Noninvasive prenatal screening at low fetal fraction: comparing whole-genome sequencing and single-nucleotide polymorphism methods.
OBJECTIVE
Performance of noninvasive prenatal screening (NIPS) methodologies when applied to low fetal fraction samples is not well established. The single-nucleotide polymorphism (SNP) method fails samples below a predetermined fetal fraction threshold, whereas some laboratories employing the whole-genome sequencing (WGS) method report aneuploidy calls for all samples. Here, the performance of the two methods was compared to determine which approach actually detects more fetal aneuploidies.


METHODS
Computational models were parameterized with up-to-date published data and used to compare the performance of the two methods at calling common fetal trisomies (T21, T18, T13) at low fetal fractions. Furthermore, clinical experience data were reviewed to determine aneuploidy detection rates based on compliance with recent invasive screening recommendations.


RESULTS
The SNP method's performance is dependent on the origin of the trisomy, and is lowest for the most common trisomies (maternal M1 nondisjunction). Consequently, the SNP method cannot maintain acceptable performance at fetal fractions below ~3%. In contrast, the WGS method maintains high specificity independent of fetal fraction and has >80% sensitivity for trisomies in low fetal fraction samples.


CONCLUSIONS
The WGS method will detect more aneuploidies below the fetal fraction threshold at which many labs issue a no-call result, avoiding unnecessary invasive procedures. © 2017 Counsyl Inc. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
Counsyl Inc., South San Francisco, California, USA.
Carlo G
http://orcid.org/0000-0001-6403-6924
CG
Artieri
Counsyl Inc., South San Francisco, California, USA.
Carrie
C
Haverty
Counsyl Inc., South San Francisco, California, USA.
Eric A
EA
Evans
Counsyl Inc., South San Francisco, California, USA.
James D
JD
Goldberg
Counsyl Inc., South San Francisco, California, USA.|Freenome, South San Francisco, California, USA.
Imran S
IS
Haque
Genetic Institute, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel Aviv University, Israel.
Yuval
Y
Yaron
Counsyl Inc., South San Francisco, California, USA.
Dale
D
Muzzey
D004247:DNA / Q000032:analysis; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005333:Fetus / Q000737:chemistry* / Q000378:metabolism; D005820:Genetic Testing; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D057230:Limit of Detection; D008297:Male; D046228:Microarray Analysis / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods*; D012680:Sensitivity and Specificity
D004247:DNA