Quality Assurance of Non-Invasive Prenatal Screening (NIPS) for Fetal Aneuploidy Using Positive Predictive Values as Outcome Measures

Abstract

Non-invasive prenatal screening (NIPS) based on the analysis of cell-free DNA in maternal plasma has been shown to have high sensitivity and specificity. We gathered follow-up information for pregnancies in women with test-positive NIPS results from 2014–2017 with quarterly assessments of positive predictive values (PPVs). A non-inferiority analysis with a minimum requirement of 70%/80% of expected performance for trisomy 21 and 18 was used to ensure testing met expectations. PPVs were evaluated in the context of changes in the population receiving testing. For all quarters, PPVs for trisomies 21 and 18 exceeded the requirement of > 70% of the reference PPV. Overall observed PPVs for trisomy 21, 18, 13 and monosomy X were similar for women aged <35 (90.9%, 95% Confidence Interval (CI) 88.6–92.7%) compared to women with advanced maternal age (94.5%, 95% CI 93.1–95.6%). Despite significant declines in test-positive rates from 1.18% to 0.62% for trisomy 21, and from 0.75% to 0.48% for trisomies 18, 13 and monosomy X combined, PPVs remained stable through the four-year interval. We conclude that quarterly evaluation of PPV provides an overview of past testing and helps demonstrate long-term consistency in test performance, even in the setting of increasing use by women with lower a priori risks.

Observed and Modeled Positive Predictive Values Using Cell-free DNA Testing for Fetal Trisomy in a Clinical Laboratory Population

“…Other laboratories performing cell-free DNA testing have reported clinical experience using retrospectively obtained pregnancy outcome information in similarly large series [17][18][19]. The observations in the current study are consistent with these previous reports, showing PPV to be higher for trisomy 21 than trisomies 18 and 13.…”

“…One study also examined PPV in different subgroups of the clinical population. DiNonno et al [19] compared PPV in women <35 to women ≥35 years and de- scribed the PPV in younger women as only modestly lower. In that report, the combined PPV for trisomy 21, 18, and 13 was 87.0% in the <35 age-group and 93.5% in the ≥35 agegroup.…”

“…The primary limitation of this study is that it relies on retrospective follow-up and thus does not have complete outcome information. Other laboratories studying clinical experience are similarly challenged and report similar proportions of cases with diagnostic outcome obtained, generally between 30 and 40% [17][18][19]. In each of these studies, the calculation of PPV is based on the concordance observed in cases with outcome information and assumes that the ratio of concordant and discordant cases reported to the laboratory accurately reflects the entire cohort.…”

Non‐invasive prenatal testing in the management of twin pregnancies

“…The importance of a well‐defined estimate of the prior risk becomes much less important with cf‐DNA testing where the positive predictive value is driven much more strongly by the discriminatory power of the assay and only secondarily by the prior risk. 44 There is therefore a strong expectation that the cf‐DNA based testing would be highly effective for twin pregnancies.…”

Re: Clinical experience across the fetal‐fraction spectrum of a non‐invasive prenatal screening approach with low test‐failure rate

“…First, accurate calculation of sensitivity and specificity requires the true outcome to be known for all tested samples, otherwise, ascertainment and reporting biases can distort estimates of performance 2,3 . Hancock et al .…”