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Cell-free DNA analysis for noninvasive examination of trisomy: comparing 2 targeted methods

      Introduction

      Cell-free DNA (cfDNA) tests for major fetal trisomies are highly effective among high- and low-risk women, with a detection rate of 99.7% for trisomy 21 and a false positive rate of 0.04%.
      • Gil M.M.
      • Accurti V.
      • Santacruz B.
      • Plana M.N.
      • Nicolaides K.H.
      Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis.
      • Norton M.E.
      • Jacobsson B.
      • Swamy G.K.
      • et al.
      Cell-free DNA analysis for noninvasive examination of trisomy.
      • Gil M.M.
      • Galeva S.
      • Jani J.
      • et al.
      Screening for trisomies by cfDNA testing of maternal blood in twin pregnancy: update of The Fetal Medicine Foundation results and meta-analysis.
      In many countries, cost and complexity are the main obstacles to the implementation of cfDNA tests as first-line aneuploidy screening tests. The Vanadis assay was recently introduced as a cost-effective method with reduced complexity. It provided a high detection rate combined with a low failure rate because samples can be analyzed readily with a fetal fraction (FF) limit of <2%.
      • Dahl F.
      • Ericsson O.
      • Karlberg O.
      • et al.
      Imaging single DNA molecules for high precision NIPT.
      This is achieved by using novel molecular probe technology that specifically label target chromosomes combined with a new readout format using a nanofilter to enrich single molecules for imaging and counting without DNA amplification, microarrays, or sequencing.
      • Dahl F.
      • Ericsson O.
      • Karlberg O.
      • et al.
      Imaging single DNA molecules for high precision NIPT.
      However, there are very limited data on the Vanadis test and no studies comparing it with a well-established, targeted cfDNA method in screening for major trisomies.

      Study Design

      We therefore conducted a prospective, single-center study in which 936 women underwent both a Vanadis test (Laboratoire Hospitalier Universitaire de Bruxelles, University Hospital Brugmann, Bruxelles, Belgium) and a Harmony Prenatal Test (Labocita, CHR Citadelle, Liège, Belgium). Participants received the results of the Harmony test but were blinded to the results of the Vanadis test. Aneuploidy status was confirmed for all women included in the final analysis by outcome at birth or following invasive diagnostic procedures. For both methods, we evaluated the performance in screening for trisomy 21, 18, and 13 and by total failure rate. Written informed consent was obtained for this ethics committee-approved study (CE2015/27).

      Results

      From September 2018 through March 2019, 936 women were enrolled and the results for 900 women were available for analysis. The median maternal age was 31 years (range, 18–51), maternal weight was 69 kg (range, 44–140), and gestational age at testing was 13.3 weeks (range, 10.0–38.1). A total of 21 (2.3%) women were carrying a twin pregnancy and 11 (1.2%) pregnancies were derived following in vitro fertilization.
      The Harmony test detected 34 of 35 cases of trisomy 21 and failed (for quality issues) in 1 case, whereas the Vanadis test detected all 35 cases. Harmony detected 11 of 15 cases of trisomy 18, classified 1 case as low-risk (FF=19.5%), and failed to detect trisomy 18 in 3 cases (all for quality issues), whereas the Vanadis test detected 14 of the 15 cases and classified 1 case as low-risk (FF=5.6%). Both tests detected all 3 cases of trisomy 13.
      Overall, and after first attempt, Harmony failed in 29 (3.2%) cases, whereas the Vanadis test failed in 2 cases (0.2%; P<.05) (Figure). Among the 29 failures with Harmony, 10 (34.5%) were secondary to a low FF. The 2 failures of the Vanadis test were caused by a high density of spot counts (exceeding 40,000) per image.
      Figure thumbnail gr1
      FigureFlowchart of the study data
      Conotte. Comparing 2 noninvasive prenatal testing methods. Am J Obstet Gynecol 2022.

      Conclusion

      Our preliminary data demonstrated that the Vanadis assay provides high performance in screening for major trisomies in addition to a low failure rate. The performance of the test when the FF is below 4% needs further investigation.
      • Revello R.
      • Sarno L.
      • Ispas A.
      • Akolekar R.
      • Nicolaides K.H.
      Screening for trisomies by cell-free DNA testing of maternal blood: consequences of a failed result.

      References

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        • Accurti V.
        • Santacruz B.
        • Plana M.N.
        • Nicolaides K.H.
        Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis.
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        Cell-free DNA analysis for noninvasive examination of trisomy.
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        Imaging single DNA molecules for high precision NIPT.
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        • Sarno L.
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        Screening for trisomies by cell-free DNA testing of maternal blood: consequences of a failed result.
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