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Q&A: Columbia’s Ronald Wapner on Applying Array CGH in Prenatal Medicine

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By Justin Petrone

wapner.jpgName: Ronald Wapner

Title: Director of Maternal Fetal Medicine, Columbia University Medical Center

Professional background: Wapner has been director of maternal fetal medicine at Columbia University Medical Center since 2005. Prior to joining Columbia, he was professor of obstetrics and gynecology at Drexel University College of Medicine in Philadelphia. Before that, he was director of maternal fetal medicine at Thomas Jefferson University in Philadelphia

Education: 1990-1991, fellowship, medical genetics, Thomas Jefferson University Hospital, Philadelphia; 1976-1978, fellowship, maternal fetal medicine, Thomas Jefferson University Hospital; 1973-1976, residency, department of obstetrics and gynecology, Thomas Jefferson University Hospital; 1972 — MD, Jefferson Medical College, Philadelphia

For more than 30 years, Ronald Wapner has been involved in developing and implementing new screening techniques in the arena of prenatal diagnostics. Board-certified in obstetrics and gynecology, maternal fetal medicine, and clinical genetics, Wapner was instrumental in the development of chorionic villus sampling, a prenatal test to assess the health of the fetus. He also helped identify a first-trimester screening method for Down syndrome.

In recent years, as director of maternal fetal medicine at Columbia University Medical Center and New York-Presbyterian Hospital, Wapner has been evaluating the use of array comparative genomic hybridization to screen fetuses for constitutional abnormalities. While Wapner is confident that arrays will mostly replace molecular karyotyping in prenatal testing in the next few years, he is concerned with other questions surrounding the clinical use of the technology: such as what content is included on the arrays, in what circumstances array technologies are used, how best to counsel patients based on array findings, and how to win reimbursement for what are, at the moment, relatively expensive tests.

Wapner is also the principal investigator on a National Institute of Child Health and Development-funded project that seeks to blindly compare 4,400 samples tested with arrays and molecular karyotyping to determine which method yields more accurate results. Findings of the project are expected to be published by the end of next year.

Wapner discussed this study as well as general trends in the clinical adoption of arrays in prenatal diagnostics during Signature Genomics' Scientific Microarray Conference, held in Spokane, Wash., last week. BioArray News spoke with Wapner after his presentation. Below is an edited transcript of that interview.


You have been doing prenatal diagnosis for 35 years. What interested you in this area?

Genetics has always been fascinating. The important issue is identifying birth defects, helping parents understand what’s going on with their pregnancy. I think those are the things that are most important and why it’s been intriguing for me. Don’t forget that when I started doing this, there was no ultrasound. When I started doing this, all prenatal testing was limited by our tools. So I have been incredibly lucky because from early in my career there have always been technologies that have dramatically moved forward our ability to do prenatal diagnosis. [With] ultrasound, nowadays, you can see very well the anatomy of a fetus so we can identify these things early. [Amniocentesis] moved to [chorionic villus sampling, or CVS] so that we could, as early as 11 or 12 weeks, identify problems with the pregnancy. Now with microarrays coming along, we are making another giant leap in terms of what we can tell parents about the pregnancy. It’s been a combination of liking the area and seeing the technology move so dramatically and rapidly forward, plus it's the marriage of genetics and pregnancy management.

When did arrays, specifically array comparative genomic hybridization, first cross your radar?

For years, I would sit in meetings and hear about CGH, and the question always was, ‘When is that going to become clinically applicable?’ I would argue that it’s been over the past seven years or so that we have begun to see the clinical applicability. It’s taken five years to go from, ‘We should be able to do this,’ to ‘Yes, this is the next logical step.’

When did you actually implement it?

What I have done through most of my career is taken the technology that made a lot of sense at its development stage and done the testing to move that technology into clinical care. We were the first people to do CVS in this country. When that technology developed, and we were part of the development, we did the clinical trials, and we looked at what it could do from both the technical standpoint and also the laboratory standpoint. We did the first series of publications in this country about how that technology would change things. What I have seen our role in being is seeing what is on the forefront and then moving it and gaining enough information about it so that clinicians can know how to use it in their care. And that’s what happened. With CGH, it was decided that the next best step was putting together a clinical trial, putting together lab investigators, understanding how it’s going to be used, and that’s exactly what we are doing; we are right in the middle of testing to see how it will be used.

