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      Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol

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          Non-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK’s National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials.


          NIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down’s syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk ≥1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7–10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals.


          The results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice.

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          Most cited references 48

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          Validation of a decisional conflict scale.

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          The study objective was to evaluate the psychometric properties of a decisional conflict scale (DCS) that elicits: 1) health-care consumers' uncertainty in making a health-related decision; 2) the factors contributing to the uncertainty; and 3) health-care consumers' perceived effective decision making. The DCS was developed in response to the lack of instruments available to evaluate health-care-consumer decision aids and to tailor decision-supporting interventions to particular consumer needs. The scale was evaluated with 909 individuals deciding about influenza immunization or breast cancer screening. A subsample of respondents was retested two weeks later. The test-retest reliability coefficient was 0.81. Internal consistency coefficients ranged from 0.78 to 0.92. The DCS discriminated significantly (p < 0.0002) between those who had strong intentions either to accept or to decline invitations to receive influenza vaccine or breast cancer screening and those whose intentions were uncertain. The scale also discriminated significantly (p < 0.0002) between those who accepted or rejected immunization and those who delayed their decisions to be immunized. There was a weak inverse correlation (r = -0.16, p < 0.05) between the DCS and knowledge test scores. The psychometric properties of the scale are acceptable. It is feasible and easy to administer. Evaluations of responsiveness to change and validation with more difficult decisions are warranted.
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            Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood.

            We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure the over- and underrepresentation of chromosomes from an aneuploid fetus. The sequencing approach is polymorphism-independent and therefore universally applicable for the noninvasive detection of fetal aneuploidy. Using this method, we successfully identified all nine cases of trisomy 21 (Down syndrome), two cases of trisomy 18 (Edward syndrome), and one case of trisomy 13 (Patau syndrome) in a cohort of 18 normal and aneuploid pregnancies; trisomy was detected at gestational ages as early as the 14th week. Direct sequencing also allowed us to study the characteristics of cell-free plasma DNA, and we found evidence that this DNA is enriched for sequences from nucleosomes.
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              DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study.

              Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement. A blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequencing in 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory. Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alternative interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance. When applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis.

                Author and article information

                BMC Pregnancy Childbirth
                BMC Pregnancy Childbirth
                BMC Pregnancy and Childbirth
                BioMed Central
                16 July 2014
                : 14
                : 229
                [1 ]North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Level 5, York House, 37 Queen Square, London WC1N 3BH, UK
                [2 ]Genetics and Genomic Medicine, UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
                [3 ]Centre for Medical Statistics & Bioinformatics, Plymouth University, Plymouth, UK
                [4 ]Fetal Medicine Unit, University College London Hospitals NHS Foundation Trust, London, UK
                [5 ]UCL Genetics Institute, London, UK
                [6 ]Clinical Biochemistry Department, Barking, Havering & Redbridge University Hospitals NHS Trust, Essex, UK
                [7 ]Antenatal Results and Choices, London, UK
                [8 ]PHG Foundation, Cambridge, UK
                [9 ]Research Department of Applied Health Research, University College London, London, UK
                Copyright © 2014 Hill et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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