Statistical analyses were performed according to recommendations described in the EUnetHTA guideline “Meta-analysis of Diagnostic Test Accuracy Studies” [29].
Statistical analyses were mainly conducted with use of the metandi command in STATA 13. This command fits both hierarchical summary receiver operating characteristics (HSROC) and bivariate random-effects models. Forest plots and measures of variability (variances and covariance of logit sensitivity and logit specificity across studies) were used to assess between-study heterogeneity.
A bivariate random-effects model was used to estimate mean sensitivity, specificity, positive likeli-hood ratio (LR+), negative likelilikeli-hood ratio (LR–) and diagnostic odds ratios (DORs) with 95% CIs for each trisomy to provide aggregate result for all three trisomies. When the bivariate effects model failed to converge or provided unreliable parameter estimates, two univariate random-effects models were used [36].
To summarise overall test performance, the HSROC curve was constructed.
Publication bias was assessed by funnel plots representing DOR versus effective sample size [37].
This analysis was performed only when more than 10 studies were available.
technology and the health problem and current use of the technology domains were elaborated by different medical colleges or societies from the UK, USA, Australia, etc. (see Appendix 1, Table A1).
Only one was evidence based [38].
The clinical effectiveness and safety were assessed for five screening pathways:
1. NIPT as a primary screening test as a replacement for FCT 2. Prenatal screening based on NIPT as part of FCT
3. NIPT as an add-on to FCT for the high-risk population
4. NIPT as an add-on to FCT for the high- and intermediate-risk population 5. NIPT as a replacement for invasive testing
Direct evidence for the clinical effectiveness and safety domains was found only for the first pathway (total replacement of FCT). This evidence derives from five paired comparative studies and four noncomparative studies performed in singleton pregnancies. Moreover, two studies on twin preg-nancies offered NIPT as a primary screening strategy to some of the women included, alt hough results were reported jointly with those of women offered NIPT as a second-tier test (high-risk preg-nancies). The question regarding NIPT as an add-on to FCT in women with high risk of aneu-ploidies was answered indirectly from pooled data derived from 26 retrieved studies on singleton pregnancies which assessed NIPT as a second-tier test in these populations. The add-on strategy for intermediate-risk patients was addressed in only one study. Six studies provided data on the accuracy of NIPT for twin populations. No evidence was found regarding the performance of these tests in combination with FCT and/or NT assessment. The scenario of NIPT as a diag nostic test will not be considered as none of the tests are currently indicated for this purpose. No data exist regarding patient-relevant outcomes (Table 2). Detailed information about studies included in the assessment can be found in Appendix 1 (Tables A2–A5).
The evidence included in the ethical analysis, organisational aspects, patients and social aspects, and legal aspects domains comes from 14 quantitative surveys, questionnaires or interviews and two systematic reviews. One of the systematic reviews, which focused on factors affecting the clinical use of noninvasive testing, used a mixed method approach to identify key features of the studies included. The other used thematic analysis to explore Internet advertising of NIPT.
Ongoing clinical trials and research projects identified can be found in Appendix 1 (Table A6).
The search identified five systematics reviews and/or meta-analyses and five health technology assessment reports which were not included because they did not comply with the PICO question.
Detailed information about these documents can be found in Appendix 1 (Table A7).
Authors and year or study name
Study type and target condition Number of women enrolled
Intervention(s) Main endpoints
Sarno et al. [39], 2016
Prospective DTA trial (cross-sectional design) Trisomies 21, 18 and 13
10,698 Index test trademark: Harmony® prenatal test Comparator: no intervention
Reference standard: fetal karyotype (method used not specified)
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Comas et al. [40], 2015
Prospective DTA trial (cross-sectional design) Trisomy 21
333 Index test trademark: Harmony® prenatal test or Panorama™ test
Comparator: no intervention
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Norton et al. [31], 2015
Prospective, multicentre comparative DTA trial (cross-sectional design) NIPT analysis blinded to clinical information
Trisomies 21, 18 and 13 and other an-euploidies (45,X maker
chromosomes, unbalanced translocations, unbalanced translocations, 7p deletion, 5p deletion/duplication, 1q41 deletion and isochromosome Yp)
18,955 Index test trademark: Harmony® prenatal test Comparator: standard screening (NT and biochemical analytes, i.e., PAPP-A and total hCG or β-hCG
Reference standard: CVS, products of conception or neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV.
Effectiveness of prenatal screening with NIPT vs. screening without NIPT Reduction in children born with undiagnosed trisomies 13, 18 and 21 Reduction in uptake of invasive testing
Pérez-Pedregosa et al. [41], 2015
Prospective comparative DTA trial (cross-sectional design)
Trisomies 21 and 18
582 Index test trademark: Harmony® prenatal test Comparator: standard screening, i.e., NT with serum biochemical assays (PAPP-A and total hcG or β-hCG) Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV Effectiveness of prenatal screening with NIPT vs. screening without NIPT Reduction in uptake of invasive testing Quezada et al.
[42], 2015
Prospective, comparative DTA trial (cross-sectional design)
Trisomies 21, 18 and 13
2905 Index test trademark: Harmony® prenatal test Comparator: standard screening, i.e., NT and fetal CRL with serum biochemical assays (PAPP-A and total hCG or β-hCG)
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV Effectiveness of prenatal screening with NIPT vs. screening without NIPT Reduction in children born with undiagnosed trisomies 13, 18 and 21
or study name women enrolled
Reduction in uptake of invasive testing Zhang et al. [43],
2015
Prospective, multicentre DTA trial (cross-sectional design)
Trisomies 21, 18 and 13
147,314 Index test trademark: NA (Illumina HiSeq200 platform) Comparator: no intervention
Reference standard: CVS or amniocentesis and neonatal follow-up
Safety and effectiveness of NIPT: FN, FP, test failure rate, S, Sp, PPV, NPV
Bianchi et al.
[30], 2014