What exactly is MaterniT21, Harmony, verifi, & Panorama testing?

Fig. 2 Implantation of embryo

Fig. 2 Implantation of embryo

If more women were accurately counseled about what exactly cell free DNA is testing, they would immediately understand that their test results are never diagnostic.

Over at the blog for the Prenatal Information Research Consortium, I have a summary of a report from the largest study of cell free DNA (cfDNA) testing in a clinical setting. It reports some key findings:

  • For all of Sequenom’s, Ariosa’s, Illumina’s, and Panorama’s marketing that their tests are “99% accurate,” the study found that in a high risk population, the positive predictive value (PPV), i.e. the actual chance that a “screen-positive” was a “true positive,” was only 77.4% for all conditions tested. (Some may recall a study of cfDNA in the general population only had a PPV of 45.5%).
  • Nine patients terminated their pregnancies based on a “maybe,” i.e. without having diagnostic testing to confirm their cfDNA test results.

But, the study also makes clear what is being tested–and it’s NOT fetal DNA.

Labs say cell free fetal DNA

What do the labs say they are testing?

Sequenom continues to say “Using a maternal blood sample, the VisibiliT and MaterniT21 PLUS tests analyze chromosomal material in cell-free fetal DNA of pregnant women.”

Sequenom fetal DNA

Ariosa, maker of Harmony, says on its website for healthcare professionals that it carefully measures fetal DNA, with a graphic showing how fetal DNA enters the mother’s blood stream:

Harmony fetal DNA measure

 

Ariosa Fetal DNA

Illumina states that its test verifi “directly analyzes cell-free fetal and maternal DNA”:

illumina fetal dna

In a white paper from March 2014, Natera says that its test Panorama “analyzes maternal and fetal cell-free DNA” with a graphic showing fetal DNA entering the mother’s blood stream:

Panorama fetal dna

 

Natera cell free fetal dna

(All screenshots taken June 14, 2015).

Turns out, though, it’s not cell free fetal DNA.

Placental cytotrophoblastic cell line

In the report from the University of Washington Medical Center, the researchers reviewed over 600 patient files who had had NIPS testing. Their research showed that while cfDNA testing, also referred to as Non-Invasive Prenatal Screening (NIPS), can be a reliable screen when used as a second-tier test for women already determined to be high-risk, false positives and false negatives still occur.

One of the reasons for why false positives and false negatives occur is because of what is actually tested:

During pregnancy, placental cytotrophoblastic cells are shed into maternal circulation and contribute to the cfDNA in the maternal bloodstream.

* * *

the source of non-maternal cfDNA during gestation is the placental cytotrophoblastic cell line. Aneuploidy in the cytotrophoblastic cell line with a diploid fetus may cause abnormal discordant NIPS result, whereas diploidy in the cytotrophoblastic cell line with a trisomic fetus may cause a normal discordant NIPS result.

Translation:

  • what is tested by NIPS is cell free DNA from placental cells shed into the mother’s bloodstream. It is this placental cfDNA that is tested by NIPS.
  • There is a phenomena called “confined placental mosaicism,” where confined to the placenta, there will be cells with a chromosomal condition called “aneuploidy,” an extra or missing chromosome, like Trisomy 21 (Down syndrome) and Trisomy 18. Conversely, there are fetuses with those same aneuploidies while the placental cfDNA tested does not have aneuploidy cells.
  • In the case of a false positive, the placental cells had aneuploidy, but the fetus did not and vice versa for a false negative, the placental cells did not have aneuploidy, but the fetus did.

Now, “placental cytotrphoblastic cell line” doesn’t roll off the tongue as easily as “cell free fetal DNA” and it doesn’t suggest the degree of certainty that “fetal” DNA does for a prenatal test. But even if “placental cytotrophoblastic cell line” is a mouthful, it’s what MaterniT21, Harmony, verifi, and Panorama are testing–not fetal DNA.

Standard of care recognizes cfDNA as testing of placental, not fetal, DNA

The American College of Medical Genetics and Genomics (ACMG) plainly stated that NIPS is testing placental DNA in its statement from 2013:

the sequences derived from NIPS are derived from the placenta

The graphic at the top of this post is from a talk given at the 2013 ACMG conference explaining how the cell free DNA tested is from the placental cell line.

The National Society of Genetic Counselors stated in its 2015 Fact Sheet on NIPS:

During pregnancy, cell free DNA from the placenta (predominantly trophoblast cells) also enters the maternal blood stream and mixes with maternal cell free DNA.   The DNA of the trophoblast cells usually reflects the chromosomal make-up of the fetus.

And, now, in an article published on the largest review of cfDNA testing’s performance in a clinical setting it is again made clear that cfDNA tests placental cells, not fetal.

Yet, the testing laboratories still represent that it is fetal DNA.

Maybe if it was accurately labeled as placental DNA instead of fetal DNA, everyone–doctors, genetic counselors, geneticists, and patients–would understand that whatever the NIPS result, it remains a screening test with the chance of a false positive and a false negative.

A related post on this subject is at this link.

Comments

  1. no no no says:

    sick. I was already sickened but now I’m more so

    Do we know the chances of these mismatches between the baby and placenta? Is this info even a stat that is collected? If it can vary by cell that’s too much to fathom.

    Thanks

  2. mark you saw the ad in spain with alittle down syndrom girl?

  3. Hi Mark. First of all I’d like to thank you for the immense wealth of knowledge you present on your blog. I received a “positive” T21 NIPS result last Thursday, August 6th. I received the results over the phone while at the law firm I work for, and I fell apart. I was only expecting to hear the sex of our baby, as I was previously low-risk. Without any genetic counseling before the test, or with the results, the only information I had was what our midwife told us when she offered the test: that NIPS testing is more accurate than a first tri screen/NT scan. Usually I am very thorough, but we made a knee-jerk decision and had my blood drawn the very next day at 12 weeks, 1 day. The test was offered to me at absolutely no cost, something my husband now says should have set off alarms. We were told that Natera would not charge us, regardless of what our insurance offered them, because they are trying to have this test become recognized as a necessary medical test. We thought we were helping in the advancement of something that was lauded as a scientific breakthrough.

    To give you some background information, this is my first pregnancy, I am 27 years old, (26 when I conceived), my husband is 30 years old, and our Panorama results indicated 68% chance of T21 with a fetal fraction of 2.9%. I’ve poured over your website and medical journals and I’m angered that this test was even presented to me (and might I say presented as a test that analyzes fetal DNA), let alone without any sort of genetic counseling. Furthermore, that the test was run with such a low fetal fraction. My blood was drawn on August 25th at 12 weeks 1 day, and it arrived at Natera on August 28th. I am now 14 weeks 5 days pregnant with our son.

    We saw a perinatologist the day after we received our results. She indicated that our PPV would not be 99%, and she was dismayed to see that this test was ordered for me. We had a level two ultrasound, monitored by a sonographer and the perinatologist. I was exactly 14 weeks pregnant, but our son’s neck was still transparent, and the sonographer said she was able to conduct an NT scan. They saw no red flags. The nuchal measurement was normal and a nasal bone is present. I am not scheduled for another ultrasound until August 21st, when they hope to be able to do an amniocentesis at 16 weeks, but if the placenta has not fused with my uterus, they will hold off until 17 weeks. We are very troubled by the risk of miscarriage, as even though it is a small one, we initially thought we were at a low risk for chromosomal abnormalities. A such, this small risk seems very real. We know that the only way to receive a true diagnosis is to have the amniocentesis.

    I spoke to a Panorama genetic counselor yesterday, who at first tried to call it fetal DNA, and I corrected her, and she agreed that yes, it’s actually placental DNA. She further said that although she could not give me an exact number, my uncommon result of 68% meant that the PPV was less than 91% (and she definitely said 91% more than once, not 99%). She said their high risk result is usually reported as 99:100. I asked questions about the clinical study used to bring their test to the market, as the perinatologist said the initial study was a very high risk population (I’ve read, and now cannot remember where, that the risk was 1:8), and the second study was still a highly skewed mixed risk population. The Panorama genetic counselor offered to send me the studies, so I could answer my questions. She said that their studies indicated no substantial difference between the “accuracy” of the test in high and low risk populations, but I told her I’ve found much to the contrary, which she tried to attribute to studies including other NIPS tests that do not utilize the same technology as Natera. I also expressed my dismay at my test being run with a fetal fraction that just barely made their cut off of 2.8%, and she said it would not have been run if they weren’t confident that they could report results. When I asked her why their own literature (taken from the provider portion of the website) shows a study that excluded samples with fetal fractions less than 5.8%, she said that she could not locate the table I was referring to and it was likely so that their data could be compared to other NIPS tests that could not test lower than that figure, but she could not give me an definitive answer. I have yet to receive the promised email with the studies, but if you do not already have them, I would be happy to send them to you when I receive them, if I ever do.

