Diagnostic testing needed to confirm cfDNA results for aneuploidy and microdeletions, finds retrospective study
Researchers at the David Geffen School of Medicine at the University of California-Los Angeles, found a 73.5% positive predictive value (95% CI, 63%-82%) for cfDNA screening for autosomal aneuploidy, a lower-than-reported rate. The positive predictive value for microdeletion testing was found to be 0%.
This was a retrospective cohort study published in June in the American Journal of Obstetrics and Gynecology. It included 105 patients with abnormal or nonreportable cfDNA results for trisomies 21, 18, or 13, and 26 patients with positive or nonreportable microdeletions. Of the 105 patients with abnormal results for the trisomies, 92 results (87.6%) were positive for trisomy 21 (48, 52.2%), trisomy 18 (22, 23.9%), trisomy 13 (17, 18.5%), triploidy (2, 2.2%) and positive for >1 parameter (3, 3.3%). An additional 13 results (12.4%) were nonreportable.
Abnormal cfDNA results were associated with positive serum screening (by group: trisomy 21 [17/48]; trisomy 18 [7/22]; trisomy 13 [3/17]; nonreportable [2/13]; P = .004), and abnormal first-trimester ultrasound (trisomy 21 [25/45]; trisomy 18 [13/20]; trisomy 13 [6/14]; nonreportable [1/13]; P = .003). There was no association between false-positive rates and testing platform, but there was a difference between the 4 laboratories included in the study (P = .018).
In all, 26 patients had positive (n = 9) or nonreportable (n = 17) microdeletion results. Seven of 9 screens positive for microdeletions underwent confirmatory testing; all were false positives.
When is NIPT appropriate for use as a diagnostic tool? Large-scale systematic review evaluates the answer.
Many systematic reviews and meta-analyses evaluating the accuracy of cell-free fetal (cf) DNA−based testing have been published. This May 2016 study in the British Journal of Obstetrics and Gynecology was the most comprehensive of singleton pregnancies to date, say researchers, who aimed to reduce analysis bias by including only cohort studies (117 analyzed), undertaking bivariate meta-analysis when possible, and including all indications for antenatal use, which allowed for a uniform comparison of NIPT use in actual clinical practice.
The researchers concluded that cell-free fetal (cf) DNA−based NIPT is diagnostic for fetal sex and rhesus D (RHD) status. For trisomies 21, 18, and 13, however, they concluded that the lower sensitivities and specificities found and disease prevalence, combined with the biological influence of confined placental mosaicism, designates NIPT as a screening test (with invasive testing required to confirm a positive test result). They advised that these factors be considered not only when clinicians are counseling patients but also in the overall assessment of the cost of introducing NIPT into routine care.
2016 update on NIPT from the American College of Medical Genetics and Genomics
The American College of Medical Genetics and Genomics (ACMG) has published an updated position statement in Genetics in Medicine in July 2016 that replaces its 2013 statement. Among its recommendations, the ACMG advocates:
- providing up-to-date, balanced, and accurate information early in gestation to optimize patient decision making, independent of the screening approach used
- that laboratories work with public health officials, policymakers, and private payers to make NIPT, including the pretest and posttest education and counseling, accessible to all pregnant women
- informing all pregnant women that diagnostic testing (chorionic villus sampling or amniocentesis) is an option for the detection of chromosome abnormalities and clinically significant copy-number variants.
ACMG also recommends:
- informing all pregnant women that noninvasive prenatal screening (NIPS) is the most sensitive screening option for traditionally screened aneuploidies
- referring patients to a trained genetics professional when an increased risk of aneuploidy is reported after NIPS
- offering diagnostic testing when a positive screening test result is reported after NIPS
- laboratories provide readily visible and clearly stated detection rate (DR), clinical specificity (SPEC), and positive predictive values (PPV), and negative predictive values (NPVs) for conditions being screened
- laboratories not offer screening for Patau, Edwards, and Down syndromes if they cannot report DR, SPEC, and PPV values for these conditions.
ACMG does not recommend:
- NIPS to screen for autosomal aneuploidies other than those involving chromosomes 13, 18, and 21.
Public health perspective: Long-term study concludes implementing cfDNA in high-risk women could be cost-effective
Researchers in Italy retrospectively analyzed the performance of first-trimester screening (FTS) test in a general obstetrics population, including a cost-benefit analysis of a hypothetical model that implemented universal FTS testing using cfDNA. A 2-step strategy based on nuchal translucency, serum screening, and ultrasound assessment of the nasal bone was applied when analyzing the FTS results of 6,679 women. The researchers identified 3 groups: high-risk: >1:250; intermediate-risk: 1:251-1:999; and low-risk group: <1:1000. Women at intermediate-risk underwent NB assessment and recalculation of individual risk. All women at high-risk were offered fetal karyotyping.
The investigators concluded that the Italian public health system would not be able to sustain the cost of universal cfDNA testing in women undergoing FTS. However, a possible scenario based on use of cfDNA FTS in women at high-risk would result in a 6-fold reduction in the number of invasive procedures. It would also avoid 2 false-negative results (trisomy 21) diagnosed in women with intermediate-risk using the current screening strategy of combined invasive and noninvasive testing.