You still consider yourself to be in an evaluation period?

I think that there are different levels of evaluation. One level of evaluation is, 'Does this technology work?' Absolutely, there is no question about that. It works. But there are lots of things that work that haven’t been adapted to clinical care. It either hasn’t been available to patients or it hasn’t given them the information they wanted, so the next logical step is to test it in real practice. The question we are working on now is how those arrays will be best used by patients, what’s the best way to do it, what unexpected problems will come up. You really need to put a technique into clinical use and evaluate it from the standpoint of technology, the applicability, and also patients’ counseling, because that’s important. So that’s the stage we are in. We are translating it from the lab to clinical care.

But if a patient had an abnormal ultrasound, then she could obtain access to this kind of service today?

That’s not clear. If you had an abnormal ultrasound, there is a strong likelihood that an array would give us more information than a karyotype. Is that standard of care around the country? No, it’s not because somebody has to make sure that’s true before it sells in Oshkosh, so to speak. That’s what is going on right now. We are pushing to understand the right indications. I think it’s clear that fetal anomalies are a correct indication. But are there are some anomalies where arrays may add some information and others where it may not? The answer is that we don’t know. The other question is that we find too many things on arrays that are confusing [when it comes to] counseling patients. We are working those kinks out. Those are the things that need answering.

For what indications do you provide array-based testing in your lab?

I think right now, there are certain indications. When you have cases in which it’s likely that a karyotype will give you insufficient information, like a de novo translocation, like a marker. In New York right now, if we see a pregnancy with an anomaly that doesn’t look like a typical anomaly we’ll do an array. Now, when I say it doesn’t look like a typical anomaly, I mean it doesn’t look like Down syndrome or trisomy 13 or 18. There are also certain other indications: like for a heart defect, we’ll almost always do an array nowadays, [or with] other central nervous system anomalies. So, I would say that we now know enough about the use of arrays and anomalies that it’s become an additional important tool in making a diagnosis.

What platform are you using?

In the trial, we are using two platforms, an Agilent and an Affymetrix. Actually, we are not using the SNP component of the Affy array. It is really just a copy number variant array. The Agilent array was designed specifically for this study and we have masked the software so that the arrays are comparable. Our job was not to compare the two arrays; it was to ask the question of what is the value of arrays in clinical practice. So the array has somewhere around 70 known targeted deletion or duplication syndromes. It’s got telomere probes, it’s got sub-telomere probes, and it’s got a backbone that’s approximately one megabase apart. We didn’t want something that was any denser for prenatal because we didn’t want a lot of copy number variants or findings of unknown clinical significance. It’s proved to work fine.

In your talk, you said this will replace some, if not all, classical cytogenetic methods.

My bias is that it will replace karyotyping in prenatal within three to five years. The only reason why it might not is that there are patients who don’t want that much information and who can’t deal with uncertainty. I think we have to handle that and design arrays that minimize uncertainty. But there is absolutely no logical reason why it won’t replace karyotyping. One argument is that it can’t detect triploidy, but there are some tricks being worked out that will allow you to detect triploidy. The other argument is that you can’t detect a balanced translocation. But who cares if you can’t detect it? If it’s balanced, that means it won’t have any impact on the kid. It’s easy to do, the results are quicker, and it’s more informative. Why wouldn’t you do it? And I am not talking as a lab person who wants to use arrays. I am talking as a clinical physician who is anxious for more information to give to my patients.

There is the issue of using targeted arrays versus a whole-genome scan.

Prenatal has got to be targeted. Prenatal is different from postnatal. With postnatal, you can discover. You can find a kid with a problem, say, this is an array finding, and check him every six months to see what that finding means. Prenatal is a whole different world. You don’t have a decision to follow the pregnancy. You sometimes have to make irreversible decisions. There are things that are very appropriate to know postnatal that may not be of importance to know in prenatal. That’s why we should have a targeted array and why it should be targeted for prenatal.

