News and Notes from PNDx 2016 (Diagnostics World News)

By Benjamin Ross|December 9, 2016

The fourth annual Advances in Prenatal Molecular Diagnostics Conference took place last week in Cambridge, Massachusetts. The conference focused the bulk of its efforts on addressing two important, parallel issues: the science involved in cell-free vs. circulating fetal cells, and the angle of genetic counseling that impacts both the patient and the clinician. These topics are far from insignificant, and rich, conversation is vital in order to ensure that these issues continue to evolve.


The conference featured lectures from prominent experts in the field of gene sequencing and NIPT, and included discussions on topics of prenatal diagnosis and the genetic counseling, which often go hand in hand. Here are just a few highlights from the program.


Trends and Implications of Fetal Anomalies


The conference opened with Ronald Wapner, Director of Reproductive Genetics and Vice Chair of Research for the Department of Obstetrics & Gynecology at Columbia University Medical Center, delivering a lecture on the trends and implications of fetal anomalies. “The most important thing we see,” said Wapner, “if you look at the frequency of common atrocities—the disorder, or the malformation, or the birth defect… that we spend all of our money on right now, billions of dollars—that occurs in 2 per 1,000 pregnancies in general, and about 1% percent of pregnancies if you’re 40 years of age.” It’s a very low percentage, and Wapner stressed that the bulk of these disorders are the result of de novo mutations. After laying out the significance of data accessed through diagnostic testing, Wapner stressed that non-invasive prenatal testing methods are improving and will be the future of prenatal screening. “The next step will be sequencing fetuses, I have no doubt about that,” Wapner said.


Making a Case for Cell-Based NIPT


After giving a brief historical perspective of the scientific understanding of fetal cells, Ripudaman Singh, COO for ARCEDI Biotech Aps in Denmark, laid out the challenges of enriching rare cells. Singh spoke of how he and his research team resorted to other NIPT technologies. One such technology relied on cell-based NIPT, testing whole fetal cells drawn from maternal blood instead of cell-free fetal DNA. Singh provided insight into tests currently underway at ARCEDI. “We have recruitments in pregnancies in different gestational ages. So we would collect the blood sample from week 8, week 12, and week 19 and see whether there is any correlation between gestational age and the number of fetal cells that we enrich.” Preliminary results show that there are no changes as of week 8. Singh went on to describe results from various tests using cell-based NIPT. A bright spot in the results showed that none of the cells picked up as fetal cells were actually misclassified maternal cells.


Pushing Toward Noninvasive Prenatal Diagnostics


Hsian-Rong Tseng, Professor of Molecular & Medical Pharmacology at the University of California, Los Angeles, laid out his group’s latest progress in the analysis of trophoblast cells. Tseng focuses on cell-based NIPT, saying that “we need to hit the ‘gold standard.’ That is, obtaining fetal cells for analysis, however you want to conduct it, in a noninvasive manner.” The bar is high, according to Tseng, because researchers try to push the boundary of fetal cell-based noninvasive technology. Tseng’s solution pointed to NanoVelcro Chips, engineered nanostructures which latch onto the rough surface of cells in the placenta. Tseng’s co-presenter, Li-Ching Chen, from the Cathay General Hospital in Taiwan, showed the success of the NanoVelcro Chips. “In a normal pregnancy, we have successfully detected the fetal cells by micro-array,” Chen stated. In regards to mistaking female fetal cells for maternal cells once a cell is captured by the Chip, Chen suggested that STR (short tandem repeats) fingerprinting of the trophoblast, of maternal blood, and paternal blood to distinguish the fetal cell. Tseng concluded by saying that there are challenges ahead moving forward, one being the issue of cell isolation.


KC Allen Chan, Professor of Chemical Pathology at the Chinese University of Hong Kong, also contributed to the idea of pushing the boundaries of noninvasive prenatal diagnostics, presenting data for chromosomal aneuploidies. Since 2008, Chan, Dennis Lo, and other colleagues have been detecting whether a woman is carrying a trisomy fetus by sequencing a portion of plasma DNA in a pregnant woman. Based on the sequence, they align them to the reference human genome to determine the chromosomal origin of each DNA fragment. From this, Chan can determine the proportional representation of each chromosome in maternal plasma, and this can accurately determine if there is any alteration in the representation of each chromosome. Chan concluded by favoring sized-based analysis, as it could potentially improve the accuracy of chromosomal and aneuploidy detection, and differentiate the source of an aberration.


What Comes First, the Patient or the Clinician?


While it is important to evaluate the latest innovations in NIPT, it is also of vast importance to keep in mind the perspective of those who receive these tests: the patients.


This fact fueled Mark Evans, President of Fetal Medicine Foundation of America, who spoke of the expectations patients bring with them when discussing DNA screening with their physicians. According to Evans, “The communication that we have between doctors and patients, support groups and patients, doctors to doctors, doctor to other professionals is just abysmal and it’s only getting worse as people have less and less time to think about what they want to accomplish.” Evans drew a distinction between the lab technicians running diagnostic tests and the clinician who deals directly with the patient. The most important question he poses is, Can the lab replace the clinician? “That’s the battle being fought now,” said Evans.


The patient was a topic of discussion throughout the many lectures and presentations, especially on the second day of the conference, which included a panel discussion featuring Solomon Moshkevich, Vice President of Product & Strategy at Natera; William Denman, CMO at Premaitha Health; Douglas Rabin, Medical Doctor of Women’s Health at Quest Diagnostics; Daniel Grosu, CMO at Sequenom and Integrated Genetics; and Gautam Kollu, Head of Market Development, RGH Market at Illumina. Questions floated around the room as the audience interacted with the panel. Discussions involved topics including the implications of extending availability of NIPT to average-risk patients, no-call rates, and whether or not there is a limit to the number of genetic tests that the providers are willing to do. A notable comment was on the trends of genetic counseling and the opportunity for other approaches that allow patients to be well-informed regarding genetic testing. “In a sense, the increasing breadth of content has perhaps simplified at least the pre-test counseling,” said Grosu. “On the backside [of the testing], when you do find an issue that is simple or complicated, then the expertise of the counselor to bear upon just that particular issue.”


Predicting the Landscape for Prenatal Molecular Diagnostics


The final session of the conference was a panel discussion featuring previously covered Mark Evans; William Lambert Richardson Professor of Obstetrics at Harvard Medical School Cynthia Morton; Joe Leigh Simpson, Senior Vice President of Research & Global Programs at March of Dimes Foundation; and previously mentioned Ronald Wapner. Topics focused on the future of Prenatal Molecular Diagnostics, with interesting comments made throughout the discussion. According to Evans, “the future is clearly deep sequencing. The only question is whether it’s going to be on whole blood, amniotic fluid, villi, or non-invasively from the subject.” Despite issues concerning the capability and efficacy of sequencing, Simpson points out that one thing will solve these problems: success. “What we need to do is simplify the approach,” said Simpson. “The way to do that is to ask simple questions. [For example,] ‘Would you like to be sequenced?’ [and] ‘What would you like to know?’” Wapner spoke of broadening our understanding of what choices the science leaves with us. “We have to be smarter,” said Wapner. “We no longer have to think that there’s only two options with prenatal diagnosis: you either terminate a pregnancy or you continue a pregnancy… For lots of people that have a copy number variant that might be associated with  a learning disorder, or a particular epilepsy, or a lot of other things, it’s allowing them to modify the healthcare of that child and make the best of it.”