    I asked the Panorama genetic counselor for further information about my results, as I did not receive my risk report. With this information I found it very interesting that they calculated my initial risk at 1/949, which is a higher risk than the calculations I’ve seen for someone of my age. She said that typically risk calculations only take into account maternal age, whereas their initial risk also takes into account gestational age, so my initial risk was higher because of the early age of my pregnancy. She said being that many babies who are chromosomally abnormal are miscarried, the initial risk is recalculated based on gestational age at the time the blood is drawn. This test is being marketed as being able to analyze cfDNA as early as 9 weeks, which seems very irresponsible, given that the initial risk score will be recalculated as a higher risk the earlier the gestational age. That initial risk then influences the Panorama risk score.

    Additionally, I’m located in Florida, and I read your post on the Down Syndrome Information Act. I see that 383.141 calls for counseling and information to be paired with the delivery of positive results. We did not receive this from my obstetrician’s office. Essentially, I was given results over the phone, told that a low fetal fraction could indicate a false positive, and referred to a perinatologist, who originally scheduled me for an appointment a week out. Thankfully, we were rescheduled for the following day. At the specialist’s office, we received some information from an RN manager, but it was basic information that I had already learned in high school biology, or in research conducted in the hours prior to the appointment. The perinatologist then gave me some additional information, again, mostly what I had learned the night before.

    If you are able to offer any opinion or insight on our situation, it would be immensely appreciated. Thank you so much for your time and effort.

    • Courtney–thank you for sharing your experience, though I regret you were not properly counseled at every step of the way.
      When NIPS debuted, most labs used 4% fetal fraction as the cut-off. Some, in an effort to distinguish themselves from other labs touted their test reporting results at less than 4%, but there were also a higher percentage of “no-calls” and false results associated with lower fetal fractions. At the recent ISPD conference, a presenter showed how in their clinic’s experience, results were able to be reported at lower fetal fraction rates and attributed this to the labs getting better at performing their own tests as more tests are performed.
      Regardless, it is odd that you would receive results of “68%” even with the higher-stated baseline chance based on gestational age. Even at that higher chance, it is essentially that of a 30-year old mom’s baseline and as the graph in this post shows, a screen-positive NIPS result would only mean a 51% positive predictive value, not a 68%.
      It is further disappointing that you were not provided the information mandated under Florida law and even further disappointing that Natera did not provide you with a copy of the Lettercase booklet Understanding a Down syndrome diagnosis, as they have received 2,000 of these booklets and it is recommended by the ACMG guidelines to accompany a NIPS result (even though NIPS is not a diagnosis).
      All this said, it sounds as though you are proceeding on an appropriate path: understanding NIPS is not diagnostic, you are having further ultrasound evaluations and an amnio, which you are also being cautious about given its associated risk of miscarriage. I would be curious if you ever ultimately receive a bill for the Panorama test and am troubled that it is being offered at no cost to entice patients to accept it. As far as failing to receive the information required under Florida law, I would consider sending an email or letter to your provider with a link to either my blog post and/or a link to the state’s website. While these laws are on the books, many provider remain ignorant of their requirements.
      I hope the accuracy of information and level of care you receive improves.

      • Mark, again, thank you for your response. So is this to say that data suggests lower fetal fractions still produce reliable results? The perinatologist conveyed that in her opinion, it reduced the reliability of the test.

        Furthermore, it was explained to me that the PPV describes the probability that the 68% chance is correct. Even on the phone with the geneticist, she said it would normally mean a 91% chance that the 68:100 positive was reliable, but in her opinion, my PPV would not be 91%. At the perinatologist, it was presented to us as a 68% chance our son has ds, and that the PPV was 1/3 of what Natera claimed, due to my initial low risk. Now I’m starting to think I’m misunderstanding what these figures mean.

        Natera did mention sending me something, I believe it was that booklet, in the email I was promised. I recall the geneticist saying the provider was sent a copy with the results. I too am very troubled that Natera is absorbing the cost in an effort to entice mothers to choose their product.

        We have strongly considered speaking to the OB at the practice, who we are to meet on the 21st, about our experience, including our disappointment over how the news was delivered and the lack of accompanying information. I want to specifically mention that the presentation of this information is mandated under Florida law. On the other hand, I don’t want to create a rift in our relationship, because at this point, it seems as though switching to a new practice (this was our second, after finding out at our initial visit that the provider didn’t deliver, and the hospital has extremely high C-section rates) would just mean more stress on us and thus, our baby. Then again, I’d like to prevent this from happening to another unsuspecting mother.

        • Courtney–Regarding fetal fraction, the relationship remains that the lower the fetal fraction the less accurate the results are, but the research presented at ISPD from a single clinic’s experience is that the difference in accuracy between low fetal fraction and 4% or higher is becoming less significant (and this was just from a single clinic).
          Regarding the PPV, that is very poor logic on the geneticist’s part, “Well, since Natera typically quotes 91%, if they said 68%, that must be reliable.” The fact is the 91% (or the more often hyped “99%”) almost never applies to PPV, but instead goes to different probabilities called specificity and sensitivity. This post discusses this in more detail.
          I sympathize with your concern over creating a rift with your current OB. I think that can be lessened in how you approach the situation. Instead of coming from a position of complaining about inadequate care, you could instead simply provide the link to the Florida website in a way of sharing information, e.g. “after I received my results, I learned there is a Florida law that actually requires certain information be provided, which I didn’t receive. Here’s the link.” This could also be done easier in an email (and have more of an impact since things in writing tend to receive more attention).

          • Mark, have you come across a concept known as “false positive paradox” in your research? I happen to come across this today.

          • I’m not familiar with that phrase. Please share what you’ve learned if you wish.

          • Normally I would not cite Wikipedia, but that’s where I initially learned of it, and thought it provided a good explanation. I came across it on Reddit late last night and haven’t done any additional reading. I wasn’t doing research, but thought it applied to cfDNA testing.

            The false positive paradox is a statistical result where false positive tests are more probable than true positive tests, occurring when the overall population has a low incidence of a condition and the incidence rate is lower than the false positive rate. The probability of a positive test result is determined not only by the accuracy of the test but by the characteristics of the sampled population.[1] When the incidence, the proportion of those who have a given condition, is lower than the test’s false positive rate, even tests that have a very low chance of giving a false positive in an individual case will give more false than true positives overall.[2] So, in a society with very few infected people—fewer proportionately than the test gives false positives—there will actually be more who test positive for a disease incorrectly and don’t have it than those who test positive accurately and do. The paradox has surprised many.[3]

            It is especially counter-intuitive when interpreting a positive result in a test on a low-incidence population after having dealt with positive results drawn from a high-incidence population.[2] If the false positive rate of the test is higher than the proportion of the new population with the condition, then a test administrator whose experience has been drawn from testing in a high-incidence population may conclude from experience that a positive test result usually indicates a positive subject, when in fact a false positive is far more likely to have occurred.

            Not adjusting to the scarcity of the condition in the new population, and concluding that a positive test result probably indicates a positive subject, even though population incidence is below the false positive rate is a “base rate fallacy”.

          • Thank you for sharing Courtney. Very interesting.

          • Mark, for posterity’s sake, I thought it important to let you and your readers know that our Panorama result of 68% T21 was a false positive. Our FISH results from our amniocentesis came back today. Our NT scan and 14w and 16w anatomy scans were also normal, save for a pinky bone the sonographer was unable to find (likely due to gestational age) and a choroid plexus cyst; the latter being identified in fetuses via ultrasound at least once a week, according to our perinatologist. Though we would have loved and raised our little boy either way, we see this as good news. Thank you for all your help.

          • Thank you for sharing your experience and I’m glad I was of some help. May I ask what state you’re in? I only do so to see if it is one that has passed the Down Syndrome Information Act and whether you were given any of the required information if the Act applied.

