Cell-free DNA (cfDNA) testing performed better than did standard screening plus measurement of nuchal translucency and biochemical analytes for detecting trisomy 21 in a large, prospective, multicenter study of women undergoing routine prenatal screening.
In 15,841 women included in the study, known as the Noninvasive Examination of Trisomy (NEXT) study, the area under the curve (AUC) for trisomy 21 was 0.999 for cell-free DNA testing, compared with 0.958 for standard screening – a statistically significant difference. Trisomy 21 was detected in 38 of 38 cases using cfDNA, compared with 30 of 38 cases using standard screening (sensitivity of 100% vs. 78.9%), Dr. Mary E. Norton of the University of California, San Francisco, and her colleagues reported online in the New England Journal of Medicine.
Dr. Mary E. Norton
Further, the false positive rate with cfDNA was nearly 100 times lower than that with standard screening (0.06% vs. 5.4%), and the positive predictive value was 80.9% vs. 3.4%, respectively, the investigators said (N. Engl. J. Med. 2015 April 1 [doi:10.1056/NEJMoal407349]).
Although the study was powered to compare only the detection of trisomy 21, cfDNA also appeared to be better for detecting trisomies 18 and 13, and the lower false-positive rate and higher positive predictive value with cfDNA testing support its use in risk assessment for these trisomies, they said.
Participants in the blinded study, which was conducted at 35 centers in six countries in the United States, Canada, and Europe, were pregnant adult women with a mean age of 31 years and a mean gestational age of 12.5 weeks at the time of testing. The women presented for aneuploidy screening between March 2012 and April 2013 and underwent both cfDNA screening and standard screening, which included measurement of serum pregnancy-associated plasma protein A, total or free beta-subunit of human chorionic gonadotropin, and nuchal translucency.
Birth outcome was determined by diagnostic genetic testing in 557 women, and by newborn examination in the remaining subjects.
Cell-free DNA testing was introduced in 2011 and is reported to be highly effective for detecting trisomy 21.
“In practice, the use of this test could result in a significant reduction in diagnostic procedures,” Dr. Norton and her associates wrote.
They noted, however, that while several large proof-of-principle studies have confirmed the high sensitivity and specificity of cfDNA testing for detecting trisomy 21, few direct, well-powered studies have compared cfDNA testing and standard screening in a routine prenatal screening population. Rather, most studies have included only selected populations of high risk women who were sampled prior to invasive testing.
The current findings demonstrating the value of cfDNA in a general screening population are encouraging, but careful consideration of the screening method and costs is necessary before cfDNA testing can be widely implemented for general prenatal aneuploidy screening, Dr. Norton and her associates said.
Expectations regarding prenatal genetic testing also should be considered, they noted.
“For trisomy 21 and other common aneuploidies, cfDNA testing represents a highly accurate screening option … however, maternal serum and nuchal translucency screening can identify risk for a broad array of abnormalities that are not detectable on cfDNA testing,” they said, explaining that cases of trisomy 21 comprised just over 50% of aneuploidy in the study population and that women who desire a comprehensive assessment may prefer to undergo karyotyping or chromosomal microarray analysis.
This study is strengthened by the large sample size in a general prenatal screening population but is limited by the comparison between cfDNA testing and only standard first-trimester screening, the investigators said, explaining that methods such as integrated first- and second-trimester screening with nuchal translucency and biochemical analytes have higher sensitivity and specificity.
Further, the trisomy 21 detection rate of standard screening in this study was 79%, which is lower than the 82%-87% seen in a prior study.
“It is possible that standard screening has worse performance in clinical practice than under the stringent experimental conditions in which previously reported data were collected,” Dr. Norton and her associates noted.
This study was supported by Ariosa Diagnostics and the Perinatal Quality Foundation. Dr. Norton, in addition to most of her coauthors, reported receiving grant or other support from Ariosa. Multiple authors also reported a financial relationship with Natera outside the submitted work. Additionally, Howard Cuckle, Ph.D., is director of Genome Ltd., a provider of prenatal screening services including noninvasive prenatal testing, and Dr. Ronald J. Wapner reported relationships with Illumine and Sequenom, in addition to Ariosa and Natera. The remaining authors had no relevant financial disclosures.