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At Prenatal Molecular Dx Conference, NIPT Providers Offer Glimpse into Strategies

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NEW YORK (GenomeWeb) – Noninvasive prenatal screening for chromosomal aneuploidies from cell-free DNA in the mother's blood has been taking off in recent years, and recent studies have shown that it performs well in both high-risk and average-risk pregnancies.

During a panel discussion at Cambridge Healthtech Institute's Advances in Prenatal Molecular Diagnostics conference in Boston earlier this month, representatives from four NIPT providers – Ariosa Diagnostics, Natera, Sequenom, and Illumina − shared their vision for their own tests and the future of NIPT.

Over the course of this year, several providers published studies on the use of their respective tests in the general population, and Ariosa is about to add its own.

Adam Wolfberg, associate director of medical affairs for Ariosa, said at the conference that the Non-invasive Chromosomal Examination of Trisomy (NEXT) study that the firm conducted with a number of collaborators compared its Harmony test for trisomy 21 detection with standard combined first semester screening in almost 16,000 women from the general population. The results were recently submitted to a journal for publication.

The study found the positive predictive value of the Harmony test to be 81 percent, and the false positive rate 0.06 percent, while its sensitivity was 100 percent. This compared favorably to first semester screening, which had a PPV of only 3.4 percent, a false positive rate of 5.4 percent, and a sensitivity of 79 percent.

Other studies have yielded similarly encouraging results, for example one published earlier this year by Illumina and its collaborators in the New England Journal of Medicine that used the Verinata test and included almost 2,000 women from the general obstetrical population. That study reported a positive predictive value of 45.5 percent and a false positive rate of 0.3 percent for trisomy 21, and a PPV of 40 percent and a false positive rate of 0.2 percent for trisomy 18, considerably better than standard screening.

Also, Natera and its collaborators published a study in the American Journal of Obstetrics and Gynecology this summer that included almost 18,000 women for whom follow-up analysis was available, a mix of high- and low-risk pregnancies, and found a PPV of 90.9 percent for trisomy 21 and a combined PPV of 82.9 percent for trisomies 21, 18, 13, and monosomy X.

Given those results, providers appear confident about the wider adoption of their tests for screening in the future. Ariosa's Wolfberg, for example, said he expects NIPT to be universally covered by health insurance for use in high-risk pregnancies in 2015, and partially covered for average-risk pregnancies. He also believes that professional organizations, including the American Congress of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine, will endorse the use of NIPT for general pregnancies next year, and he said he expects the number of NIPT providers to grow to more than 10 in 2015 as providers outlicense their test technologies.

LabCorp, for example, launched its own NIPT, the InformaSeq Prenatal test, this summer based on Illumina's Verinata Verifi test. Also, Quest Diagnostics and Mayo Medical Laboratories have both licensed intellectual property from Sequenom to develop their own in-house NIPTs.

In addition, Natera plans to distribute its Panorama tests as an in vitro diagnostic that is CE-marked starting next year, according to Solomon Moshkevich, vice president of marketing and medical education as well as business development at Natera. "Our assay transfers to other labs in a more robust fashion" than other NIPTs, he claimed, because it has built-in quality controls, such as fetal fraction detection, and requires fewer sequencing reads per sample. He said he also expects Panorama to be offered for low-risk pregnancies in the near future.

However, NIPT companies have different ideas about how they plan to further develop their tests. According to Wolfberg, providers have "some choices to make." They could either add more content, for example microdeletion disorders, which he said would result in tests that would have a relatively low overall sensitivity, a higher false positive rate than current NIPT, and a relatively low PPV.

Ariosa's idea, instead, is to create a "highly reliable" and "affordable" screening test for a limited set of conditions "that patients care deeply about" with very high sensitivity and an "incredibly low" false positive rate of less than 0.1 percent, as well as a high PPV.

He did not elaborate how the company plans to achieve this, but Ariosa recently published a study on the use of microarrays for noninvasive prenatal testing for trisomies 21, 13, and 18, an approach it said is "more accurate" and faster than next-gen sequencing-based testing.

Others are taking a different route. Natera, for example, expanded its Panorama test to include five microdeletion syndromes earlier this year, including 22q11.2 or DiGeorge syndrome, 1p36 deletion syndrome, Angelman syndrome, Cri-du-chat syndrome, and Prader-Willi syndrome. It also partnered with the International 22q11.2 Foundation this spring to raise awareness about DiGeorge syndrome. In addition, the company recently demonstrated that its test can detect unrecognized twin or vanished twin pregnancies, as well as fetal triploidy, setting it apart from others.

Sequenom has been reporting on several sub-chromosomal microdeletions as part of the "enhanced sequencing series" for its MaterniT21 Plus test since October of 2013 and recently added three more. In a yet-to-be published study of 54,200 samples, the test picked up 22q11.2 deletion syndrome in 20 samples, according to Mathias Ehrich, the company's senior vice president of research and development. Follow-up data was available for 12 of these patients, and all turned out to be true positives. Ehrich acknowledged that microdeletion testing with NIPT is "more challenging than the common trisomies" and "has to be done right," noting that Sequenom reports them as "additional findings" and does not promote the test for ruling out a suspected microdeletion, for example from an abnormal cardiac ultrasound.

Illumina, on the other hand, has been focused on delivering a low no-call or technical failure rate, according to Richard Shippy, the company's director of product management for reproductive and genetic health. Illumina's Verifi assay, originally developed by Verinata, currently tests for the three common trisomies and, as an option, sex chromosomal aneuploidies but not microdeletions. According to Shippy, the company has tested the performance of Verifi in more than 34,000 patients and had a technical failure rate, or no-call rate, of only 0.1 percent, less than others. "No-calls are often excluded from the analysis but there is a large impact for samples with a no-call" because up to 22 percent of them turn out to be aneuploid, he said.

All four companies have genetic counselors on staff and see a need to better educate both patients and doctors on the capabilities and limitations of NIPT, tests that are often ordered without having the patient consult with a genetic counselor.

Ariosa has educational materials for clinicians, developed by its in-house genetic counselors, on its website, which is "a good start but not sufficient," Wolfberg said. "We need to figure out how to effectively and efficiently communicate the options because the complexity is increasing."

Natera has more than two dozen genetic counselors on staff and continues to hire more, according to Moshkevich. The company is considering video conferencing and other solutions to "make it easier to get an appointment with a genetic counselor," he said.

Sequenom, too, has had in-house genetic counselors "from day one," according to Ehrich, who added that the need for counseling is not new "but the scale has grown with NIPT." His company, too, is looking into the use of new media to educate users.

Illumina has more than a dozen genetic counselors on staff, according to Shippy, and provides documentation about its assays on its website.

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