Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory

American Journal of Obstetrics and Gynecology

5 years ago

Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory

Since its debut in 2011, cell-free fetal DNA (cffDNA) screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, has lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre and post-test counseling, pre/perinatal decision making and medical risk assessment/management.

Objective

The objective of this study was to determine the positive predictive value (PPV) and false positive rates (FPR) for different chromosomal abnormalities identified by cffDNA screening using a large dataset of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies.

Study Design

We tested 712 patient samples sent to our laboratory to confirm a cffDNA screening result indicating high-risk for a chromosome abnormality. We compiled data from all cases where the indication for confirmatory testing was a positive cffDNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid or postnatally obtained blood samples. PPVs and FPRs were calculated from tabulated data.

Results

The PPVs for trisomy 13, 18 and 21 were consistent with previous reports at 45, 76 and 84%, respectively. For the microdeletion syndrome regions, PPVs ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome, to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had PPVs of 26% for monosomy X, 50% for 47,XXX and 86% for 47,XXY.

Conclusion

The PPVs for detection of common autosomal and sex chromosomal aneuploidies by cffDNA screening were comparable to other studies. Identification of microdeletions was associated with lower PPVs and higher FPRs, likely due to the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained PPVs compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cffDNA screening tests. Improvement of the cffDNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision-making/management.

Publisher URL: www.sciencedirect.com/science

DOI: S0002937817311870