Discordant Non-invasive Prenatal Testing and Cytogenetic Results: Is There a Cause for Concern? J. Wang1, T. Sahoo1, 2, S. Schonberg3, K. Kopita1, L. Ross1, K. Patek3, C. Strom1 1) Cytogenetics Laboratory, Nichols Institute, Quest Diagnostics, San Juan Capistrano, CA; 2) CombiMatrix, 300 Goddard Suite 100, Irvine, CA 92618, USA; 3) Cytogenetics Laboratory, Quest Diagnostics Nichols Institute, 14225 Newbrook Drive, Chantilly, VA, 20151, USA.

   Recent published studies have demonstrated the incremental value of the use of cfDNA for non-invasive prenatal testing (NIPT), with 100% sensitivity for trisomies 21 and 18, and specificity of 99.7% for both. Data presented by two independent groups suggested positive results by NIPT were not conformed by cytogenetic studies. Concordance of results between cases with positive NIPT results referred for cytogenetic prenatal and/or postnatal studies by karyotyping, FISH, and/or oligo-SNP microarray were evaluated for 98 consecutive specimens. Cytogenetic results were positive for trisomy 21 in 38 of the 41 NIPT-positive cases (true positive rate: 93%) and for trisomy 18 in 16 of the 25 NIPT-positive cases (true positive rate: 64%). The true positive rate was only 44% (7/16 cases) for trisomy 13 and 38% (6/16 cases) for sex chromosome aneuploidy (SCA). Confined placental mosaicism was confirmed in 2 of 98 cases (2%). Our data (N = 98) and that presented by the above mentioned two groups (N = 80 and N = 46) show that the positive predictive values (PPV) is highest for cases positive for trisomy 21 (119/126, 94.4%). A significantly lower PPV (p < 0.001) is displayed for trisomy 18 (25/42, 59.5%), trisomy 13 (12/27, 44.4%), and SCA (11/29, 37.9%). These findings raise concerns about the limitations of NIPT and the need for analysis of a larger number of false positive cases to provide true PPVs for such non-invasive testing and search for potential biological or technical causes. It is very important to understand that PPV is not intrinsic to the test; it depends also on the prevalence of the condition in the tested population. The difference of PPV for trisomy 21 by NIPT from other aneuploidies could be due to either a more prevalence or a higher specificity of NIPT for Down syndrome than other aneuploidies, or both. These findings suggest the need for a careful interpretation of NIPT results and cautious transmission of the same to providers and patients. It is vital to educate ordering physicians regarding the differences between specificity and PPV. To an average clinician, the claim that a test is >99% specific leads him or her to expect that the false positive rate will be less than 1%. As can been seen from the data here, the performance of NIPT for correctly predicting positive for trisomy18 and trisomy 13 is less than 60%, necessitating a cautious evaluation of the causes and consequences before NIPT is made available to the general population.

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