy-and-genetics/noninvasive-prenatal-testing-the-real-deal-and-what-you-need-to-know
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My daughter-in-law 28 yrs 20 weeks had Just Taken An Amnio test. Even Though her Ultrasound 4 showed a very good Nasal passage hands, Legs, head, 4 chambers hearts rate all perfect as stated my her Phone call by her reg doctor baby is perfect in growth. Why do I write. Because she is physically depressed since she talked to a Counsler prior to her U3/U4. she took a T21 test – two doctors checked on the Ultrasound 3/4 and they also just shook their heads this baby is perfect no markers and same as above on all checks on baby were perfect.. now mind you, this counsaler was not present, she talked to both my son & daughter-in-law through Skype. Yes Skype. She gave no hope, no compasion, Just how to Abort her fetus with a 99/100 rate That it has DS. Just waiting now for Amnio- NOT HAPPY WITH A COUNSLER THE WAY SHE TALKED TO THEM WITH NO HOPE> THAT IS ALL MY DAUGHTER-in-LAW HEARS. in her head. I Just needed To vent.
Dear Linda and Family,
I am commenting because I went this a few short months ago. I was 44 at the time and had the genetic testing done via bloodwork. I am sitting at my desk working when I get a phone call from my doctor. She says that she has BAD NEWS (exactly her words). Says that my baby tested 99% positive for Trisomy 18 and that I should abort. I then asked if she could tell me the gender as we paid extra to find out. She said, Oh! You still want to know???? I was soooo upset. When I googled Trisomy 18 I was in shock and couldn’t not speak for days. For the record we did lose our beautiful son to Trisomy 18. He was perfect on the outside, his heart was not formed properly. I carried him until 34 weeks and would do it all over again. I can relate to how your daughter-in-law must be feeling. The medical world is so insensitive today. I did switch to a new doctor in my fifth months which was a blessing. I PRAY for your son, daughter-in-law, and God’s precious gift coming to all of you soon.
Melisa,
I am so so sorry for your loss. Samantha had the T21 and that is exactly what they said (BAD NEWS NOT GOOD) well she will have to wait for the Amnio result. I saw her last night – because of her being so worried, you can see it in her face. She asked me what are we going to do Linda If it is bad news. All I said to her was “God gave you a hand and we will all deal with it” To you Melisa and Family, may God look over your baby & Family and I will say prayers to you and all of the mothers to be.
Thank You, Linda
Linda,
Thank you for the reply. I just read it and I KNOW what she is feeling and it cannot be described. I was a zombie because I could only think of what I was told. God will carry her through this if it is T21. My prayer to Him is that the baby is perfect 🙂 She is blessed to have you. Take care.
Melisa
Katie,
I am also experiencing the uncertainty after receiving a high risk score for T21 on the panorama test. I am unwilling to undergo the amnio because of the risk. I am 41 and my ultrasound showed a soft marker and a couple very borderline ones. I know that a few factors can skew the results. I have had 6 prior children without chromosomal issues and one pregnancy that resulted in a first trimester miscarriage less than a year ago. Could this possibly increase the risk for a false positive?
Tonya
Well results are in on my Daughter-in-law. Amnio confirmed DS. Their Genetic Counsler has no side manners just the worse. My son called lab himself and they confirmed, I saw May daughter-in law this morning and she is a mess. My son is in distress and can not handle this. I Just so Not Know what to say. I have no words. Now my husband thinks we should get checked and see if it was from us. What a heartach. Her Ultra sound showed no markers and baby looked great. Just do Not Understand.
Linda
Dearest Linda and Family,
My heart aches with all of you, especially Samantha. I’ve been there when getting devastating news and I know what she is going through. God will get all of you through this. PRAYERS going up for all of you. Linda, I may be wrong but I don’t believe it is hereditary so you and your husband are not to blame. I believe that God is in control and is still in the business of healing. No matter test results or what doctors say, HE is a healer!
I wish all of you PEACE.
Melisa
Dear Linda,
I am simply checking in on Samantha and your son. She is on my mind daily . Can you please let her know that for me. I will keep all of you in my prayers as go through this journey.
Melisa
This article and comment thread really helped give me hope the last 2 weeks, so I want to share my experience in the hopes it will help someone to not have to go through this unnecessary stress!
The only screening we chose to do in this pregnancy was originally the NIPT Trisomy 13, 18 and 21. When we received the form for the NIPT, I checked off the microdeletion test boxes thinking “why not?”…well now I know why I would never check off those boxes again.
The test results came back with “high risk” (1 in 19 chance) for DiGeorge microdeletion 22q11. I was pretty stressed about this result and we decided to have the amnio after having met with a genetics counselor.
The first thing she said was that she tells all people she’s counseling to NOT get the microdeletion tests which have a 95% false positive rate. In my research, I also saw a post by an OBGYN who said they do not allow these microdeletion tests to be done in their clinic – only trisomy. It is ridiculous that this test can even go to market.
The amnio went well and it took 10 days for the microdeletion tests to come in. I received the call and it turns out I was yet another FALSE POSITIVE. I was so relieved that I burst into tears when the genetics person told me.
Now I am on a mission to help educate and spread the word about these microdeletion tests/screenings. I would never, ever, ever get the microdeletions again! I’m so happy to be in a peaceful space again…:D
I received a negative result for all disorders including Down syndrome when did Panorama test at 10 weeks of my pregnancy. Fetal fraction was about 8%. All ultrasound tests were also fine. However , my second blood screening showed 1:18 risk for Down Syndrome ( I am 38 years old).
The discussion above was more about false positive , but can we really rely on negative results of NIPT ? I am currently on 19 week of my pregnancy and I am thinking about doing amnio next week.I understand that the real answer if my baby has Down syndrom or not could be done only through amnio, but taking into account the high specificity of NIPT and good ultrasound , would be the predictive value of NIPT together with ultrasound as the same level as amnio?
I hope you will have an opportunity to meet with a genetic counselor. It is a challenge when you have two screening results that say different things. Yes, the negative predictive value for NIPT testing is high, but not 100%. Although infrequent, false negatives can occur.
Thank you so much for writing this article. After being called by my doctor and told my NIPT test came back with trisomy 18 detected and told nothing else other then you need to go get an amniocentesis I was lost. After doing my own research I came across your article that was one of the only ones that truly explained what these results mean. It has helped ease my mind that after two healthy pregnancies our third has a chance at being healthy as well. Do you suggest an amnio if you do test positive or first an ultrasound ?
So I found this article a few years ago when I also was in disbelief about the NIPT. Unfortunately the amino confirmed the results. I was able to meet my little girl but I only had her on Earth for one week. There is a whole community of living trisomy children though. If you are on Facebook please look up the Support Organization for Trisomy (SOFT). I hope your results are in error but if they are not there will be an entire community to support you. Doctors are often unkind. Don’t believe all the horror on the Internet.
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