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Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples.

ABSTRACT: The aim of this study is to report the experience of noninvasive prenatal DNA testing using massively parallel sequencing in an accredited clinical laboratory.Laboratory information was examined for blood samples received for testing between February and November 2012 for chromosome 21 (Chr21), Chr18, and Chr13. Monosomy X (MX) testing was available from July 2012 for cystic hygroma indication. Outcomes were collected from providers on samples with positive results.There were 5974 samples tested, and results were issued within an average of 5.1 business days. Aneuploidy was detected in 284 (4.8%) samples (155 Chr21, 66 Chr18, 19 Chr13, 40 MX, and four double aneuploidy). Follow-ups are available for 245/284 (86%), and 77/284 (27.1%) are confirmed, including one double-aneuploidy case concordant with cytogenetics from maternal malignancy. Fourteen (0.2%) discordant (putative false-positive) results (one Chr21, six Chr18, three Chr13, three MX, and one Chr21/13) have been identified. Five (0.08%) false-negative cases are reported (two trisomy 21, two trisomy 18, and one MX). In 170 (2.8%) cases, the result for a single chromosome was indefinite.This report suggests that clinical testing of maternal cell-free DNA for fetal aneuploidy operates within performance parameters established in validation studies. Noninvasive prenatal testing is sensitive to biological contributions from placental and maternal sources.

SUBMITTER: Futch T

PROVIDER: S-EPMC3709117 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples.

Futch Tracy T Spinosa John J Bhatt Sucheta S de Feo Eileen E Rava Richard P RP Sehnert Amy J AJ

Prenatal diagnosis 20130601 6

<h4>Objective</h4>The aim of this study is to report the experience of noninvasive prenatal DNA testing using massively parallel sequencing in an accredited clinical laboratory.<h4>Methods</h4>Laboratory information was examined for blood samples received for testing between February and November 2012 for chromosome 21 (Chr21), Chr18, and Chr13. Monosomy X (MX) testing was available from July 2012 for cystic hygroma indication. Outcomes were collected from providers on samples with positive resu ...[more]

PMID: 23592485

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Project description:BackgroundNoninvasive prenatal testing (NIPT) has been wildly used to screen for common aneuplodies. In recent years, the test has been expanded to detect rare autosomal aneuploidies (RATs) and copy number variations (CNVs). This study was performed to investigate the performance of expanded noninvasive prenatal testing (expanded NIPT) in screening for common trisomies, sex chromosomal aneuploidies (SCAs), rare autosomal aneuploidies (RATs), and copy number variations (CNVs) and parental willingness for invasive prenatal diagnosis in a Chinese prenatal diagnosis center.MethodsA total of 24,702 pregnant women were retrospectively analyzed at the Women and Children's Hospital from January 2013 to April 2019, among which expanded NIPT had been successfully conducted in 24,702 pregnant women. The high-risk expanded NIPT results were validated by karyotype analysis and chromosomal microarray analysis. All the tested pregnant women were followed up for pregnancy outcomes.ResultsOf the 24,702 cases, successful follow-up was conducted in 98.77% (401/446) of cases with common trisomies and SCAs, 91.95% (80/87) of RAT and CNV cases, and 76.25% (18,429/24,169) of cases with low-risk screening results. The sensitivity of expanded NIPT was 100% (95% confidence interval[CI], 97.38-100%), 96.67%(95%CI, 82.78-99.92%), and 100%(95%CI, 66.37-100.00%), and the specificity was 99.92%(95%CI, 99.87-99.96%), 99.96%(95%CI, 99.91-99.98%), and 99.88% (95%CI, 99.82-99.93%) for the detection of trisomies 21, 18, and 13, respectively. Expanded NIPT detected 45,X, 47,XXX, 47,XXY, XYY syndrome, RATs, and CNVs with positive predictive values of 25.49%, 75%, 94.12%, 76.19%, 6.45%, and 50%, respectively. The women carrying fetuses with Trisomy 21/Trisomy 18/Trisomy 13 underwent invasive prenatal diagnosis and terminated their pregnancies at higher rates than those at high risk for SCAs, RATs, and CNVs.ConclusionsOur study demonstrates that the expanded NIPT detects fetal trisomies 21, 18, and 13 with high sensitivity and specificity. The accuracy of detecting SCAs, RATs, and CNVs is still relatively poor and needs to be improved. With a high-risk expanded NIPT result, the women at high risk for common trisomies are more likely to undergo invasive prenatal diagnosis procedures and terminate their pregnancies than those with unusual chromosome abnormalities.

Project description:Background: The existence of maternal malignancy may cause false-positive results or failed tests of NIPT. Though recent studies have shown multiple chromosomal aneuploidies (MCA) are associated with malignancy, there is still no effective solution to identify maternal cancer patients from pregnant women with MCA results using NIPT. We aimed to develop a new method to effectively detect maternal cancer in pregnant women with MCA results using NIPT and a random forest classifier to identify the tissue origin of common maternal cancer types. Methods: For examination, 496 participants with MCA results via NIPT were enrolled from January 2016 to June 2019 at BGI. Cancer and non-cancer participants were confirmed through the clinical follow-up. The cohort comprising 42 maternal cancer cases and 294 non-cancer cases enrolled from January 2016 to December 2017 was utilized to develop a method named mean of the top five chromosome z scores (MTOP5Zscores). The remaining 160 participants enrolled from January 2018 to June 2019 were used to validate the performance of MTOP5Zscores. We established a random forest model to classify three common cancer types using normalized Pearson correlation coefficient (NPCC) values, z scores of 22 chromosomes, and seven plasma tumor markers (PTMs) as predictor variables. Results: 62 maternal cancer cases were confirmed with breast cancer, liver cancer, and lymphoma, the most common cancer types. MTOP5Zscores showed a sensitivity of 85% (95% confidence interval (CI), 62.11-96.79%) and specificity of 80% (95% CI, 72.41-88.28%) in the detection of maternal cancer among pregnant women with MCA results. The sensitivity of the classifier was 93.33, 66.67, and 50%, while specificity was 66.67, 90, and 97.06%, and positive predictive value (PPV) was 60.87, 72.73, and 80% for the prediction of breast cancer, liver cancer, and lymphoma, respectively. Conclusion: This study presents a solution to identify maternal cancer patients from pregnant women with MCA results using NIPT, indicating it as a value-added application of NIPT in the detection of maternal malignancies in addition to screening for fetal aneuploidies with no extra cost.

Project description:ObjectiveTo assess the detection efficiency of noninvasive prenatal testing (NIPT) for fetal autosomal aneuploidy, sex chromosome aneuploidy (SCA), other chromosome aneuploidy, copy number variation (CNV), and to provide further data for clinical application of NIPT.Materials and methods25,517 pregnant women who underwent NIPT testing in Anhui Province Maternity and Child Health Hospital from September 2019 to September 2020 were selected, and samples with high-risk test results were subjected to karyotype analysis for comparison by using amniotic fluid, with some samples subjected to further validation by chromosomal microarray analysis, and followed up for pregnancy outcome.ResultsA total of 25,517 pregnant women who received NIPT, 25,502 cases were tested successfully, and 294 high-risk samples (1.15%) were detected, there were 96 true positive samples, 117 false positive samples and 81 cases were refused further diagnosis. Samples with high risk of autosomal aneuploidy were detected in 71 cases (0.28%), and 51 cases were confirmed, including: trisomy 21 (T21) in 44 cases, trisomy 18 (T18) in 5 cases, and trisomy 13 (T13) in 2 cases; the positive predictive value (PPV) was 91.67%, 45.45%, and 33.33%, respectively, and the negative predictive value was 100%, the false positive rate (FPR) was 0.02%, 0.02%, and 0.02%, respectively.13 samples with high risk of mosaic trisomies 21, 18, and 13 were detected, and 1 case of T21mos was confirmed with a PPV of 8.33%. Samples with high risk of SCA were detected in 72 cases (0.28%), and the diagnosis was confirmed in 23 cases, with a PPV of 41.07% and a FPR of 0.13%. These included 3 cases of 45,X, 6 cases of 47,XXY, 8 cases of 47,XXX and 6 cases of 47,XYY, with PPVs of 12.00%, 50.00%, 72.73%, and 75.00%, respectively, and false-positive rates of 0.09%, 0.02%, 0.01% and 0.01% respectively. Samples with high risk of CNV were detected in 104 cases (0.41%) and confirmed in 18 cases, with a PPV of 32.14% and a FPR of 0.15%. Samples with high risk of other chromosomal aneuploidy were detected in 34 cases (0.13%), and the diagnosis was confirmed in 3 cases, which were T2, T9, and T16 respectively. The overall PPV for other chromosome aneuploidy was 12.50%, with a FPR of 0.08%.ConclusionNIPT is indicated for trisomies 21, 18 and 13 screening, especially for T21. It also has some certain reference value for SCA and CNV, but is not recommended for screening of other chromosomal aneuploidy.

Dataset Information

Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples.

Publications

Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples.

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