          • I believe we talked about this, but we are in Florida, and we did not receive the required counseling or materials. The only information I received was that of the supposed 99% accuracy, and a pamphlet written by Natera at the facility where the blood was drawn. I still have the pamphlet, but it contains very little information, and nothing that would satisfy the requirements of the act.

          • You’re correct, Courtney–sorry for the memory lapse and thank you for the reminder.

          • No apology necessary. Thanks for all you do.

  4. Hi Mark,

    Great site so thank you!

    My wife and I had an ultrasound with absent nasal bone(maybe) week 16 and then present week 17. They also saw EIF in the heart which we are told is fine typically. However they suggested Harmony test due to nasal bone; so we took it and it came back 99% High Risk (probability) for trisomy 21; which I now understand is not PPV. We met with the genetic counselor and she suggested that it could be wrong but there is high chance. Would not provide PPV, nor does the one pager harmony results, My wife is 31 and baby is now 19 weeks. We are trying to decide on an amino just to know for sure and plan for a child with DS. Just wondering about your thoughts.PPV etc. Thanks in advance!

    • Jeremy–I’m glad this site has been somewhat helpful. It’s unfortunate that Ariosa (the lab that performs Harmony) would not provide the PPV; they were one of the few who used to do that. I am unsure what your ultrasound findings would suggest as to recalculating your wife’s probability of having a child with Down syndrome. Based on just her age, a high risk result from Harmony would mean her PPV is slightly higher than 50/50, but the false positive chance would also be relatively high (around 47%). Through your counseling about an amnio, hopefully one of your medical providers can give you a more certain answer–ironic that there is this much uncertainty given the promised accuracy of these new tests. I would also recommend asking your practitioner what his or her risk of loss has been with amnio and the facility where he/she will do the procedure. The risk of loss with amnio is now regularly cited as less than 1%, but that is based on only a couple of studies at specific facilities. The only relevant risk of loss figure is the practitioner who is performing it and the facility where it will be done. Hope that helps as well.

  5. I really appreciate this wealth of information. I tested very low-risk for Trisomy 21 during my first trimester quad tests. However, I received a positive NIPT result at 21 weeks gestation for trisomy 21 for this current pregnancy. I found it odd that I was asked if I wanted to terminate even though I never completed an amnio to confirm the T21 DX.

    Prior to this pregnancy, I had 3 re-current miscarriages; 2 fetuses were tested and returned negative for any chromosome abnormalities. However, they did find an abnormality within my placenta (which was never fully explained to me). This pregnancy (my T21 pregnancy) started off as a twin gestation– the twin was re-absorbed at about 9 weeks gestation. is it possible that my NIPT results are a false-positive given my low-risk factors, placental issues in the past, and a vanishing twin during this pregnancy? Also, can one have a hard marker for DS (via level !! ultrasound) and still have a false-positive NIPT?

    • As this post shares, what cell free DNA (cfDNA, aka NIPT) tests are testing are largely DNA originating from the placenta. Another phenomena of pregnancy is that the mother retains cfDNA from all other pregnancies she had. So, in your case, in a previous pregnancy, your placenta had some chromosomal abnormalities. The placenta is a unique organ and can have cells with confined mosaicism–i.e. where most of the cells have 46 chromosomes, but some having 47, e.g. an extra 21st chromosome, the cause of Down syndrome. Further, your current pregnancy has experienced the “vanishing twin” phenomena.” Because twin gestations are rarer, cfDNA testing is not recognized as providing the level of accuracy for twins as for singleton pregnancies. Ultrasound findings are simple screen suggestions, but are in no way diagnostic. Therefore, you have a variety of reasons for receiving a screen positive cfDNA result: [1] it tested cfDNA from your previous pregnancy; [2] it tested cfDNA from the vanishing twin; [3] it tested cfDNA from your fetus; or [4] it is simply a false positive, as these happen in women who have never been pregnant before, are not carrying a child with Down syndrome, but the cfDNA tests still is reported as screen positive. I would have all of this discussed with a genetic counselor or medical geneticist. I would also consider writing to your health care provider to explain before termination is offered, a diagnostic test should be performed to confirm any screening results.

      • Mark, thank you so much for the information. I found it very surprising that the cfDNA picks up remnants of my previous 3 pregnancies/miscarriages (all within a 2-year span). Unfortunately, my high-risk OB team are treating the NIPT findings as a 100% accurate result due to a congenital heart defect finding (Atrioventricular Septal Defect) via echo-cardiogram. As mentioned, I never completed the amnio so I find it odd that my health care team is treating this as a definite case of Trisomy 21. I suppose I will know for sure in November once my son is born.

        Given my history and issues with my placenta and back-to-back miscarriages, I am truly hoping for a false-positive. However, the heart issue makes it very difficult to believe otherwise.

        Thank you again for your enlightening response.

        • Tina–the book Diagnosis to Delivery has a section on health issues, including heart conditions. I hope it will be helpful. And, while the book is written for moms with a prenatal result for Down syndrome who are continuing their pregnancy, I do not mean by suggesting it to be like your medical team and treating your results as a diagnosis, since it is not. But, having been a reviewer for the book, I know I learned a lot about the heart conditions with links to further sources of information provided therein. The book is available in English and in Spanish translations.

      • Hi Mark – I just had to clarify something – A mother does not retain cfDNA from all of her previous pregnancies. She does retain cells from previous pregnancies and this is the reason why cfDNA is tested rather than fetal/placental cells. If a mother retained cfDNA from her previous pregnancies then this testing would not be accurate at all. Your other possible explanations for a false positive are correct. However, in a case where there is a cardiac defect (particularly an AV canal defect) and an abnormal cfDNA result, the chance of a false positive is extremely low. We typically recommend amniocentesis to confirm, but we have a fair number of patients who decline because they are planning on continuing the pregnancy and they have concerns regarding the risk of miscarriage (even though it’s low). In this case we do follow the pregnancy working under the assumption the baby has it, and then we test the baby after birth to confirm. We would certainly give the patient appropriate information on Down syndrome in this situation.

        • Thank you for the clarification. The lingering cfDNA from prior pregnancies had been discussed at professional conferences I’ve attended, but based on this study here, I appreciate you clarifying that while whole fetal cells may persist, cfDNA does not. I will adjust my comments going forward.

    • Tina, I know you’re writing to Mark, but I wanted to chime in just in case you didn’t see my comments. I had a false positive with Panorama by Natera, verified via 16 week amino. I had two “soft” markers on my 16 week level 2 ultrasound; choroid plexus cyst and an absent pinky bone. I was told the former isn’t actually abnormal, and the gestational age could account for the missing pinky bone. I went back to the perinatologist today and the cyst is gone and the pinky bone is now there. Everything else is normal. Of note, this is my first pregnancy, no miscarriages. I wish the best of luck to you and your baby. Hopefully the results reflect moscaism in the placenta or the very least, T21 of the absorbed twin. I’ll be thinking of you.

      • Courtney,

        Thank you for commenting. I can only hope my results are false-positive due to a confined placental mosaicism; however, my ultrasound findings resulted in a hard-marker (severe congenital heart defect).

        I can only hope that my baby is born as healthy as possible, and that the results were skewed due to my array of previous pregnancy and placental issues–but I am being realistic. The heart defect gives a strong foundation for a true positive NIPT result….unfortunately.

      • Hi Courtney _ I know that this post is old but it sounds like we had some similarities in how things were calculated and what was reported. We had our Harmony test done at 11wks 5 days and the lab called with a 90-95% chance my son has down syndrome. I was in the office as well and could not dig as much as I wanted. I was devastated and as a scientist naturally wanted more information. At the scan they did the NT measurement was perfect but they could not find the nasal bone. They mentioned that we were in the office about a week and a half earlier than they really liked to see people and that it may just be too early to see it, plus our son was moving around so much. My OBGYN did not get the results before we were back in her office almost 2 weeks later and she actually had to call the other office and speak with the doctor there. We will be going in at the end of the week to get a second scan and speak to her about what the results mean. I am just struggling to believe that anything is “wrong” with our baby though. I am 34, healthy and ugh this has just been a nightmare. The scientist in me completely understands that this is not diagnostic at all, but the mother in me struggles with not freaking out. We will love our baby no matter what, but it is devastating to hear news like this so early on. I am still on the fence of whether or not we want to do an amnio as we have already lost one baby last year. I know risks are small, but I couldn’t bare if something happened. Any ways – I read your story and thought I would reach out. IT would be very nice to get in touch with someone who has been there and through a similar situation as my husband as I have been. Thank you for sharing your results….it gives me some peace of mind as we move forward with everything.

