Masha G. Savelieff, PhD
|Megan Allyse, PhD, is an assistant professor of biomedical ethics at Mayo Clinic. She completed her PhD in sociology and social policy at the University of Nottingham, and her postdoctoral research at the Stanford Center for Biomedical Ethics at Stanford University. At Mayo Clinic, her research is centered on the translation of emerging medical technologies from research into clinical practice. In particular, she is interested in issues around reproductive ethics, women’s health, and health disparities in access to care. She is also interested in enhancing the practice of clinical genomics. The overall goal of her research is to provide appropriate, high-level care to all patients, regardless of socioeconomic status.|
Q: What is noninvasive prenatal testing (NIPT), and how does it differ from standard screening methods?
A: The current screening standard of care, in the United States at least, is a maternal serum test. Women are offered a draw, and what it does is detects markers in the maternal serum that are associated with the presence of a fetal anomaly.
You’re looking at about an 85 percent detection rate with that screening protocol. With regard to NIPT, I actually prefer the term cell-free fetal DNA. Although we call it “fetal” DNA, it actually derives from the placenta. The cell-free DNA test uses an algorithm to detect differences between placental and maternal DNA, and then sequences the placental DNA fragments. Obviously, in pregnancies where the placenta is not representative of the fetus, for instance in placental mosaicism, you can get inaccurate results. In theory, you can run the cell-free DNA test as early as 10 weeks. What we call fetal fraction—the amount of fetal (placental) DNA in maternal serum—is detectable at 10 weeks, although I think that most labs prefer to have a 12-week sample to make sure they get enough DNA.
Q: What are some advantages and disadvantages of cell-free DNA (NIPT) compared with pre-existing prenatal testing technologies?
A: It has a higher detection rate for trisomy 21, around 99 percent—better than traditional screening. Again, this is in comparison with other screening mechanisms and not diagnostic mechanisms, such as amniocentesis or chorionic villus sampling. Cell-free DNA also has a slightly wider reach than traditional screening, which detects only trisomies 13, 18, and 21. Most cell-free DNA panels currently on the market do trisomies 13, 18, and 21, as well as XY chromosome disorders such as Klinefelter’s, XYY, and XXX. Some companies have started adding certain sub-chromosomal anomalies, like 22q11 deletion. But the positive predictive value and negative predictive value of those are still not very clear.
On the other hand, cell-free DNA is much more expensive. These tests are all offered by for-profit companies, so they are not part of most states’ screening. All the algorithms are proprietary, so if you get a false positive or a no-call from the lab, there is no way to get any insight on the result. Plus, you have to agree to very specific contracts with the company, and those can get complicated.
Q: What are the most exciting technological future trends for cell-free DNA?
A: There are at least two cases thus far of successful whole-genome sequencing using cell-free DNA. But it is very expensive, because you need a lot of coverage. I don’t necessarily think in the near future that’s really where we will be going with the technology, mostly because I don’t think it is necessary for the vast majority of pregnancies. There are various labs that have been targeting microdeletions and duplications. However, in my mind, this is not yet at the point where it can be accurately translated to the clinic, though I think that will improve.
Q: What is the focus of your research on cell-free DNA?
A: I actually started in Stanford in 2010. That was the same year Stephen Quake, who was the original IP holder for NIPT at Verinata Health, started the trials. And so we’ve been with NIPT almost since its inception. We’ve done a variety of studies. We’ve surveyed the national population about their hypothetical desire for the technology and their concerns about the technology. In one study that’s just out, we interviewed women who got the cell-free DNA test but who got a false positive or a no-call result. They felt like they had trusted the test because it was genetic and should therefore be accurate, and really felt betrayed that it had let them down. But I will say that about half of them said they would still do it again, if they had a future pregnancy. That was an interesting finding. We’ve also done a lot of work on cell-free DNA in comparison with other options. Traditional serum screening is cheap, if not free, and it’s right most of the time, but it doesn’t do certain things like sex chromosome aneuploidy. Cell-free DNA is expensive and is right most of the time, but not all of the time, and then diagnostic testing is right pretty much all of the time, but it does involve risks. So it is important that women understand their various options and what each means.
Q: What are some of the changes you’ve seen that have taken place in recent years in the use of cell-free DNA in the clinic?
A: The first prenatal cell-free fetal DNA test was commercialized in 2011. So you’re looking at only about seven years of technology, which is incredibly fast.
There has certainly been an expansion of the applications offered by cell-free DNA. I will say that the data are excellent for trisomies 13, 18, and 21, and good for XY disorders. For microdeletions, they’re pretty terrible. My personal opinion would be that the expansion has been too aggressive in places. Robust trials were carried out for the initial trisomies 13, 18, and 21. But after that, the industry sort of gave up on academic clinical trials and just started adding things to the panel without really good evidence. There are definitely a lot of things this technology has done to benefit pregnant women and their families. But I think we also need to be cautious; more may not necessarily be better in this case.
Q: What are some of the challenges with expanding the use of cell-free DNA in prenatal care practice?
A: I think in most states in the United States, a woman who is pregnant can get traditional screening for free. It’ll be covered by state screening, and even if it’s not, it would be covered by Medicaid. That’s pretty much the standard of care, and it has a fairly low health disparity rate. However, cell-free DNA is not covered in most states, so you are reliant on either private insurance or out-of-pocket costs. California and New York, however, will pay for a cell-free DNA test under Medicaid if the pregnancy is high risk with a history of fetal abnormalities.
As far as expanding access, there is an industry group called The Coalition for Access to Prenatal Screening. It’s a lobbying group put together by the six biggest testing companies to pressure the government to cover cell-free DNA under Medicaid. I don’t know how effective it will be, because Medicaid is very localized. So I think from the industry’s perspective, the challenge is reimbursement— how to get the test covered.
Another challenge is that we don’t have sufficient resources in place. I think that most obstetricians are prepared to explain Down syndrome, but are they prepared to explain Klinefelter’s? Are they prepared to explain 22q11? The answer is probably no, because they don’t get the training. That’s what a medicinal geneticist is for. So all of a sudden we’re taking something that clinically has traditionally been the realm of genetic counseling and moving it into family medicine and obstetrics.
Here at Mayo Clinic we have Mayo Medical Labs, which is one of the larger testing labs, and we’re just starting a pilot. When we send out test results, especially unexpected results, we include on the bottom a reference back to the Clinic: “If you or your patient has any questions about this result, you can call us at XYZ.” We are really trying to provide resources both to providers and to patients who may be getting results they don’t expect. There’s a lot of information coming from these genetic tests, so we need to prepare for that.