Stokowski et al., report on the performance of a counting based NIPT using a microarray to measure the number of DNA fragments present. The detection rates were: trisomy 21 107/108 (99.1%), trisomy 18 29/30 (96.1%), trisomy 13 12/12 (100%) and the false-positive rate for all three trisomies was 0/641 (0%) for all three trisomies. The no-result rate due to insufficient DNA was 8/799 (1%). The results were consistent with data using sequencing for the quantification.
Stokowski et al. Prenat Diagn. 2015. Eprint ahead of publication.
Osborne et al., (1) reported in 2013 that maternal cancer could be a reason for false-positive results using counting-based NIPT. Several recent reports have now further documented this finding (2-4). In the largest study, Bianchi et al., (4) identified 10 cases of maternal cancer in 3,757 women with positive NIPT findings. Under the crude assumption that perhaps 50% of the cases with positive findings are false-positives, this translates to over 1 in 200 false-positives potentially explainable by maternal cancer. In cases where NIPT is positive for more than one aneuploidy, 7/39 (16%) were attributable to maternal cancer.
Although many maternal cancer cases could be identified through imbalances involving multiple region-specific gains and losses, some malignancies have a relatively simple abnormal karyotype (such as trisomy 21 as a sole abnormality in acute myeloid leukemia and myelodysplasia). Apparent inconsistencies in the “fetal” fraction across regions or analysis of SNPs that differ between maternal and fetal genotypes could also be used to distinguish between fetal aneuploidy and maternal cancer. However, these approaches would each involve analyses beyond that usually required for fetal aneuploidy assessment. Diana Bianchi suggests that patients are counseled and consent prior NIPT if they wish receive information that may reflect maternal as well as fetal health (5). These considerations would not be applicable to a NIPT format that only returns information related to the fetus (6).
Osborne et al., Prenat Diagn. 2013;33:609-611
Vandenberge et al., Lancet Hematol. 2015;2:e55-e65.
Amant et al. JAMA Oncol. 2015;1:814-819.
Bianchi et al. JAMA 2015;314:162-169.
Bianchi. Nature 2015;522:29-30.6.
6. Gross et al. Nature 2015;523:290.
Several new studies have revisited the economics of NIPT for the full US pregnancy population. Fairbrother et al., (1) modeled the expected economic benefits of NIPT for t21, t18 and t13. After allowing for the additional cases of trisomy detected as result of the use of NIPT, they estimated that, if the NIPT were offered to the general pregnancy population, the cost would need to be $665, or less, for it to be advantageous over the first trimester Combined test. Walker et al., (2) considered NIPT cost for the detection of trisomy 21, 18 and 13 from three different perspectives, societal (includes cost of testing, all direct and indirect lifetime costs of affected individuals), governmental (testing, medical and educational costs), and payer (cost of testing only). They concluded that offering NIPT to all women would be advantageous from the societal perspective, but contingent NIPT would be preferred by government and payers. Benn et al., (3) also included monosomy-X in the analysis and considered the costs associated with second trimester follow-up screening tests (sequential quadruple testing, ultrasound) for women receiving the Combined test. For NIPT to be applied to the general pregnancy population, the cost would need to be $744 or less.
An entirely different conclusion is drawn by Kaimal et al. (4) who reported that cf-DNA as a primary screening approach only becomes the optimal screening strategy at maternal age 40 and older, and that at younger ages multiple marker screening (MMS, first and second trimester serum markers and nuchal translucency measurement) is preferable. This study attempted to consider all chromosome abnormalities present including variants of uncertain significance (VOUS) identified through chromosome microarrays. Lifetime costs associated with affected liveborns were not included but maternal quality-adjusted life-years (QALYs) were considered. A cost of $1,796 was used for NIPT and some other costs, rates and components differed markedly from the other studies. The analysis did not appear to fully consider the additional costs (follow-up ultrasound, counseling, array studies on parents) or consequences of VOUS detection. Based on the rates and assumptions used by the authors, for every 100,000 pregnancies screened by MMS, there would be 88 pregnancy terminations where there would be fetal VOUS, but no intellectual disabilities would occur if the pregnancies continued. There would, therefore, be far more common than procedure-related losses.
Fairbrother et al. Mat Fetal and Neonat Med. 2015; [Epub ahead of print]
Walker et al. PLOS One 2015; 10:e0131402.
Benn et al. PLOS One 2015; 2015;10:e0132313.
Kaimal et al. Obstet Gynecol. 2015;126:737-746.
NIPT is being extended to screening for selected microdeletion syndromes. Helgeson et al.,(1) reported results for microdeletions and “subchromosomal events” in 175,393 women using a DNA fragment counting-based approach. For 22q11.2 deletions, they found 32 (0.02%) positive results including 31 true or suspected true positive, 0 false-positive, and 1 unknown outcome. Of the 32 cases, 20 (1/8,770) were maternal deletions, and an additional 12 (1/14,616) were fetal deletions. Based on expected prevalence (2,3), only a proportion of the deletions were detected. For 1p36, 15q, and 5p deletions, they found 20 (0.01%) positive tests including 16 true- or suspected true-positive, 3 false-positive, and 1 unknown outcome. The 20 cases included 4 (1/43,845) maternal deletions and 13 (1/13,492) fetal deletions.
Using SNP-based NIPT, Gross et al., (3) report initial results of screening for the 22q11.2 microdeletion. In 21,948 samples referred for testing, there were 95 (0.5%) positive results that included 11 true-positive and 50 false-positive (PPV 18%). There were also two maternal deletions identified. Ultrasound anomalies were present for 81.8% of true-positive and 18.0% of false-positive cases. Overall incidence of all 22q11.2 fetal deletions in the referral population was estimated to be at least 1/946. Reflex retesting of positive cases at a high depth of sequencing could raise the PPV from 18% to 42%.
Expanding NIPT to include microdeletion syndromes was the subject of a debate at the Washington ISPD meeting. The arguments presented will be summarized in an article to be published in Prenatal Diagnosis
Helgeson et al. Prenat Diagn. 2015 Epub ahead of print
Grati et al., Prenat Diagn. 2015;35:801-9
Gross et al. Ultrasound Obstet Gynecol. 2015 Epub ahead of print
Rose et al. Prenat Diagn. In Press.