How accurate is the new blood test for Down syndrome?

Dice open sourceWhen receiving a test result from the new blood test for Down syndrome that says “positive,” do patients understand there may be a one-in-five chance of a false positive? Or even a one-in-two, depending on the mother’s age? Even genetic counselors admit this is difficult to grasp.

Yesterday, I featured an article from the New England Journal of Medicine raising concerns about Non-Invasive Prenatal Screening (NIPS), the new blood test for Down syndrome, being offered by Sequenom, Ariosa, Verinata, and Natera. The article cautioned against offering NIPS to every expectant mother. One reason noted in the article was that:

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.

In a post on a blog for genetic counselors earlier this month, a genetic counselor further explained the importance of PPV and how it is not being understood with NIPS results.

Katie Stoll is a genetic counselor in Washington State. On the blog, The DNA Exchange, she examines the role of the incidence rate for Down syndrome and a test’s Positive Predictive Value (PPV).

The NIPS labs (and the media reporting on them) highlight their sensitivity and specificity levels as being greater than 99%–meaning their tests can identify greater than 99% of those pregnancies carrying a child with Down syndrome and rule out greater than 99% of those pregnancies not carrying a child with Down syndrome. But, unless some further calculations are done, a mother cannot understand how likely receiving a “positive” NIPS test actually means she is carrying a child with Down syndrome. As Stoll explains, this is because of the role of the condition’s incidence rate.

Incidence rate is how often a condition appears in the population. Down syndrome remains a rare condition, becoming rarer the younger the mother is.

Stoll takes as her example a population of 100,000 35-year old women who have an incidence rate of 1-in-250 carrying a child with Down syndrome. Therefore, of the 100,000 35-year old moms, 400 will be pregnant with a child with Down syndrome (100,000 X 1/250 = 400).

NIPS labs report a sensitivity rate of 99.5%, meaning 99.5% of those actually carrying a child with Down syndrome will be detected by NIPS. Therefore, of the 400 35-year old moms, 398 will receive a “positive” NIPS result (400 X 99.5% = 398). Note as well that 2 will receive a “negative” NIPS report–a false negative, since they are carrying a child with Down syndrome.

NIPS labs also report a 99.9% specificity rate–the percentage of those pregnancies not carrying a child with Down syndrome that will receive a negative NIPS report. In Stoll’s example, there are 99,600 moms not carrying a child with Down syndrome (100,000 moms – the 400 carrying a child with Down syndrome = 99,600). Of those 99,600 moms, 99,500 will receive a negative report (99,600 X 99.9% = 99,500). This then means 100 will receive a “positive” NIPS result (99,600 – 99,500 = 100)–making these 100 false positives.

So, in this example, there were 400 pregnancies actually carrying a child with Down syndrome. Of these, 398 would receive a positive NIPS result, but 100 false positives would also be reported, making for a total of 498 positive NIPS reports when only 400 pregnancies were actually carrying a child with Down syndrome. This means that a positive NIPS report means the mother has a one-in-five chance of a having a false positive (100 false positives / 498 = 20%, or 1-in-5). And, this false positive rate goes up the lower the incidence rate.

Take for example 100,000 expectant moms in their late 20′s. The incidence rate is about 1-in-1,000. This means there are only 100 moms actually carrying a child with Down syndrome (100 X 1,000 = 100,000). Of these, 99.5 would receive a positive NIPS result, given the 99.5% sensitivity rate. But, 100 of the moms who were not carrying a child would also receive a positive NIPS report (100,000 minus the 100 carrying a child with Down syndrome = 99,900 X 99.9% (specificity rate) = 100). So there are 100 true positives and 100 false positives reported. A “positive” NIPS result in this low risk population means only a 50% chance of actually carrying a child with Down syndrome (100 true positives out of 200 total positive reports = 50%).

Stoll’s post and the New England Journal of Medicine article make the same point: the accuracy of NIPS remains unknown because of the way the labs report both their research and their test results. The professional societies have called on the NIPS labs to standardize their reporting so the accuracy of each companies’ test can actually be determined. The NIPS labs have not done so, but as these articles, and hopefully this post demonstrates, a positive NIPS result is not a true positive.

Update: the subsequent posts in this series explain positive predictive value and its relation to maternal age, with graphs visually displaying the percentages. See these posts at this link and this link.

Comments

  1. Thanks for crunching the numbers on this. The claims to accuracy look a whole lot less impressive when you see what it actually means.

  2. Mark, I can’t tell you how much your articles are giving me hope for a healthy baby. I am 28 years old and recently received Panorama results with a 99/100 chance for my little boy have T21. I am still so confused and sad about such results. I took the Panorama due to two spots on his heart. After receiving the Panorama results I met with a genetic counselor, MFM ultrasound specialist, and followed that with a fetal echo cardiologist specialist. The 2d and 3d ultrasound depicted a healthy baby from head to toe with no further markers from the MFM specialist. Additionally, the fetal echo cardiologist ultrasound showed a perfectly healthy heart with only the two calcium/soft markers showing. However, when I talked to the genetic counselor she informed me the Panorama is 99% accurate and by receiving a positive result it is pretty much a guarantee that he has T21. I know the ultrasound does not diagnose T21 but I find it so hard that his eyes, nose, neck, feet, spine, leg and arm length showed no sign of T21. He was measuring at 50th percentile. I opted to not have the amnio as we will raise this child no matter the circumstances. We have known of this information for three weeks and I still have 12 weeks remaining until my due date. I am so confused and the anxiety is killing me. I have contacted Panorama as well as quest diagnostics and both companies refuse to talk with me. Both companies refer me to my Dr. My Dr. Office has only used this test for a few months and I am the first test to show positive.

