A Leader in Noninvasive Prenatal Testing
Eric J. Topol, MD: I'm Eric Topol, Editor-in-Chief of Medscape, here for a One-on-One session with a terrific leader in the field of noninvasive prenatal testing, Dr Diana Bianchi from Tufts University. This is an exploding field, and you are right in the middle of it. How did you get started in this hot new area? Where were you before, and how did you get into it?
Diana W. Bianchi, MD: It's not a hot new area for me; I have been working in this area for more than 30 years. My mentor in medical school as a first-year medical student was Leonard Herzenberg, who had a son with Down syndrome. Dr Herzenberg knew that I was interested in genetics and said he would like me to work on a noninvasive prenatal test for Down syndrome. There were a lot of hills and valleys in between, but what made the big difference was using cell-free DNA, as opposed to intact cells.
Dr Topol: Until this time, we used very indirect measures: nuchal size and alpha fetoprotein. They weren't very good though, were they?
Dr Bianchi: They were good when used in combination, and there is certainly a lot of clinical experience with them, but you are right. They measure proteins that are made by the fetus or placenta, but they don't directly have anything to do with the chromosome abnormality. What is different now is that we are using cell-free DNA and looking at specific parts of the DNA that relate to chromosome 21 or other chromosomes of clinical interest.
Dr Topol: Between 8 and 12 weeks of pregnancy, a single tube of blood gives a lot of information—is that correct?
Dr Bianchi: Generally, we like to wait until at least 10 weeks to have a sufficient fetal fraction—the amount of fetal DNA relative to the amount of maternal DNA. When we take a tube of blood, it's maternal DNA and placental DNA, which serves as a proxy for the fetus. The placenta doesn't get big enough until about 9 or 10 weeks, so from 10 weeks onward, we can take a tube of blood and begin to analyze the DNA from the placenta.
Dr Topol: Although this is called "fetal sequencing," in terms of 40× coverage, this is a very low-pass sequencing to pick up the major chromosomal abnormalities?
Dr Bianchi: Right. The big difference is that we are not sequencing to look at the AGCT; we are sequencing to map a particular location in the human genome so we can identify where that extra fragment of DNA comes from. We are interested in certain chromosomes that are associated with problems in fetuses and babies. Those are chromosomes 13, 18, and 21. We are using DNA sequencing to count molecules of DNA and to determine whether there is too much present from chromosome 21 or chromosome 18, for example.
One Million Tests and Counting
Dr Topol: This test is the most rapidly growing molecular test in the history of medicine. About 800,000 of these tests have been done?
Dr Bianchi: Worldwide, I believe it is 1 million now.
Dr Topol: That's pretty quick over a couple of years.
Dr Bianchi: Correct. It first become available in the fall of 2011, and it is now March of 2015, so in that time there has been a rapid incorporation globally.
Dr Topol: The high-risk validation has been extraordinary for trisomy 21, but the question is, where do you draw the line for risk, and should this test eventually be undertaken by all pregnant women?
Dr Bianchi: Many women who have no intention of terminating their pregnancy, regardless of chromosomal abnormalities, want to know whether they are going to have a baby with Down syndrome. They like the test because it's a blood test. It doesn't harm the baby in any way. Approximately 40% of women in the United States, even when they know they have a fetus with Down syndrome, choose to continue their pregnancies.
Your question relates to women of average risk, and how does this function as a primary screen? In the literature, there are 24 large-scale clinical trials that show that the detection rate for Down syndrome is 99.2% using cell-free DNA testing. The test is by far the best screen available. The limitations are mainly cost and education, so that providers know the benefits and limitations of the testing—and particularly when they receive false-positive results, what do those mean? What does a positive screen mean?
False-Positives and Ethical Dilemmas
Dr Topol: You mentioned that you are particularly interested in the false-positives. Can you tell us more about that?
Dr Bianchi: When women get a positive result, it is a screening test, and they are given the information that they should have a diagnostic test to confirm that result. Every professional society is very consistent in saying that a diagnostic test should be performed. When the diagnostic test on the fetus shows that the fetal karyotype is normal, but the noninvasive prenatal test was abnormal, there is a discordance. There are multiple reasons for that, including the death of an unappreciated twin; confined placental mosaicism; and a maternal condition, such as cancer or an organ transplant.
Dr Topol: Over time, we are starting to learn that we have much more mosaicism than we ever thought. Today there is a cut-off of just a few major chromosomal aberrations, but obviously we can derive a lot more information from this testing. Is this the major bioethical concern in the field?
Dr Bianchi: There are some big concerns when you are dealing with pregnant women. It's a very emotionally vulnerable time. Unborn patients are very different from your adult patients, because we can't physically examine them. We can look with an ultrasound, but it's not the same as a physical exam. We don't have a health history. The person is not born yet. We have a family history. We are dealing with incomplete information. That is going to be the challenge moving forward. The technology is moving so fast that we are already getting into daily ethical dilemmas about what to do with the information.
Dr Topol: Is it a situation in which the pregnant women are requesting the test more than the obstetricians are suggesting that they have it? Where is that headed?
Dr Bianchi: Yes. I talk about the parallel universe, because pregnant women in general are very Internet-savvy; they are very aware of these noninvasive tests. They are asking their physicians about them. In many cases, the general obstetricians are less familiar with the test, and its benefits and limitations, than the patients are.
A Disruptive Prenatal Care Technology
Dr Topol: It's fascinating to see this education among consumers and women. You mentioned, which I think is very striking, a 70%-80% reduction in amniocentesis, to the point where your trainees can't get the training.
Dr Bianchi: It's disruptive technology, because for 30 years we have had a very standard set of recommendations for how to screen for fetal chromosome abnormalities. It is a multistage algorithm that gives pregnant women time to reflect on the information they have been given. This changes everything—it changes training, and it changes care.
Worldwide, 50%-70% fewer invasive procedures are being performed, but for a good reason. It's because this test has a much lower false-positive rate. Many women don't need to have those procedures, and we are saving them from having the procedures, but we do want the women who need the procedures to have them.
Dr Topol: It's a revolution. Prenatal medicine is leading all genomic medicine in terms of this disruption, and taking advantage of this little bit of fetal DNA in a maternal sample. It is remarkable. You have been a pioneer. The work that you and your colleagues are doing is fantastic and obviously is having a big impact worldwide.
You are of the most interesting people in medicine, and it has been a pleasure to talk with you. Thank you for joining us for this segment of One-on-One on Medscape.