A Critical Evaluation of Validation and Clinical Experience Studies in Non-Invasive Prenatal Testing for Trisomies 21, 18, and 13 and Monosomy X

Abstract

Non-invasive prenatal testing (NIPT) for trisomies 21, 18, 13 and monosomy X is widely utilized with massively parallel shotgun sequencing (MPSS), digital analysis of selected regions (DANSR), and single nucleotide polymorphism (SNP) analyses being the most widely reported methods. We searched the literature to find all NIPT clinical validation and clinical experience studies between January 2011 and January 2022. Meta-analyses were performed using bivariate random-effects and univariate regression models for estimating summary performance measures across studies. Bivariate meta-regression was performed to explore the influence of testing method and study design. Subgroup and sensitivity analyses evaluated factors that may have led to heterogeneity. Based on 55 validation studies, the detection rate (DR) was significantly higher for retrospective studies, while the false positive rate (FPR) was significantly lower for prospective studies. Comparing the performance of NIPT methods for trisomies 21, 18, and 13 combined, the SNP method had a higher DR and lower FPR than other methods, significantly so for MPSS, though not for DANSR. The performance of the different methods in the 84 clinical experience studies was consistent with validation studies. Clinical positive predictive values of all NIPT methods improved over the last decade. We conclude that all NIPT methods are highly effective for fetal aneuploidy screening, with performance differences across methodologies.

Overview of Noninvasive Prenatal Testing (NIPT) for the Detection of Fetal Chromosome Abnormalities; Differences in Laboratory Methods and Scope of Testing

“…A recent meta-analysis evaluated the difference in rates between prospective and retrospective validation studies. 39 Both the detection and false-positive rates were significantly higher for retrospective studies (Table 2), consistent with these biases. The observed differences between prospective versus retrospective studies might also be due to an association between test performance and prevalence.…”

“…Numerous studies have validated the performance of NIPT for CATs and the results have been summarized in a series of meta-analyses, [35][36][37][38][39] and are summarized in Table 2. Validation studies fall into 2 main groups; (i) retrospective design in which plasma is banked and tested only after the presence or absence of aneuploidy was established (usually through CVS, amniocentesis, or phenotype at birth); (ii) prospective studies where plasma samples are tested, and fetal karyotype subsequently established through CVS or amniocentesis or based on the outcomes of the pregnancies.…”

Screen‐positive rate in cell‐free DNA screening for microdeletion 22q11.2

“…Current antenatal screening for common trisomies is based on ultrasound and cell‐free DNA analysis (cfDNA) 1–3 . Several studies have summarized the test performance of cfDNA screening and reported on a detection rate for common trisomies of about 92%–99% for a false‐positive rate of 0.1% 4,5 …”

“…[1][2][3] Several studies have summarized the test performance of cfDNA screening and reported on a detection rate for common trisomies of about 92%-99% for a false-positive rate of 0.1%. 4,5 There is an ongoing discussion on whether the scope of the cfDNA analysis should be extended to other chromosomal abnormalities, such a sex-chromosomal anomalies, rare autosomal trisomies, and structural chromosomal defects. 6 Many study groups have focused on microdeletion 22q11.2 syndrome as it belongs to the most common structural chromosomal defects.…”

Live-Born Double Aneuploidy at the Johns Hopkins Cytogenomics Laboratory: Case Report and Review of the Literature

“…Currently, the availability of non-invasive prenatal screening (NIPS) has resulted in the identification of fetal aneuploidies [55], among other findings. In comparing the performance of different NIPS platforms for the common trisomies, the SNP-based method has a higher detection rate and lower false positive rate than massively parallel shotgun sequencing [56]. While NIPS is considered to have a high positive predictive value (PPV) for the detection of trisomy 21 or trisomy 18 in singleton pregnancies (99%, 97.7%, respectively) [57], the detection rate for 47,XXY is lower (93%) [58].…”