    • Thank you for your comment and I’m glad my writing has provided you comfort. Anxiety is barely discussed, despite it being almost ever present in prenatal testing. It is unfortunate that your genetic counselor suggested that a NIPS result is “pretty much a guarantee,” since given your age and your other prenatal tests, i.e. the ultrasound, would suggest the NIPS results may still have a high false positive. Nonetheless, I would suggest reviewing the book, Diagnosis to Delivery, which is available for free as a .pdf at http://www.downsyndromepregnancy.org. The book is written for mothers with a positive result who intent to continue their pregnancy, and addresses the issues mothers have reported when they have known prenatally that their child will have Down syndrome. While your case remains a maybe, the book can help prepare you in the event that the Panorama test is indeed correct. Regardless, it sounds as though your child is developing well and I hope that you have a healthy, and smooth delivery.

    • Dear Ms. BETHK, Thanks for sharing your life experience. Sorry to be nosy and I apologize in advance, we have had a positive Panorama test as well and was wondering if your baby turned out to be ok?.

      Thanks and god bless.

      • Our baby does in fact have down syndrome. Fortunately our little one did not need surgery as we feared shortly after birth so health wise there is no issue there and all other tests have come back great. I can tell you once the little one arrived the diagnosis was much easier to deal with emotionally. I will be praying for the best for you and your family.

        • Beth–I’m glad to hear your baby did not need surgery. And I understand Harry’s phrasing of wondering if your “baby turned out to be o.k.,” but I hope you will share my appreciation if you don’t already that our children with Down syndrome are o.k., even with having Down syndrome. I further hope you are receiving the support you need and have found helpful written resources. The National Society for Genetic Counselors has a list of approved resources at this link. I particularly appreciated Babies with Down syndrome (we had a postnatal; the book can be overwhelming particularly prenatally, but it helped in providing information in a postnatal setting); I found “Expecting Adam” to be extremely well written and a unique way of experiencing having a child with Down syndrome; and I know many mothers, particularly, who enjoyed the stories shared in Gifts. I contributed a chapter to Gifts II. Congratulations on the birth of your child.–Mark

          • I understand where he is coming from with the wording. No hurt feelings here.
            I am about ten pages into Gifts and it is my favorite book regarding DS. I will be sure to check out Gifts II. I didn’t realize there was a second so I will definitely look for this book as well.

          • I’m glad you’re finding Gifts a useful resource. From my post from yesterday, we found it tremendously helpful to link up with our local support group and talk with fellow parents. I wish you and your child well.

          • Thank you again for your words of wisdom and support. I look to seek a local support group soon. It has just taken me some time to be at a place where I am mentally ready to partake in a support group.

          • Beth and Mark, Thanks for being an awesome support, I truly appreciate it, I am glad to hear Beth that your little one did fine and you are enjoying your parenthood, again if I used the wrong choice of words I apologize with all humility. Once again this blog give us all so much hope and support, cannot thank you two enough.

  3. GiveMerealScience says:

    What kind of test is that? It sounds that the test has 99% specificity (true positive) but 99% sensitivity (false positive). Is it like 50/50 chance?

  4. My friend is 44years old and 4 months pregnant. The test results are 1:42. She does not know how much of baby being with downs syndrome. She wa just she is a positive and to research on internet what that mrans. She is so broken now even considering abortion. They told her they will di amnioscentesis in january and give her an option of abortion then
    I heard that this amnioscentesis can also be risky to baby. Please help us understand these results before this dreaded abortion.

    • A report of 1:42 means that she has a 1 out of 42 chance that her child has Down syndrome. This can also be understood as a 2% chance of having a child with Down syndrome. You’ll see at the chart in this post, though, how she had a 2% chance based just on her age, so the test really does not show much of an increased chance for having a child with Down syndrome. The test that provides a diagnosis in the 2nd trimester is an amniocentesis and it does have a risk of miscarriage associated with it. Studies report a wide range, from less than .5% to over 1%, but really the only relevant rate is the one your friend’s doctor has with his or her procedures, so that is something to ask about. I hope your friend will review the resources recommended by medical professional organizations at the Prenatal Resources tab to provide her up-to-date, accurate information about what it means to have a child with Down syndrome.

  5. I did the Panorama test with Natera and received and 87% chance of DS. My baby was born with DS in October. I just wanted to pass along the score and the results because when I was researching what everything meant while I was still pregnant, it was difficult to find a score that was high but not in the nineties range.

Trackbacks

  1. [...] question was prompted by a comment  by Robert Resta on the blog post that I discussed on Tuesday. Resta is the same Genetic Counselor who noted that in this century, most Down syndrome [...]

  2. […] as compared to 1st trimester screening has been introduced in Mumbai. [has not been shown more accurate in all populations] It can detect chromosomally linked diseases like Down’s syndrome with a […]

Leave a Reply

%d bloggers like this: