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Title: A novel array CGH-based non-invasive prenatal test for common trisomies
Author: Karampetsou, Evangelia
ISNI:       0000 0004 7659 663X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Objective: The main objective of this study was to evaluate array Comparative Genomic Hybridisation (CGH) for the non-invasive prenatal testing (NIPT) for trisomy 21 (T21) based on analysis of cell-free DNA (cfDNA) in maternal plasma. In addition, the potential for detection of trisomy 18 (T18), trisomy 13 (T13) and common microdeletion syndromes was explored. Method: Pregnant women attending maternity units for invasive diagnostic testing were consented to donate a blood sample. CfDNA was extracted from maternal plasma. Results of invasive testing were known. In the Pre-evaluation Study 100 samples, including 20 T21, were tested on the array CGH based NIPT assay (arrayNIPT) and a variety of statistical analyses and methods were evaluated for results analysis. In the Evaluation Study 438 plasma samples, including 92 T21, 20 T18 and 5 T13, were tested by arrayNIPT. The potential to detect subchromosomal changes was explored using both spike-in and maternal plasma samples. Results: The Stouffer analysis method was found to be the best performing for T21 detection, showing 98.8% sensitivity and 97.2% specificity. For T18 detection, the assay sensitivity was 77.8% and specificity 99.7% when using the Stouffer analysis method. Re-designing the assay and using the Pooled control analysis method, assay sensitivity for T13 could reach 75.0% and specificity 100.0%. All microdeletions were identified in spike-in samples, with the exception of two 5% spike-ins. When considering maternal plasma samples, three with fetal fraction ≤3.8% were not identified and two samples with fetal fraction ≥14.5 were correctly identified. A sample with 7.5% fetal fraction was correctly identified, while two DiGeorge Syndrome samples with 6.9% and 9.6% fetal fraction were false-negatives. Conclusions: ArrayNIPT promises a low cost, rapid and easily transferrable test for the detection of T21, that could allow in-house NIPT with minimal capital outlay and running costs compared to Next Generation Sequence technologies. The detection of T18, T13 and subchromosomal changes is also feasible, but further research is required to improve performance and establish assay sensitivity and specificity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available