Dr. Charlotte Brasch-Andersen is a clinical laboratory geneticist at Odense University Hospital in Southern Denmark and an associate professor in human genetics at the University of Southern Denmark—a position she has held since 2010. Previously, she held positions as a senior consultant at the National Genome Center in Denmark, an assistant professor in pharmacogenetics at University of Southern Denmark, and a board member of the Danish Society of Medical Genetics. Additionally, Dr. Brasch-Andersen was the chairperson of a committee that implemented a formal education program for clinical laboratory geneticists in Denmark.
Dr. Brasch-Andersen’s clinical work focuses on examining copy number variations in DNA from blood or tissues that are implicated in intellectual disabilities, developmental delay, dysmorphisms, prenatal diagnostics and miscarriages. This interview with Dr. Brasch-Andersen discusses the process her lab underwent when choosing the best platform for her prenatal diagnostics workflow.
Thermo Fisher Scientific: You were originally using the Agilent platform at Odense. What was it that first drew your attention to Applied Biosystems™ CytoScan™ products?
Dr. Brasch-Andersen: My team was using the 400K Comparative Genomic Hybridization (CGH) Microarray from Agilent for postnatal samples, but had to start running prenatal samples as well. Adding prenatal samples to the array workflow made me evaluate the present setup. So, I made a list of which factors were important to consider in a setup of both postnatal and prenatal samples. One of the more important considerations was in clinical applications, I wanted to be able to detect polyploidy (an extra set of all chromosomes), which in rare cases can be seen in prenatal samples. To detect polyploidy, single-nucleotide polymorphisms (SNPs) are needed on the platform, as without them the algorithms behind CGH will just normalize all the data resulting in a normal result. Back then, few CGH arrays had enough SNPs to detect polyploidy. Even though the ultrasound gynecologist said that they could tell by the ultrasound if the fetus was polyploid, I felt I needed a method that could detect it using molecular means.
Another issue to consider was the workflow and staff in the lab. Time, or specifically report time, and economy is always an issue, even in a government-funded healthcare system like ours in Denmark. I didn’t need the same array resolution for pre- and postnatal arrays, but I wanted an array solution and protocol where we could do postnatal arrays at the same time as prenatal arrays. It wasn’t optimal economically to have one group of technicians running one protocol and another running a different one. It wouldn’t be robust enough when people go on vacation or are sick. What’s really neat about the CytoScan suite is that it is essentially the same protocol in the lab for the various array formats, so the only difference really is which cartridge you load. The benefit of the same protocol is that it would allow us to run the postnatal arrays alongside the regular prenatal array batches. That gave a lot of flexibility and thus allowed potentially faster turnaround times on the postnatal arrays, as we run the prenatal analysis twice a week.
“The CytoScan products require less DNA than a majority of the other products on the market that compete in the same space. The low DNA input requirement is a significant advantage of the CytoScan products and was another factor that drove our decision to convert.”
The added flexibility also had an additional benefit: with the very different numbers and types of samples we were receiving every week, it meant we could allow for changes in volumes of each sample type more easily. Sometimes prenatal sample volumes are small and it is not possible to extract a lot of DNA. The CytoScan products require less DNA than a majority of the other products on the market that compete in the same space. The low DNA input requirement is a significant advantage of the CytoScan products and was another factor that drove our decision toc onvert.
“The CytoScan products and ChAS have both a CNV track and a SNP track, and I learned these were totally independent. If I saw a deletion in the copy number variation track, then it was independently confirmed in the SNP track and I didn’t have to verify it using another method.”
Another important feature is that CytoScan products have two data tracks in the Applied Biosystems™ ChAS (Chromosome Analysis Software) analysis package compared to CGH; the CytoScan products and ChAS have both a CNV track and a SNP track, and I learned these were totally independent. If I saw a deletion in the copy number variation track, then it was independently confirmed in the SNP track and I didn’t have to verify it using another method. I just had the confirmation right there.