Another issue is what content goes onto that array.

That’s the crux of the matter. I think that, right now, some people use whole-genome arrays and they don’t need to make this decision. I believe that it should be targeted, and I believe that there should be reasonable people who get together and there should be consensus among people in the area and fortunately there are a limited number of people doing this right now. There have to be consensus meetings among the genetics colleges and the maternal fetal medicine colleges about what content should be on the array. Certainly, the content should be associated with some serious problem. This serious problem should be clear cut. As more information develops about these things, then we should be able to redesign the array. There has to be a group of people that can decide this. And that will come.

What about the ethical questions of applying arrays prenatally? Just years ago, it seemed more of an issue.

I think that there are two levels. Certainly, patient autonomy would dictate that patients should be able to have any information that they want. There are also societal constraints about what information you should be looking for. I have been absolutely impressed with the constraints that people using these arrays have shown. They have asked the right questions and have not pushed it. I think we have to be careful because the people doing this have been on the cutting edge and have been doing it in an investigational setting. As things translate into the public domain and it becomes more and more used that will be an ever increasing question. I think that anyone who’s going to be doing it has the social responsibility to ensure that these tools are being used properly. However, all that being said, I don’t have a fear of arrays because most of the things being found with arrays are pretty significant. For the study we are doing, it’s got to be a megabase or bigger to be reported. So you have to come up with limits: If something is too small or not associated with a serious problem, then you shouldn’t be reporting it. This is not a technology where people are looking for hair color or eye color. These are serious disease processes that are being identified.

What is its objective of the NICHD Trial?

We are in year three right now and the objective is to compare prenatal arrays with standard karyotyping. It’s a head-to-head blinded comparison of the two [and] 4,400 patients are getting their samples drawn. It’s going to one lab for a karyotype, one lab for an array, and at the end, we will see which gave more information, which gave more accurate information, which gave less false information. So we will know by next year how the two will compare head to head. And that’s what you need to do before you change your technology. We expect to be able to report our findings by the winter of 2012 at the latest. And not only are we testing the patients with the technology, we are doing questionnaires with the patients about acceptance, finding out the indications why patients want to have array testing done. So we are evaluating not only the scientific component but also the sociological and psychological components. There’s a giant impact of getting this information, and we want to make sure that we are getting it right.

You also mentioned in your talk a study of stillbirth infants.

There is a stillbirth network, also sponsored by NICHD, that has about a thousand samples from stillbirth infants, and we are running arrays on that to see if we can identify causes of stillbirth, and also to see some of the things we thought were unexplained [where] stillbirth had a genetic cause. Nobody knows why stillbirths occur. We want to answer the question of what percentage of stillbirths are caused by a genetic etiology. The other critically important part, particularly in prenatal diagnosis, is not only to make the diagnoses; it’s giving us genetic clues to the etiologies. If we see 10 kids with X, Y, and Z in the ultrasound, and all 10 are missing a certain gene or gene pathway, now we are learning the cause of these birth defects. The ultimate goal is not just to diagnose and give the person the option to terminate the pregnancy. The ultimate goal is to have some kind of treatment, albeit that will take more time.

Are there are any obstacles for adoption of arrays, such as insurance cost?

Absolutely. The issue there is that it takes a while for things to transition and insurance companies, if something is more expensive, then they are not going to be very anxious to change. And the way insurers work is that if there is a new technology or new test, they don’t read the literature and decide to change. It takes an evolutionary process where you bring your technology to each insurance company, and there are thousands of them. You explain why it’s valuable, they have medical review groups, and then they make decisions about whether it’s cost effective. I think in this case, it’s going to be a five- to seven-year transition. Insurance companies will have to make those decisions. They need to be pushed by physicians and laboratory personnel. It’s not a bad thing that it takes a while. Being cautious is not a problem. Reimbursement, though, is one of the reasons why acceptance of this technology might be delayed.

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