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UNC Reports Data from First Year of Non-Invasive Prenatal Testing Using Verinata and Sequenom Tests

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Researchers from the University of North Carolina's department of obstetrics and school of medicine have published a report on the center's first year offering non-invasive prenatal fetal aneuploidy tests from both Illumina-owned Verinata Health and Sequenom.

Overall, the report, published late last month in Genetics in Medicine, found that between January and September 2012, noninvasive prenatal testing showed a combined sensitivity of about 85 percent, and a specificity of 99 percent at UNC. Rates of both false-positive and false-negative results were higher than anticipated based on earlier published data. And unclassified results, reported by the Verinata test, were also more numerous than previous trials have suggested.

During this first year of offering NIPT, the group also saw both uptake of the new non-invasive testing and a decline in amniocentesis procedures, which would be expected according to previous studies. Over the study's nine months, the obstetrics team provided NIPT for a total of 208 patients, the authors reported, with the number of tests increasing from just one in January to 43 in September and the rates of amniocentesis and other invasive procedures decreasing in tandem.

Neeta Vora, the study's corresponding author told Clinical Sequencing News that when UNC began offering NIPT, the team initially used Verinata's test exclusively, having participated in the validation trial of the assay in high-risk women. The group then added the Sequenom test later in the study period, using both tests from that point on.

"Some of [that decision] had to do with insurance reasons, things like that. But there wasn't a single specific reason," she said.

In the UNC team's report, Vora and her colleagues outlined how the testing performed over the first nine months it was offered at UNC regardless of which assay was used and without breaking down accuracy or outcomes data by test platform.

In addition to Sequenom and Verinata, two other companies, Ariosa and Natera also offer sequencing-based NIPT.

Vora said UNC has continued to offer patients both the Sequenom and Verinata tests, basing the decision to go with one or the other on individual patient characteristics and preferences.

"It’s a really rapidly moving target," she said. "Now some of the companies are offering expanded microdeletion panels and expanded trisomies, but that has not been as well validated."

Two separate groups — from Verinata Health and Dennis Lo's group at the Chinese University of Hong Kong, from whom Sequenom licenses IP for its MaterniT21 Plus aneuploidy test — recently published proof-of-principle studies on methods to detect sub-chromosomal abnormalities in fetal DNA and are now looking to validate their methods in larger cohorts and eventually incorporate them into a commercial test.

Sequenom also expanded its test last year to report on sex chromosome aneuploidies, including Turner syndrome, Triple X syndrome, Klinefelter syndrome, and another Y-chromosomal syndrome, as well as trisomies 16 and 22, and select subchromosomal microdeletions, including DiGeorge syndrome, Cri-du-chat syndrome, Prader-Willi/Angelman syndrome, and 1p36 deletion syndrome.

"Some companies are offering the sex chromosome abnormalities and letting patients opt in or out. Others are [reporting those in a blanket fashion.] So we talk to patients about all these different scenarios, and then also based on their insurance and patient preference we are sending [their samples] to either Verinata or Sequenom," Vora said. The center also sends some samples for testing using Natera's test if there is a suspicion of triploidy.

In the UNC team's recent study the authors wrote that NIPT detected aneuploidy in chromosomes 21, 18, or 13 in 3.8 percent, or eight patients of a 208-patient cohort, and that the Verinata test — which at the time reported "unclassified" results in addition to positive and negative results — sent back an unclassified result in 11 percent, or five of the samples.

According to Vora, the rate of "unclassified" results the researchers saw using the Verinata test contradicted somewhat what they might have expected based on earlier data from the validation study of the test, which showed an overall unclassified rate of 2.8 percent versus the 11 percent seen in the UNC cohort.

Among patients with either a definitive aneuploidy or an unclassified result, eight underwent subsequent invasive testing. None of the patients with normal NIPT results opted to receive additional invasive testing.

Overall, the group found that NIPT had high sensitivity and specificity although not quite as high as reported in previous validation trial data. Overall, the testing showed a sensitivity of 87.5 percent and a specificity of 99.5 percent for aneupoloidy detection among the 208-patient cohort. There were seven true positives for trisomies 21 and 18, one false negative for trisomy 18, and one false positive for monosomy 18/trisomy 13, the authors wrote.

In the one false negative case, NIPT returned an "unclassified" result for trisomy 13, and negative results for trisomy 18 and 21 in a case where the fetus was confirmed by karyotype to have trisomy 18.

In the false positive case, meanwhile, the NIPT result was positive for monosomy 18 and trisomy 13, while the fetus was found to be normal by microarray testing. The mother in this case was later diagnosed with metastatic cancer, which the group wrote was likely the cause of the abnormal NIPT result.

According to the study authors, the team's experiences, especially the one false positive "highlight the importance of confirming abnormal results with invasive testing."

However, in the study only about 60 percent of the patients with an abnormal NIPT result went on to receive invasive testing.

In addition, no patients in the study who received normal NIPT results went on to get an amniocentesis, despite the presence of other indications of fetal abnormalities in several participants. Two of these women, the study authors wrote, went on to deliver infants diagnosed with genetic syndromes.

Overall, the authors wrote that their experiences highlight NIPT's potential for increasing uptake and displacement of amniocentesis, as well as the potential pitfalls of this shift.

If and when NIPT begins to be offered more widely — not just to high-risk women, but also in low-risk populations where the prevalence of aneuploidies is much lower — "the rate of false positive will increase," the authors wrote.

Moreover, Vora said, for patients with fetuses with multiple anomalies, NIPT, at least in its current form, may not give the correct answer.

"We did have some patients in our cohort who had microdeletions, for example, which wouldn't be picked up [by NIPT]," she said. "So I think it's important to remember those limitations. It’s a promising technology, but at this point it does not replace the diagnostic ability of amniocentesis."

In addition, providers should be aware of the tests' ability to detect underlying maternal conditions, such as sex-chromosome abnormalities, mosaicism, and — as in the UNC study — maternal cancer, the study authors wrote.

Occurrence of both false positives and false negatives in the team's high-risk study cohort should emphasize that NIPT is "only a screening test, and [should not be] considered a replacement for amniocentesis or CVS in terms of diagnostic accuracy," the group concluded.

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