For all prenatal analysis, report and analysis time is really important so you need something that’s super robust and provides an answer quickly, I felt that no other platform offered both of these advantages.
Thermo Fisher Scientific: At which point were you convinced that you should switch to CytoScan arrays?
Dr. Brasch-Andersen: I weighed the pros and cons and I think the arguments were strong despite CytoScan products having a longer protocol compared to other products we were evaluating.
Thermo Fisher Scientific: So it was the benefits of the systems that made you make the change?
Dr. Brasch-Andersen: Absolutely, and I have to say, they are very robust systems. During the first six months of running it, we analyzed 27 prenatal arrays; as of October of this year we’d already done 1,000. It’s been an enormous increase. We are getting referrals from other hospitals too as the obstetricians can see that it is a robust system and few samples fail. It’s the results that make the difference.
Thermo Fisher Scientific: When you first introduced the CytoScan solution into the lab, what was it that Thermo Fisher offered that made it easier to deploy within your department?
Dr. Brasch-Andersen: Well, we got help from all of the support teams, including a dedicated applications scientist, and they ironed out any early troubles very quickly. We also have a unique Nordic community involved with this application in the form of the Thermo Fisher Scientific cytogenomic user group. This group holds annual meetings facilitated by Thermo Fisher and is backed up strongly by all the users in the region. During the Nordic meetings, we have open discussions around our applications and use of the system. I’m of the conviction that if I find a problematic issue, then I’m not the only one who has seen it—somebody else has probably had a similar finding. Open debates are discussed, and it’s really been a great help to implement improvements in the lab and in the analytical stages. The user group meetings have provided a lot of value.
“We also have a unique Nordic community involved with this application … the user group meetings have provided a lot of value.”
Thermo Fisher Scientific: You mentioned earlier one of the main reasons you chose the CytoScan suite of products was because of reliability.
Dr. Brasch-Andersen: Yes, I think I can count on two hands the number of arrays that we’ve ever had fail. I mean it is really robust.
Thermo Fisher Scientific: Is the robustness something that you saw in the other platforms?
Dr. Brasch-Andersen: No, we had to redo a lot of arrays previously. We came from the 400,000 probe arrays from Agilent, but we’re now using the CytoScan suite of products for both prenatal and postnatal. We didn’t change to a system with more probes because we wanted to detect smaller aberrations, but because having more probes gives a stronger, more robust answer.
“I think I can count on two hands the number of arrays that we’ve ever had fail.”
Thermo Fisher Scientific: What are your reasons for continuing to use the CytoScan suite?
Dr. Brasch-Andersen: For a lot of the reasons that I’ve mentioned already (independent SNP track, flexible protocol, low DNA input), but mainly because of robustness. When you’re conducting analysis and you have people waiting for rapid, accurate results—and in the majority of these cases pregnant women are worried because they have an abnormal risk assessment for the pregnancy—robustness is important. It is just enormously important and nice not to have to tell the patient, “I’m sorry, your sample failed and now you’re going to have to wait another five days.” It just happens so rarely now. Even sometimes with samples from miscarriages, the DNA can be very degraded; but most of the time we’re still able to get results for those samples, and it means a lot to the parents that they get an answer.
“Even sometimes with samples from miscarriages, the DNA can be very degraded … we’re still able to get results … and it means a lot to the parents that they get an answer.”
Thermo Fisher Scientific: How do you view the future of arrays now that NGS applications are developing in this field?
Dr. Brasch-Andersen: We do see more and more analyses moving to NGS applications, but I think it is still going to be a while before genome sequencing will take over copy number arrays in diagnostics. I see the methods coexisting for a while and even supplementing each other as long as exome sequencing is the preferred NGS method for diagnosing rare diseases. I am uncertain if NGS will replace the screening of the prenatal samples from the first trimester, which are the majority of our samples now. So I’m sure these robust arrays will be the core of our work for the foreseeable future.
“We do see more and more analyses moving to NGS applications, but I think it is still going to be a while before genome sequencing will take over copy number arrays in diagnostics.”
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