        • Amber, according to this calculator, the chances that your pregnancy is positive for Down syndrome is not 90-95%, but instead only 75%, with the result having a 25% chance of being a false positive. This post explains further and contains other links you may find helpful.

          • Thank you Mark, I have read through the article and it has given me much more peace of mind. My husband and I are going in tomorrow to speak with the MFM/geneticist about their results. I know that the Lord has a plan and nothing is a mistake, but to be told results in this manner I think can have devastating results. I am really curious to see where the 90-95% chance came from ( I can only imagine that it is a mixture of the blood results and one soft marker possibly being off). These doctors really need to be careful with how they present data because I think that a lot of decisions are being made on a screening test, not a diagnostic test. Plus the stress that it puts on the pregnant mother. My husband is most upset that there was a cold call with no further information given – and the call came from an office that did not even do the test. I was considering doing the amnio, but am now back to thinking we won’t as our baby will be loved no matter what!

          • I would suspect the reason you were told 90-95% is because they simply misunderstand sensitivity and specificity as being the same as PPV. Perhaps they have an explanation that 90-95% was your PPV, but I’d be surprised if that were the case. I hope the resources at the Prenatal Resources tab are helpful to you and your husband. Downsyndromepregnancy.org has articles and downloadable books for moms with a test result who intend on continuing–as a reviewer, I gained a greater appreciation for the experience of expecting with a prenatal resort.

          • Thank you Mark. We had our follow up appointment on Friday with the actual doctor who saw me to begin with. I left the office very upset and angry because of how this particular office is choosing to present this data to the patients. When I first arrive the sonographer was a little snarky with me and asked me why in the world I was back so soon as I wasn’t supposed to come back until the anatomy scan was to be completed. I reiterated that I was there to discuss the results of the NIPT – that calling me and saying that they are 90-95% sure my son has Down syndrome was not acceptable and I wanted to speak one on one with the doctor to understand the parameters of the test better. She took some more measurements (all of which are spot on with where our son should be – meaning he is most likely healthy). However, when the doctor came in she told me that the likely hood is actually 99% true and that there is only a 1% chance that it is a false positive from something such as placental mosciacism. When I tried to get more information out of how they came to that conclusion (knowing that 99% is the manufacturer’s specificity – not accuracy of the test), I was shown a cartoon of how a baby is made and how each parent contributes chromosomes etc etc. I looked at her and was dumbfounded that she was actually going through this with us – both who have a science background and understand that. She was very evasive and unwilling to show me the actual results of the test and continued to say it was 99%. My husband and I both had very pointed questions and all we were told was that these results were right – but we would need to get the amnio to be sure. I’m thinking – then you can’t say that they are right if you have to have another diagnostic test to actually prove it with 100% certainty. Somehow the conversion turned to termination was a possibility. I absolutely lost it – I pointed at the pictures of my son on the screen and told her that we have seen his heartbeat, that we have heard his heartbeat and that I love my son more than anything in this world that that termination would not be brought up again – to stop bringing it up because it is not a option. I cannot believe that a doctor would tell a woman that this is an option off of a screening test. Am I emotional – yes. Does it mean I won’t love my son, absolutely not. Everything that we asked was countered with this test is right and that we just need to accept it. Without seeing how they came to these conclusions and every other soft marker pointing to him not having DS I am having a hard time wrapping my head around this. We will not do the amnio because as small of a risk as there is, I do not feel the risk is worth putting his life in jeopardy just to confirm the test. We will continue the pregnancy and monitor his heart and development as we go. I am appalled though at how this information is being presented to patients who may not understand the differences between specificity and sensitivity. How many people are making permanent decisions off or inconclusive test results because they do not understand that this is not a diagnostic test. And 2) down syndrome is not the worst thing that can happen to a child, they are some of the most wonderful people in the world and it breaks my heart to think that a child may not have a fair shot at life because of this. I am sorry for the long rant, but I am glad that I have come across your site because even understanding the background of these tests, this has been a stressful process. I am honestly fine when I am going on in life, but every time I get a call from that doctor’s office or have to go in there now I am filled with anxiety and dread because of the way this doctor is blinding following the manufacturer on the test. To say the least we are no closer to finding out what that 90-95% or better yet what the 99% means because she wouldn’t or couldn’t show me the break down of how this all worked out. Thank you again for your responses and we will be sure to check out the resources you have provided. I am not naïve to the fact that my son may have Down Syndrome, but it really infuriates me the way these tests are being presented. I am thankful that all the scans so far show him to be healthy and on track. We continue to pray and if he does have Down Syndrome we will still love him and give him the best life that we can.

          • Thank you for your candid response and I empathize with your frustration at the poor level of care you are receiving–it is tantamount to malpractice (as covered at this post). I do hope you find the resources helpful. While your child may not have Down syndrome, learning more about a life with Down syndrome has been valued by expectant parents. Several posts on this site feature vignettes on a life with Down syndrome, including my own daughter. To the extent those may be useful, they can be viewed here.

          • Thank you again Mark. I really love to hear positive stories of love for children in every situation. I have a sister who is autistic, and as hard as it was growing up with her, I could not imagine life without her. I think that every situation has a reason and that God helps us to grow. We are just so excited to be having a child after thinking we wouldn’t be able to get pregnant because of my PCOS. It was heartbreaking to lose the first one we were going to have and I am fiercely protective of my son now. His life is precious in any capacity the Lord gives us. Sorry about the frustration earlier, I just really can’t believe the level of ignorance that is being pushed off on to folks. Can’t wait to have a few minutes to jump into the other resources you have provided.

  6. withalotofhope says:

    Hello :
    I am from Spain, 39 years old, and I have received High Risk (more than 99% ) of Panorama for T21 with only 2,9% fraction fetal. I will do amnio on wedsnesday. I expect it will be another false positive. I pray for that. I am devasted

    • At 39, you’re chance for having a child with Down syndrome based on a Panorama result is closer to just 90%, not 99%, meaning you have a 10% chance of a false positive. The false positive chance is likely higher given the lower than usual fetal fraction percentage. I hope you will check out the Prenatal Resources if your amnio confirms the Panorama result. Most all of the resources are available in Spanish.

      • Mark, today the perinatologist who performed my amnio told me that they are seeing a correlation between low fetal fractions and chromosomal abnormalities. That being said, he believes it caused Panorama to misinterpret my results, attributing a low fetal fraction to an abnormality, when really, we know for certain that is not the case.

        • For all the promised precision and accuracy, it sounds as though you are experiencing anything but that.

          • His sonographer didn’t seem to be particularly pleased with cfDNA tests, or the fact that I was recommended one at age 27. I cannot believe that Natera would perform a screening on such a low fetal fraction when the fetal fraction itself (not to mention young gestational age) increases the risk. I would have preferred being given the option of a redraw or the ability to decline testing on the sample. I’m actually about to fax my (redacted) amnio results to Panorama so I can fully/properly report my false positive. With my permission there was also a Mayo resident in my room during my 20 week anatomy scan today, I thought it was a particularly good learning experience.

          • Withalotofhope says:

            Thanks so much for your answer. My ultrasound is normal with no signs of down, and my TN 1,3. My screening based un ultrasound. hormones and TN has a risk of 1/1026 for T21. I know tejar my age is a problem. I will share next week my result of amnio

      • Withalotofhope says:

        Hello Mark :
        I am the spanish girl, 39 years old, who received high risk with panorama test for T21 with only 2,9% fetal fraction of Adn. This afternoon I received the result of the F.I.S.H and it is normal , it seems a false positive, now I have to wait for three weeks to have the entire results. Thanks so much

        • Thank you for sharing your FISH results. I’ll be interested to hear if the full test confirms the FISH result.

          • I am confused. I only received a “aneupolidy detected consistent with Trisomy 21” on my NIPT results….is Panorama test different in how they reveal the results? Do they give you a risk indicator versus what I received? (Detected vs. Not detected)?

          • Every lab reports the results a little differently, but as far as I know, at the time of this writing, only Counsyl provides a positive predictive value with its test results. You or your provider could call to see if Natera would explain your results, but how you relay your report is typically what they say. Regardless, it remains a screen and there remain false positives and false negatives.

          • Hello Mark :
            I am the Spanish girl with 39 years old who had only 2,90% fetal fraction of Adn with Panorama test. Definitely it was a False Positive for Down Syndrome. Thanks so much for yout atention

          • Thank you for sharing your full results and confirming you had received a false positive cfDNA screen result. I wish you a healthy remainder to your pregnancy and hope you will enjoy it!

  7. Hi, I was hoping someone could please shed some light on my situation as I have been left in the dark and completely terrified. I am 25 and 13 weeks pregnant, with my 1st. I was 10+5 when I got my Panorama test done. Yesterday I recieved my results which indicated I 99% high risk factor for Trisomy 13 with a fetal fracton of 5.2
    My Ob did not explain any of the results instead told me to wait for a specialist to be in contact to do an ultrasound (which i havent heard anything from yet), and to seriously consider termination. Needlesd to say I am beside myself and need some advice or help. I have been reading your comments about how some tests can pick up previous pregnancies and was wondering if this is possible for a very early miscarriage. I was 6.5 weeks pregnant in July when I misscarried and fell pregnant in August just 4 weeks later…..i feel like im holding onto any hope i can but I need till I am able to do further tests.
    I have also read about PPV but I am not sure I understand completely…..does Panorama test take into account this?? And what does the rosk score of 99/100 really mean?? My dr has told me nothing.
    Thank you in advance 😊

    • I’m sorry to hear about your experience and lack of support. With Trisomy 13 being the rarest of the major trisomies, I would be surprised if your Panorama report of 99/100 was PPV–instead it would be Natera’s claim of sensitivity. With your young age as well, even if this was for Down syndrome, you still would have a 60% chance of a false positive–given that Trisomy 13 is rarer by a factor of 10, then you likely have an even greater chance of a false positive. And to your point, the test may have tested cfDNA from your previous pregnancy. I would have your provider ask Natera what the PPV for your Panorama result and prior to making any decision to terminate, per the professional guidelines, you should confirm the result with a diagnostic test. I hope you get better information going forward.

  8. Hi Mark,
    I am carrying a baby with the help of IVF. We had done CCS testing on the embryo before transfer. We were told CCS is 95% accurate. Now my ob clinic is offering either Informed Pregnancy Screen by Counsyl or Harmony by Ariosa Diagnostics. Do you think I would be benefited from having one or the other? Or should I skip it all together?

    • Sherry: the still current ACOG Committee Opinion on preimplantation genetic screening does not recognize it as effective for detecting aneuploidies like Trisomy 21 (see opinion here). So, the question is: your lab said their CCS was 95% accurate for what conditions? If those conditions you are concerned about were not screened for and they can be screened by cell free DNA screens like Counsyl’s or Ariosa’s, then you could determine whether that information would be beneficial to you.

      • Hi Mark,
        Below is what states in the lab website. “CCS testing is performed on a few cells biopsied from a day 5 embryo called a blastocyst. The genetic material of the embryo is not altered in any way during CCS. After CCS testing, only embryos that have the correct number of chromosomes are selected for transfer. CCS is provided to patients through an Institutional Review Board (IRB) – approved ongoing clinical study.” 95% accuracy is for missing or having extra chromosome. I am leaning toward Counsyl because it can test more conditions.

        • Thank you for sharing. It seems unlike with a prenatal screening test, the 95% claimed accuracy likely means only a 5% chance of a false positive, but I could be incorrect on that (see previous comment admitting limited knowledge on IVF/ART). However, understand that Counsyl’s claimed accuracy does not necessarily mean your actual chance for having a child with a tested-for condition is that high. Fortunately, with Counsyl, they have been reporting out the positive predictive value (PPV) which should avoid the confusion with the other labs and how they recite “99%” when that is not their PPV. Long story short: if you have cfDNA screening, make certain the number quoted to you as to your chances is the PPV, not the sensitivity or the specificity rate.

  9. Thank you for your website, and for thoughtfully answering each person’s comments.

    I recently received a positive result for trisomy 21 from progenity. It stated “aneuploidy detected.” I was tested at 11 weeks.

    At my 11.5 week ultrasound, my baby had a NT of 4.1. My Hcg was slightly elevated and my Papp-a was normal. Based on the NT alone, my genetic counselor gave me a 1:5 chance of Down syndrome. She said that the other blood markers don’t matter as the NT and progenity results are more accurate). I am 34 yo (35 yo at the delivery date).

    Neither the genetic counselor nor my doctor could explain how the progenity results work. Unlike other tests, there is no fetal fraction (my counselor said that they use different technology than other tests), and my doctor’s staff is treating it as very accurate. The progenity website says that it is the most accurate test out there.

    Do you know what the chance of false positive if I didn’t receive any personalized percentages from the test result from progenity?

    Thank you so much

    • Based on your age, your chance of a false positive would be about 25%, i.e. the positive predictive value of your Progenity test would be about 75% or give you a 3-in-4 chance of having a child with Down syndrome and a 1-in-4 chance that it is a false positive. I’ve not heard of an NT positive predictive value being as high as 1-in-5 based just on the NT measurement alone, so I would question that accuracy of that estimate by your genetic counselor. Unfortunately, though, it sounds like the medical advice you’re receiving is something like, “we’re not sure how any of this works, but we’re pretty sure it’s really accurate.” That should be unacceptable. I’d have your OB ask Progenity for your PPV. And, of course, only an amnio can confirm whether you have received a true positive or false positive screen result.

  10. Hello Mark,
    I had Maternit21 drawn at 13+5 weeks and was told last week it was “high risk” for T21. I am 39 years old, so my husband and I thought we would have it drawn along with the NT screen. The doc told us that the test was 99% sensitive. We received no info about PPV. Our NT screen came back normal.

    When given the news about the T21, my husband and I were devastated but knew we would keep the pregnancy no matter what. When I asked for the risk calculation information, a nurse from the office said that Sequenom only reports results “positive” or “negative” and again said the test was 99% accurate. The doc did state that the test was a screening and counseled me about doing an amnio to find out for sure. I saw from your site and a few others that my PPV would be approx 90% for my age. We are scheduled this week for the amnio.

    Only after researching NIPS after our Maternit21 results did I find your website. Any other info or experiences you and others have with Sequenom would be much appreciated. Thank you for what you’re doing to inform women and families.

    • I’m glad you found this site helpful. I would recommend the Down Syndrome Pregnancy board at babycenter.com as another online forum where you might find others’ experiences with Sequenom. I suspect there are other boards on that same website devoted to cell free DNA as well, which you might find helpful as well. I wish you well with your amnio and that you receive compassionate information and support.

  11. Hi your post was incredibly helpful and in untreated to hear what you think of my situation. I really hope you can give me peace of mind and advice. So here is my story: I’m 24 years old pregnant with an IVF girl (no donors. male factor infertility). I’m currently 33w3d. Up until 31 weeks all tests were normal. We did NT, AFP blood, and one other one. All normal. Sonograms normal. Just some PACs arrhythmia at 20w which resolved. At 31 weeks vanticulomegaly was noticed up to 10mm. Feral MRI was done no other issues found. Panaroma test was taken – it showed “no results”. So we sent for harmony Test – I just got the test back it says for trisomy 21 (down syndrome) high risk, probablity 2/100 (2%). On the bottom of course it says it’s 99% accurate. 0.1% false positive. Doc is reading it as such and says maybe we ought to do an amnio. He’s MFM and states that for trisomy 21 this it is usually very accurate and the kid will very very likely have Down syndrome. We can do the amnio to confirm. He was sympathetic but assertive – and he has done many of these.

    Now I’m confused by my results and he couldn’t really explain it properly. Also states that he doesn’t use this lab often. And further said its 99% accurate. I’m at a loss. Also may I add the ventricles came down to 9mm which is normal. What should I do?? What would you do? What to believe? I have no idea. I’ve seen some posts about these tests NIPTs not being very accurate. I want to believe my baby is ok but I’m so lost. Help please. Which one of you had similar results and were ok?

