A cell-free DNA (cfDNA) prenatal blood exam for trisomy 21 — a forsake obliged for Down syndrome — and other fetal genetic abnormalities had significantly aloft sensitivity, fewer fake positives, and a aloft certain predictive value than customary prenatal screening, a vast investigate during 35 ubiquitous medical centers found.
The area underneath a receiver-operating bend for trisomy 21 with a Ariosa Harmony Prenatal Test, grown by Roche’s Ariosa Diagnostics unit, was 0.999 for cfDNA contrast contra 0.958 for customary screening (P=0.001), according to Mary E. Norton, MD, of a University of California San Francisco, and colleagues.
False certain rates for cfDNA contrast were 0.06% (95% CI 0.03%-0.11%) compared with 5.4% (95% CI 5.1%-5.8%) in a customary screening group. Standard screening concerned serum tests for PAPP-A and/or opposite forms of tellurian chorionic gonadotropin along with a nuchal translucency measurement, a organisation explained in their report, appearing in a New England Journal of Medicine.
Whereas customary screening had a certain predictive value of usually 3.4% (95% CI 2.3%-4.8%), a certain outcome from a cfDNA exam was scold in 80.9% of cases (95% CI 66.7%-90.9%).
Sensitivity for cfDNA contrast was 100% (95% CI 90.7%-100%), while customary screening had a attraction rate of 78.9% (95% CI 62.7%-90.4%, P=0.008), as cfDNA contrast identified all 38 cases with trisomy 21, while customary screening missed 8 of a 38.
Researchers also examined women underneath 35 who were personal as “low-risk pregnancies.” The cfDNA exam identified 19 out of 19 women with trisomy 21, along with 6 false-positive results. “Positive predictive value for cfDNA contrast was 76.0% (95% CI 54.9%-90.6%) for women underneath a age of 35 years and 50.0% (95% CI 24.7%-75.3%) for those with a disastrous outcome on customary screening,” they wrote.
The Noninvasive Examination of Trisomy (NEXT) study was a prospective, multicenter, blinded investigate of a Ariosa exam during 35 medical centers in 6 countries involving scarcely 16,000 women who had a first-trimester aneuploidy screening. Eligible participants had to be over 18, in week 10 to 14 of their pregnancy during a time of a investigate (March 2012 to Apr 2013), as good as yield created consent. Mean maternal age was 30.7 years and meant gestational age during contrast was 12.5 weeks.
Testing for Other Defects
But dual additional reports in NEJM lifted regard about fake positives in cfDNA contrast for genetic abnormalities and an concomitant editorial urged counsel in regulating these tests — accessible from a series of companies — for detecting defects other than trisomy 21.
In a apart minute to a editor, Sau W. Chueng, PhD, of a Baylor College of Medicine in Houston, and colleagues reported a formula of their possess investigate on cfDNA screening conducted during several laboratories with a accumulation of exam products, including a Ariosa exam and 4 others.
Examining a multicenter conspirator of 307 patients regulating information from several laboratories, they found 9% fake certain formula for trisomy 21, 23% for trisomy 18, 46% for trisomy 13, 62% for monosomy X, and 17% for XXX, XXY or XYY abnormalities. The authors commented that as cfDNA contrast expands over high-risk pregnancies into a ubiquitous population, there might be an increasing intensity for patients to cancel healthy pregnancies formed on fake results.
“To accurately communicate a ability of a assay, we trust it should be referred to usually as ‘DNA-based noninvasive prenatal screening’ since it is not a exam that provides a diagnosis,” they wrote.
The second was a brief news by Matthew W. Snyder, MS, dialect of genome sciences during a University of Washington in Seattle, and colleagues who examined 4 cases of fake certain cfDNA contrast formula for chromosomal abnormalities in that a babies were delivered healthy. Researchers analyzed both maternal marginal blood samples and cord blood during a delivery.
Snyder and colleagues found that dual of a infants had duplications on chromosome 18 in their DNA, that caused “a fake interpretation of a formula as indicating a fetal trisomy.” The authors distributed a luck of fake positives due to maternal copy-number variants, and found that chromosomes 13 and 18 are some-more receptive to such variants due to “higher race frequencies of vast duplications” compared with a smaller chromosome 21.
“Chromosomes with aloft race burdens of copy-number variants — quite a largest such variants — should be some-more receptive to false-positive results,” Snyder and colleagues wrote.
In a NEXT study, Norton and colleagues also examined cfDNA contrast for trisomy 18 and trisomy 13. They found a fake certain rate of 0.01% (95% CI 0%-0.04%) compared with 0.31% for customary screening (95% CI 0.23%-0.41%) for trisomy 18 (P0.001).
Similarly, for trisomy 13 a exam had a 0.02% fake certain rate contra 0.25% (95% CI 0.17%-0.36%) for customary screening (P0.001). The exam identified 9 out of 10 cases of trisomy 18 and both cases of trisomy 13 in a sample, while customary screening identified 8 of 10 and one of two, respectively.
In an concomitant editorial, Lyn S. Chitty, PhD, MS, BS, of a UCL Institute of Child Health in London, reviewed all 3 studies and resolved that while cfDNA contrast might be some-more supportive in detecting trisomy 21, serve investigate is indispensable before expanding a use.
“[cfDNA testing] in screening for other chromosomal abnormalities, quite a sex-chromosome aneuploidies and microdeletion and duplication syndromes, requires serve validation before clinical implementation,” she wrote.
Chitty also pronounced that a fake certain formula validated a need for invasive contrast (such as amniocentesis) to endorse a formula of a certain cfDNA screening.
Norton and colleagues concurred a fact that their investigate was powered to review a showing of usually trisomy 21 (and not other chromosomal abnormalities) between groups as a intensity limitation. They also note that cfDNA contrast was compared usually opposite initial trimester customary screening, and not “integrated first- and second trimester screening,” that has a aloft turn of attraction and specificity, as good as a fact that customary screening false-positive rate might be aloft since their “stringent initial conditions” are opposite than a customary clinical setting.
Cheung and colleagues and Snyder and colleagues cited a apparent particular stipulations to their studies, many particularly their distance and miss of generalizability to a total population.
But Norton and colleagues pronounced that their investigate advise that cfDNA contrast might have broader applications over high-risk pregnancies.
“Although these information support a use of cfDNA contrast in women regardless of age or risk status, serve investigate cost application studies are warranted,” they concluded.
Norton and colleagues were upheld by Ariosa Diagnostics and a Perinatal Quality Foundation.
Disclosure forms supposing by a authors are accessible during NEJM.org.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine