False-positives and false-negatives in non-invasive prenatal testing (NIPT): what can we learn from a meta-analyses on > 750,000 tests?

Abstract

Background Non-invasive prenatal testing (NIPT) has had an incomparable triumph in prenatal diagnostics in the last decade. Over 1400 research articles have been published, predominantly praising the advantages of this test. Methods The present study identified among the 1400 papers 24 original and one review paper, which were suited to re-evaluate the efficacy of > 750,000 published NIPT-results. Special attention was given to false-positive and false-negative result-rates. Those were discussed under different aspects—mainly from a patient-perspective. Results A 27: 1 rate of false-positive compared to false-negative NIPT results was found. Besides, according to all reported, real-positive, chromosomally aberrant NIPT cases, 90% of those would have been aborted spontaneously before birth. These findings are here discussed under aspects like (i) How efficient is NIPT compared to first trimester screening? (ii) What are the differences in expectations towards NIPT from specialists and the public? and (iii) There should also be children born suffering from not by NIPT tested chromosomal aberrations; why are those never reported in all available NIPT studies? Conclusions Even though much research has been published on NIPT, unbiased figures concerning NIPT and first trimester screening efficacy are yet not available. While false positive rates of different NIPT tests maybe halfway accurate, reported false-negative rates are most likely too low. The latter is as NIPT-cases with negative results for tested conditions are yet not in detail followed up for cases with other genetic or teratogenic caused disorders. This promotes an image in public, that NIPT is suited to replace all invasive tests, and also to solve the problem of inborn errors in humans, if not now then in near future. Overall, it is worth discussing the usefulness of NIPT in practical clinical application. Particularly, asking for unbiased figures concerning the efficacy of first trimester-screening compared to NIPT, and for really comprehensive data on false-positive and false-negative NIPT results.

Non-Invasive Prenatal Testing in Germany

“…A major problem of the publications reporting on NIPT, is that these technical differences between platforms are not discussed extensively [ 14 , 18 ]. NIPT results are reported for in-house developed or the application of commercially available platforms, and the comparison of the results is achieved interchangeably, as if differences in platforms and their technical restrictions do not matter.…”

“…Overall, there are dozens of variants of NIPT available, but they are not really distinguished in the literature [ 18 , 21 ]. This combination issue, if applied to all studies using molecular cytogenetics/fluorescence in situ hybridization (FISH) in prenatal samples [ 22 ], would be as if they were all reported as similar results e.g., “invasive prenatal FISH testing” (IPFT), a misnomer, which would fail to distinguish whether the results were based on interphase or metaphase FISH, and/or which and how many different probes were applied.…”

“…The concept to study cells from the placenta without bothering or endangering the developing individual is laudable. Screening the literature for bolstering-points for NIPT include conclusions that the platform: can be applied earlier than other tests during pregnancy; has the potential to reach populations with no access to centers offering invasive diagnostics [ 23 ]; can exclude and detect a trisomy 21 with the highest probability of all non-invasive approaches—the positive predictive value (PPV) in cases of a NIPT suggesting trisomy 21 is >99%; can bring a psychological relief to an anxious pregnant woman in the case of a normal NIPT result; and can lead to an early pregnancy termination in cases of an early detection of an adverse genetic condition via NIPT [ 8 , 14 , 18 ]. …”

“…can lead to an early pregnancy termination in cases of an early detection of an adverse genetic condition via NIPT [ 8 , 14 , 18 ].…”

Chromosomal Heteromorphisms and Cancer Susceptibility Revisited

“…The two-hit model for euchromatic CNVs, as suggested in 2010 [ 12 ], has already been supported as potentially valid, and maybe at a lower efficiency, is valid also for heterochromatic CNVs—especially for heterochromatic CG-CNVs [ 7 ]. The majority of constitutional syndromes in humans are suggested to result from multigenic traits [ 81 ]. Interestingly, a multigenic disorder is defined to be, in part, genetic predisposition, and at the same time, it is emerging that environmental conditions support transformation to disease—this includes cancer development.…”