    • “99% accurate” does not mean you have a 99% chance of having a child with Down syndrome. (Here’s a fact sheet that may be helpful for your doctor to understand the testing he is offering his patients). Even the Harmony test result says 2%, though I’m not exactly sure what Harmony is reporting with that number. The only number that tells you your probability for having a child with Down syndrome is the positive predictive value (PPV). Based just on your age, you have around a 1-in-1,400 chance of having a child with Down syndrome. Even with a screen-positive result from Harmony, your PPV would be 44%, or a chance of 4 out of 10, with a chance that your result is a false positive being 56%. I would ask your doctor to ask Ariosa (the lab that makes Harmony) what the PPV is for your test result. Regarding the amnio, you should consider whether a positive result would make you do anything differently with your pregnancy, how much you value knowing for certain prior to birth, and whether you’re willing to risk a miscarriage to have that knowledge. Lastly, all major medical organizations now recommend patients be provided written materials about Down syndrome with a cell free DNA screen positive, with all of them recognizing the Lettercase booklet as providing appropriate information for expectant mothers. Ariosa has received thousands of these booklets and your doctor can order one for free. You can also view it online at the link.

      • Hi Mark. Thank for replying and for all the info you provided me with.
        A few questions come to mind. Do you think my test could have been effected by IVF?
        The doc being so certain due to his experience is making me nervous. He said when he sees such tests more than usual baby has DS. I know it’s not the end of the world and it can be worse.
        I guess I should learn more about DS. I just didn’t expect all of this so late and close to the finish line…

        • Regarding IVF, the one factor that may be relevant is whether you used a donor egg. The baseline chance from your age was presuming you used one of your eggs. If you used a donor egg, then the age of the donor would apply and could alter the PPV. Your doctor being so certain based on his experience with his patients would only be relevant in your case if he saw that most of his under 25-year old patients who had a Harmony result actually had a baby with Down syndrome. But, he’s probably basing his certainty on all of his patients and as the age of the mom goes up, so too does the chance for Down syndrome and so too does the PPV for tests like Harmony. Again, I’d ask him to ask Harmony what the PPV is for your result. Regarding Down syndrome, the Lettercase book is the recommended starting place. Then, if you decide to continue your pregnancy, you may check out “Diagnosis to Delivery” a book written by moms for moms who are continuing a pregnancy with the knowledge that the baby may have Down syndrome. It’s available for free as a .pdf or you can order a hardcopy.

          • Thank you. I’ll look into the book you recommend. I already went through the pamphlet. We didn’t use any donors. I used my own eggs. They did call me a day prior to confirm “the age of the donor” I guess they were coming up with that PPV. I’ll call the doc and see what else he says.

          • I spoke to the doc. He said that my PPV is low due to my age. And we talked about the placental DNA. he was very knowledgable on all of that. However he doesn’t know my exact PPV. I need to talk to someone in the lab which he’ll set up for me. Also he said he rarely sees results that say high risk – 2/100 proabability for this specific test. He states that how they started reporting it but he needs to treat this as 99% accuracy bc that’s what the test claims. So he says we can do an amnio or wait. Also before he harmony I did the panorama and it stated “no reaults” which made him concerned. I then asked for another test – stupid me.

            Do you know what it came up this way? That’s what I’m perpelxed by the most. All the test I look up say high risk – 99/100 (99%). Do you know anyone who had similar results to mine?

          • They need to stop saying “it’s 99% accurate” because that gets confused for the number that matters, your PPV. While the test may detect 99 of the pregnancies of 100 24 year olds who are actually carrying a child with Down syndrome, it will report 150 false positives for the 140,000 other 24-year old moms and there’s no way of knowing if you’re in the “99% accurate” crowd, or one of the 150 receiving a false positive. That’s how PPV is calculated. I’m not familiar with results being reported as 2/100 and so I can’t say what that number means. I hope Ariosa can explain it and if they can’t, then that’s yet another problem with how these results are reported. I wish I could pinpoint a comment from another mom who has had a similar experience, and surfing around this site, I wouldn’t be surprised if one is on here. You could also check out the downsyndromepregnancy board at babycenter as a number of new and expectant moms post there seeking out similar experiences with test results.

          • Hello, I am 39 years old, this is my story so far .. At 12 w5d did an Nt scan, got 1:43 as the nasal bone was not seen . Did another nt scan 13w4d , nasal bone was visible , everything once again was fine 1:2244 chance of ds . We were advised to do harmony anyways and result came high risk 99/100 . Even the doctor is baffled as everything was fine at 13weeks . I am waiting to be booked for an amino at 16 weeks . What are your views ?

          • I forgot to add .. It’s IVF and I had 3 embryos originally and a high hcg to start with .. So much that the doc was convinced he was going to see twins .

          • Based just on your age, ordinarily a cell free DNA screen result (like Harmony) would mean you had around a 90% chance of it being a true positive and a 10% chance of it being a false positive. However, at your adjusted chance of 1-in-2244, those numbers are reversed, ie a 10% chance that it’s a true positive and a 90% chance that it’s a false positive. Further, that you had 3 embryos originally and your doctor thought a high chance for twins, the cfDNA tested by Harmony could’ve been from a vanishing twin. Suffice it to say, you have many variables that would make Harmony’s claim of “99% accuracy” not apply to your pregnancy. Further, with each screen-positive result, every medical organization recognizes patients should receive written information, with each recognizing the Lettercase booklet on Down syndrome as that resource. Ariosa (Harmony’s lab) has received thousands of these booklets for distribution and your physician can order one for free; you can view it online for free or order a copy yourself here. I would have your doctor ask Harmony what your positive predictive value (PPV) is for your test results given the variables you list: adjusted baseline chance; 3 embryos; high hcg. If you proceed with the amnio, I hope the procedure and recovery goes well for you.

          • Thank you , I will update on the outcome

  12. Hi Mark. I came to you when Panorama reported a 68% chance of my baby having DS. I updated you to let you know that our amniocentesis showed a male fetus without an aneupolidy.

    My baby is now just over two weeks old and most certainly does not have DS. After delivery I did overhear my midwife mention to a nurse that my placenta was to be tested given the NIPS result. I would assume they want to see if placental mosaicism was the cause of the Panorama result.

    Again, thank you for everything.

    • Thank you for sharing your story. Regarding testing your placenta, I hope they got your permission to do that and if it was for Panorama’s purposes, that you were not billed for it.

      • I did find it strange that it would be tested without my informed consent. I certainly would not pay for it. My labor was very long and I hadn’t slept for several days, so hopefully I misheard.

        • Mark, can you explain how the harmony test is done? How do they come up with this probability?
          I spoke to the genetic councilor and she said the calculate age into the probability and she said its a 2%risk. Still high risk though. Bc low is 1/10,000. Mine is 2/100.

          • I can’t explain what methodology Harmony uses to arrive at its probability assessment. However, a 2% chance then means a 98% chance of a false positive. I think it is more accurate to say that while 2% is a “higher risk” it is not what is suggested by the hyping of “99% accuracy.” If anything, based on your age and Harmony’s claimed accuracy, your risk should have been 40%, but instead it’s 2%, which in that comparison then is lower risk.

  13. I am 41 and took the Panorama test at 10 weeks. I was told that my fetal DNA fraction was 1% which is bad. I am being sent to a geneticist to determine ‘what kind of bad’. An ultrasound on the same day i received these results showed a heart rate of 160 and i was 11 weeks and 6 days, everything looked good and on schedule. From what i have read, some studies do not even report a fetal fraction number and that if it is too low, under 2.8%, it means that any results are just not possible. Some articles say there is a chance of abnormalities related to low fetal fraction % but we’ve be lead to believe the will be no chance of a positive outcome.

    • I’m equally mystified by the certainty expressed to you that a low fetal fraction number is “bad,” particularly given that you had an ultrasound that appeared healthy. I would ask them what they are basing their negative predictions on since, if anything, cfDNA labs have increasingly tried to say that fetal fraction is becoming less of an issue for the validity of their screen results.

