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Published: Feb 26, 2014 | Updated: Feb 26, 2014

By Sarah Wickline , Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner


Next-generation sequencing of cell-free DNA in maternal blood samples had lower rates of false positives for fetal autosomal aneuploidy compared with standard screening tests, researchers reported.

False-positive results for trisomies 21 and 18 were lower with cell-free DNA (cfDNA) tests compared with standard testing methods (0.3% versus 3.6%, P<0.001, and 0.2% versus 0.6%, P=0.03, respectively) in a general population of 1,914 pregnant women from 21 centers across the U.S., according to Diana W. Bianchi, MD, of Tufts Medical Center, in Boston, and colleagues.

A report on the accuracy of Illumina’s noninvasive prenatal test for an abnormal number of chromosomes, which performsnext generation sequencing on plasma cell-free DNA (cfDNA) from maternal blood samples, was published online Wednesday in The New England Journal of Medicine.

Michael F. Greene, MD, Chief of Obstetrics at Massachusetts General Hospital in Boston, and associate editor at The New England Journal of Medicine, told MedPage Todaythat before considering implementing a new test on a large scale, cost must first be considered.

“One of the issues with respect to whether a certain test should be recommended inevitably has to include the issue of cost. Until everybody has a good understanding of what this test is going to cost globally for large numbers of patients, I think we have to be careful about what we recommend … [when it comes to] replacing the current technology,” Greene said.

Bianchi and colleagues wrote that cost-analysis for widespread use was beyond the scope of their study.

Greene also noted that this study only investigated the Illumina test and not any of the four other companies that manufacture similar cfDNA tests, “It [Illumina’s test] isn’t necessarily representative of all of the different companies’ tests that are out there.”

Green told MedPage Today that a limitation he found in the study by Bianchi et al. was that only 40% of the women participating in the study had their blood sampled during their first trimester. “If this is really going to take over the prenatal testing market in the U.S., it would be nice to see a higher percentage of the tests done in the first trimester.”

“[That way] we have a better sense of not only the performance characteristics of the test, but also what percentage of women will have indeterminate results as the result of inadequate quantities of fetal DNA in the maternal circulation,” Greene said.

Bianchi and colleagues reported that samples taken during the first versus second trimester did not significantly change their results.

Greene wrote in an editorial in The New England Journal of Medicine that the results from Bianchi and colleagues concerning positive predictive value “underscore the conclusion that assaying fetal DNA is a screening tool and not a diagnostic intervention.”

“The observed negative predictive values of 100% with 95% confidence limits down to 99.8%, combined with the significantly and substantively lower false-positive rates with cfDNA screening than with standard screening, augurs well for pregnant women and their fetuses: a negative result on cfDNA screening obviates the need for invasive testing and thus the discomfort and risk to the pregnancy incurred by such testing,” Greene wrote.

Average age of the women in the study was 29.6. All had singleton pregnancies and were already planning to have standard prenatal serum screening (serum biochemical assays with or without measurement of nuchal translucency) for fetal aneuploidy. They were followed through the birth.

Blood samples were collected for Illumina’s massively parallel sequencing test for trisomies 21 (Down Syndrome) and 18 (Edwards’ Syndrome). A secondary outcome for trisomy 13 (Patau’s Syndrome) was also measured.


The six patients with a false positive for trisomy 21 and three patients with a false positive for trisomy 18 with the cfDNA test had negative test results with the standard screening.

Bianchi and colleagues wrote that the results of these tests in the general clinical setting in the U.S. were equal to results seen in high-risk populations.

Illumina, makers of DNA sequencing tests, funded this study.

Bianchi and several co-authors disclosed relevant relationships with Illumina. One co-author disclosed a relevant relationship with InClin. Another co-author holds several patents for sequencing methods.


Primary source: The New England Journal of Medicine
Source reference: Bianchi DW “DNA sequencing versus standard prenatal aneuploidy screening” N Engl J Med 2014; DOI: 10.1056/NEJMoa1311037.

Additional source: The New England Journal of Medicine
Source reference:Greene MF, et al “Screening for trisomies in circulating DNA” N Engl J Med2014; DOI: 10.1056/NEJMe1401129.

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