Non-invasive fetal RHD genotyping tests: A systematic review of the quality of reporting of diagnostic accuracy in published studies

Abstract

Articles reporting the diagnostic accuracy of non-invasive prenatal diagnostic (NIPD) tests for RHD genotyping using fetal material extracted from maternal blood have been published steadily for over a decade. Health care providers in Europe have started to use this technology for management of the small number of sensitised pregnancies (ca. 220-600 per annum in the Netherlands, Germany, France and the UK). Scientists and clinicians are also advocating widespread implementation for the far larger number of non-sensitised RhD-negative pregnancies (ca. 34,000-125,000 per annum in the same countries). Largescale, prospective trials are only now underway. Estimates of the technical performance of these tests are currently based on results from small-scale studies, together with formal meta-analysis. The issue of early assessment of test performance is one faced by many new genetic tests. As part of a wider study we have investigated the quality of reporting of diagnostic accuracy in publications and produced guidelines for future studies.A systematic search of the literature identified 27 papers which met predefined inclusion criteria. All 27 papers were, first, assessed against an international quality (STARD) checklist for reporting of diagnostic accuracy and, second, against our own in-house NIPD proforma to assess the implications of the quality of reporting specifically for the RhD NIPD test. Authors were found to generally present an optimistic view of NIPD, bearing in mind weaknesses identified in reporting and conduct of their studies and the analysis of results, as evidenced by the low STARD scores. The NIPD proforma identified that specific biases were potentially introduced through selective population sampling and/or failure to report the make-up of the population tested, omission of inconclusive results, inconsistencies in the handling of repeat results on a sample, and lack of adequate controls. These factors would inevitably affect the validity of diagnostic accuracy as reported in individual publications, as well as any subsequent meta-analyses. Together, published reports to date may provide a biased picture of the actual potential of NIPD testing for fetal RHD genotyping. Generalisation of the available evidence on diagnostic accuracy, especially to large-scale implementation of NIPD testing of non-sensitised women, will also require that decision makers consider further aspects such as test reliability and cost of routine testing in clinical practice.It is recommended that all studies of diagnostic accuracy of NIPD tests adhere to the STARD quality checklist in order to improve reporting, thereby, minimising bias and increasing the comparability of studies. Researchers should also consider specific shortcomings for NIPD and avoid selective participant sampling; report population characteristics; report handling of replicate sampling as well as their failure rates; and include controls for genotypes tested in the study. Furthermore, meta-analyses should consider the quality, as well as the sample s...

Haplotype-based approach for noninvasive prenatal tests of Duchenne muscular dystrophy using cell-free fetal DNA in maternal plasma

“…[9][10][11][12][13] Most studies thus far, however, have been restricted to the identification of paternal-specific sequences. 27 The ability to predict noninvasively whether the genetic variants that are passed from the mother to the fetus are at risk of single-gene disorders remains challenging, mainly because of the high background of maternal DNA in the plasma mixture that prevents an accurate prediction of fetal status.…”

“…9,10 The fetal sex in pregnancies at risk of X-linked genetic disorders and the Rhesus factor status in RhD-negative women represent additional noninvasive applications that have begun to transition from research to routine clinical service. [11][12][13] NIPTs for single-gene disorders remain challenging, however, because most (~90%) of the DNA in the maternal plasma is derived from the mother. throughout the 79 exons in the DMD gene without clusters make this locus-specific test laborious and time-consuming.…”

Detection of fetal RhD gene from maternal blood

“…Fetal DNA can be identified from the 5th week of pregnancy in maternal blood and is rapidly destroyed immediately after birth. However, only 3%-6% of total DNA in maternal blood is welded fetal origin (11). Genes inherited from the mother are pressured by excessive quantities of free maternal DNA.…”

“…Bu çalışmada da maternal kandan fetal DNA'da RhD geninin varlı-ğına bakılarak doğum öncesi RhD tayini yapılabilmesi amaçlanmıştır. [11][12][13][14]. gebelik haftalarında bulunan ve eşleriy-le aralarında RhD uyumsuzluğu olan 19 Rh (-) gebeden kan alınarak total serbest DNA izolasyonu yapılmıştır.…”

Noninvasive fetal RHD genotyping from maternal plasma in an admixed Brazilian population

“…In Caucasian populations, about 10% of all pregnancies involve an RhD-negative mother and an RhD-positive fetus, placing the mother at risk of alloimmunization and the newborn at risk of HDFN (Freeman et al, 2009).…”