  14. TArrington says:

    Hello Mark and others. I’m completely at a loss about my results. Let me give you some background of my case. I’m a 40 yr old mom, currently 23 weeks with my 3rd child. I had a quad screening at about 17 weeks and I was told by my OB that it came back positive for DS. I was ok with this because the same thing happened with my previous pregnancy. I was referred to MFM because of my results and my advanced age. In the mean time, my OB decided it would be a good idea to do a MaterniT21 screening and I said ok. I had no idea what it was or why she was doing it. As you can see I’m very confused and lost with this pregnancy because I am not being counseled very well. My ultrasound at 22 weeks was normal. No abnormalities found. Well last week I got a call from my OB stating , ” I’m sorry but your MT21 results are positive for DS”, I was devastated. I asked my Dr. Was it definite that my daughter has Down syndrome and she replied yes the test is 99% accurate. I was devastated! She then went on to tell me how sorry she was and she wished that she was with me in order to give me hugs but from the looks of the results of the test baby was positive for Down syndrome. An emergency appointment was made for me with geneticist which also is my Maternal Fetal Medicine doctor. I was taken into a counseling room and he proceeded to tell me that my daughter has 47 chromosomes when she should only have 46 therefore resulting in Down syndrome. I was not given any percentages or ratios as to what my chances are I have basically been told that she has it. I was I was then given three options the doctor stated abortion is out of the picture because I’m too far along with my pregnancy secondly he could take a little fluid from around the baby but that may create other problems so he’s not going to do that I was never given the option of an amnio or CVS he just said that was out of the question and thirdly he said we can offer you the option of adoption but from your demeanor I can tell you plan on raising your baby whatever happens. I’m currently nervous confused and my anxiety levels are so high I don’t know whether to seek a new OB or continue on with my pregnancy with the same doctor. I really wanted to just share my story with all of you who seem to have very good doctors and geneticist in your corner as of now I am 23 weeks pregnant and I currently don’t have any idea whether my daughter actually has Down syndrome or not I’m just waiting it out until she’s going to see what the results are. I am currently continuing to go to maternal fetal medicine every 4 weeks for ultrasounds and to be monitored. I’m not sure if you can help me Mark but reading your research it gives me hope that maybe my test was a false positive I’m not sure I don’t even know what the percentages are being that I have never been told any of that. I really just wanted to share my story with other expectant mothers to let them know that they’re not alone. If there’s anything that you can help me with Mark or let me know what route I should be taking as of now I would appreciate it again I thank you for reading my story and I continue to have hope.

    • Your story is a series of mistakes on the part of your medical team. It was a mistake for them not to offer you cell-free DNA (cfDNA) screening like MaterniT21 initially instead of quad screening, since due to your age, you are already considered “high risk.” It was a mistake for them not to counsel you about what MaterniT21 tested for, what its results would mean, and what decisions would follow receiving results. It was a mistake for them to counsel you that the test results are “99% accurate” and for the geneticist to treat the MaterniT21 result as a true positive–it never is. And, it was a mistake for them not to provide you the recommended information for expectant mothers about Down syndrome when receiving a test result. MaterniT21 and other cfDNA screening tests can always have false positives (and false negatives). This is why what is recommended is for you to be told your “positive predictive value” or “PPV.” The PPV is actually the probability you have for having a child with Down syndrome. You or your doctor could calculate it using a free on-line calculator. Since you will be continuing your pregnancy, I would recommend the approved resource “Diagnosis to Delivery,” also available for viewing online for free. Depending on how disappointed, frustrated, and/or angry you are at your health care team, you have several options, which you can choose all, some, or none: change your health care team by going to another practice; letting your current providers know of your dissatisfaction (or simply forward them this post and direct them to your comment); file a complaint with the hospital they have privileges with regarding their inadequate care; file a complaint with the state board of medical licensure for their failure to practice according to medical standards; and, if you live in a state that recognizes a claim for wrongful birth and you would have terminated this pregnancy had you been offered MaterniT21 at your first visit (as recommended), then you could meet with an attorney and consider bringing a lawsuit. All of these measures sound harsh, but, unfortunately, it is very often what is needed for practitioners to change their behavior. I hope that clicking through the links in this reply provides other helpful information, and I do hope you get the professional compassionate care you deserve.

  15. Update : I did an amniocentesis and the result was the same as the harmony test . The clinic said they never had a false positive in all the years of practice .

  16. I am currently 14 weeks pregnant and took the panorama test at 12 weeks. Got the phone cal yesterday that fetal fraction was 2.6 which was too low to report a result so they are encouraging redraw. The representative actually got on the phone with me and told me not to worry that they just don’t want to report a false negative/positive. I’m scared to death. I’ve been researching and have read that low fetal fraction has been linked to abnormalities. I’m 34 years old, will turn 35 one month before delivery and on my second child. No history of miscarriages etc. All scans have been healthy up to date. I’m considering skipping the test and doing an amnio. What are your thoughts? I haven’t slept since receiving the phone call. I couldn’t even get a call on gender.

    • At a conference last year, the labs were saying just the opposite: that low fetal fraction was not a barrier to their screening tests’ ability to detect the tested-for conditions. Amnio is the only way to know for certain and can’t be performed until after 15 weeks. If you’re not being charged for the redraw, you could see what the screen results are and then decide whether to have invasive testing with an amnio.

      • I am unsure if I even want to go further with any testing. This no result has caused unwarranted stress that I really don’t want. I am a nurse practitioner and know that some of these tests can serve a great purpose but can also cause stress on a pregnancy that is not needed. So far this week my doctors office has had 2 “no result” come back. They have only used panorama for a little over a month. The representative told me that due to my fetal fraction being just below cutoff that I should be able to receive a result. My question was more towards the disclaimer that low fetal fraction carries a high risk for aneulopy pregnancies. What are your thoughts?

        • I have not seen that reported, ie that low fetal fraction is associated with a high risk for aneuploidies. I have seen it suggested that when a lab runs a result and receives an “inconclusive” result, many of those are aneuploidies. However, that is not your situation, since you didn’t receive an inconclusive result, but rather that there was insufficient fetal fraction to screen.

          • On the lab result from panorama it states reason for low fetal fractions which are specimen collection, maternal weight, drawn too early, or chromosome abnormalities. Then it states mother should be counseled that she is at slightly higher risk for carrying aneuylopy when a low fetal fraction is found. I’m so confused

  17. Mark,
    I was wonering if you had any insight as to which NIPT test is better, The Harmony or Panorama. I am 36 yrs & considering doing the NIPT but not sure what test to do. Is one more accurate? Have less false positives? I would appreciate any information you can provide. I am finding this very overwhelming. Thank you for your time.

    • One of the criticisms against the labs that offer NIPT is that they have not published their data to allow for an apples-to-apples comparison of which is better. Instead, they each try to market based on what they say they’re better at. For example, Harmony marketed it was better based on price because it was the lowest cost, but tested for the fewest conditions. Conversely, Sequenom’s MaterniT21 was marketed as the best because it tested for the most conditions. Panorama markets that it’s the best because it’s the only one that uses SNP-array analysis. Illumina marketed verifi as the best because it was supposed to not be contingent on a fetal fraction. So, instead, discuss with your OB/GC about what’s important to you, i.e. testing for only certain conditions, cost, how results are reported, and then choose the one that fits your preferences. I know, not clear or easy despite the marketing.

  18. Hi Mark!

    I just read your supportive writing about Nipt tests. I am 24 years old and panorama risk score was >99/100, but was explained that the PPV score should be calculated with the prior risk wich was 1/1350. So this mean that I dont have any chance that my baby is healtthy? In all scans she looks perfect. Today I had an other scan . Actually I am 17 weekd and 3 days. What do you think about this?

    • This post explains how tests like Panorama are almost never 99%. It also includes a link to a calculator to determine the actual chance that your pregnancy is truly positive for a tested-for condition. I presume your result was reported as 99/100 for Down syndrome. If that is correct, then based off of your prior risk of 1/1350, the chance that your Panorama test is a true positive is only 17%, meaning you have an 83% chance of your test result being a false positive. You have a far greater chance that your baby does not have a tested-for condition.

      • Thank you very much for your reply Mark.
        Sorry for the confusion and my mistake. The prior risk was 1:3590 and for Trisomy 18. Down syndrome was low risk. So, what about this case? To be honest I am lossing my hopes because it is >99/100. How it can be wrong? However I believe in God miracles 🙂

        • See the link in the post that I sent you explaining why these sorts of test are almost never >99/100 for determining the actual chance of having a child with the tested-for conditions. Given your prior risk of 1:3590, you have an 83% chance that your Panorama test is a false positive. Plus, with Trisomy 18, often the physical associations with that condition can be seen prenatally via ultrasound, but you say your ultrasounds are clear. You have a significantly greater chance that your child does not have Trisomy 18 than that it does.

          • Thank you very much Mark. Hope everything is well

          • Kassi Brand says:

            Mark,
            I received Panorama results on Thursday of 40/100 risk score for T21. The fetal fraction is 3.1%. I am 30 years old and this is our first child. We have an amino scheduled for 8/31. My first Panorama results came back inconclusive, so we did a redraw. The test was originally done so that we could be sure of the gender. I’m absolutely terrified, of course. It’s says my risk before the test was 1/626 and my PPV is 91%. My OB/GYN said she has seen two high risk T21 results come back. One was 99/100 and a true positive. One was closer to my result of 40/100 and was a false positive. I have read that maternal weight can affect fetal fraction, and I am overweight. Any thought’s are appreciated!

          • If I’m reading your comment correctly, then your Panorama’s PPV was reported as 40 out of 100, or a 40% chance of being a true positive and a 60% chance of being a false positive. I’m not sure what you’re referring to regarding 1/626 and 91%. That said, since you’re having an amnio, you’ll find out for certain from those results, but wait for the full results–FISH results are considered screening only.

  19. Hi Mark,

    So, to sum up, which test would you advise for a singleton pregnancy and when? I am kind of inclining for Panorama since I saw some better statistics for it. I was thinking to wait till the week 13 or 14 and also I am thinking of doing the expanded test which includes microdeletions but they told me that it would just mess up my mind.

    I am 40 and I live very close to a highway. We were struggling with infertility on both sides being treated in IVF when we got a natural pregnancy. My neighbour below was young and very healthy and got a child with 9. chromosome in a ring so we do not know if it is just a chance or we are exposed to some kind of contaminant…

    I would very much appreciate any additional advice in order to best plan my appointments!

    • Because the labs do not report out publicly their actual lab experience (the claimed accuracy is based off of control studies), it is impossible to say which test is more accurate than another. The tests are not recognized as accurate for microdeletions and the false positives associated with those conditions are much higher than for the major trisomies. There is no known relation of exposure and the risk of Down syndrome or other aneuploiodies. If you are planning on continuing no matter what, then having any of the cfDNA screens later in pregnancy increases their accuracy.

  20. Hello I’m a 37 year old and I had the MarterniT21 test done on January 31. I was a day away from being 17 weeks pregnant when I got it done. I got a phone call from the nurse at my dr office about 1 1/2 weeks later. She stated that the results came back positive for trisomy 21. She stated that the perinatologist office will be in contact with me to set up an appointment for a level 2 ultrasound. That office didn’t call me back for another week. They finally set an appointment for me on February 22. When I went in I had the ultrasound done and was waiting for the dr to come in to explain the results to me. I have already had it in my mind that my baby girl has Down syndrome since my obgyn told me the test is 99% accurate. My main concern was if she was healthy. So the perinatologist comes in and tells me that the MaterniT21 test is very accurate and my baby has Down syndrome. He wasn’t even going to tell me how the ultrasound went. So I asked him how she was developing. And he said she’s fine but she has a tiny “spot” on her heart but that doesn’t mean she has heart disease and something about the pinkie bone. That’s all he told me. He was about to walk out of the room until I told him I wanted the amniocentesis done. I just want to be prepared to raise my daughter the best I can. The dr acted like I was stupid because I wanted the test done. So I went through with the amnio that day (yesterday). I should be getting my results back in 7-10 days he said. My question is, I got the one page back with the results from the MaterniT21 test so I don’t really understand them. It says positive for trisomy 21 with the lab director comments stating fetal fraction 15%. What does that mean?

    • The “positive” means their test detected Trisomy 21 and I understand fetal fraction to mean the amount of cfDNA from the pregnancy that was tested; 15% would be on the high side, adding to the accuracy of the results. That said, MaterniT21 remains a screening test and, based on your age, a “positive” result would mean you still had a 14% chance of your test being a false positive (such testing is almost never 99% for determining the actual chance of having a child with the tested-for condition). The amnio will provide the definitive diagnosis. More about cfDNA screening, what the results mean, and resources on Down syndrome recommended to accompany a test result can be found at this link.

  21. Mark,

    Just wanted to give you an update on a comment I left you previously. After receiving a high risk assessment for Down’s and being given what we considered horrible care, we asked our OBGYN to refer us to a new perinatal doctor. We saw this office for our anatomy scan in between our 20-21 week marker. At this point everything looked wonderful on our scan, we even got to see a great 3D image of our little guy. The doctor said that the only thing she saw was a bright spot on his heart that can show up on a baby that did not have DS and she was not concerned with this marker at all. After leaving we were still told that they chances were 99% and they would not answer the questions we had about PPV, but they did show more sensitivity and caring then I felt the previous doctor had. We were scheduled for a fetal echocardiogram 2 weeks later. We had our echo and again, everything looked perfect. She did not see any imperfections and was certain that our little boy is completely healthy and would not need any special things at birth. After getting the clear for his heart being good, this doctor came back to his nasal bone. My husband was a little annoyed because we had two other US saying the nasal bone was there and it was good, one being a week and half before. The doctor then admitted that at this point that they were probably looking for things to closely and that there was a good chance that they are seeing things that are not truly issues because their minds have been tainted by the NIPT we had taken. My husband and I also were discussing that the nasal bone may be a product of his heritage as we have read that certain ethnicities tend to have shorter nasal bones. He has some Native American in him and has a short broad nose himself – could it be that he is just taking after daddy? At this point my husband got right to the point and told the doctor he had a question that he was certain that she would not answer. She assured him she would do her best. My husband then said, “At what point can we say that the NIPT test is not 99% predictive after having all these other tests that do not show any signs of DS. I understand that the US will not be diagnostic, but I have a hard time believing that the predictive value has not gone down some.” They finally admitted that the test was not 99% accurate and that our PPV had dropped significantly to 79%. She even went as far as to say that if we never had the NIPT that she never would have suspected anything. She was actually confused why we had the test in the first place. I told her that we were told because of my age (34) that we were eligible for this screening test and that we could find out gender. She knew we wanted to know the gender. We had no knowledge of what can of worms this would open. She seemed very disappointed that they would push the test so much off the gender aspect even though our first trimester screening looked so good. At any rate, we do understand that we will have to wait until birth for a true diagnosis at this point, but we are a lot happier now that we are being given the PPV not the 99% accuracy that has been pushed from the beginning. I do believe that these tests can be a good thing if they are presented in the correct lighting for high risk populations. I also think that there needs to be some sensitivity training that comes along with presenting the data to patients. It deeply saddens me that a lot of women are getting presented with these results and it is a dooms day scenario. Yes, our children may be different, but that does not mean something is “wrong” per say. Also, I think doctors really need to be careful when they are presenting results to patients who do not understand what things mean – there are a lot of people making permanent decisions off of a screening test that may give them a false positive. While a decision of how to proceed with a pregnancy is personal one – I do not think that irreversible decisions should be made without a diagnostic test. Thank you again for your articles and resources that you have provided to the community at large. I have found great comfort understanding things more and actually being able to go in to these doctors appointments more informed and calmer in my approach to them.

    Thank you again!

    Amber

    • Thank you for this update. As several of the posts here report, your points about medical training being sorely needed in both understanding the test results and in how the test results are reported, to include compassionately delivering the results, has been something that has plagued the administration of prenatal genetic testing from its beginning. It is further unfortunate that this testing, which is premised on respecting your right to information, was not offered to you in a way so you understood more conditions than just gender could be reported. I wish you the best with your pregnancy, for an easy delivery, and for a happy union with your baby.

      • Thank you Mark. We are excited to meet our little boy and hold him and love on him. Looking back I wish I had not sweated the small stuff so much, it is easier said then done. The important thing is that he is healthy. He will be loved Down Syndrome or not :). I have had many other friends who have had their own experiences with these tests and I have referred them to this site as a resource to understand a little better how it all works. I hope that you and your family are well. Keep up the great work!

Trackbacks

  1. […] clinical study of NIPS noted that false positives and false negatives are due to the testing of placental, not fetal, DNA. There is a phenomenon known as “placental mosaicism” where cells in the […]

  2. […] for this description since this is what the testing laboratories misleadingly say on their websites. But, it has been known for years that what is being tested is not fetal DNA, but DNA derived from […]

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