Prenatal reflex DNA screening for Down syndrome: enhancing the screening performance of the initial first trimester test

Abstract

Objective To estimate the effect of adding three biochemical markers (alphafetoprotein, inhibin-A, and placental growth factor) and two ultrasound markers (ductus venosus pulsatility index and nasal bone examination) to enhance the initial Combined test in prenatal reflex DNA screening for Down syndrome.Methods Published data were used to estimate screening performance [detection rates (DRs) and false-positive rates (FPRs)] of reflex DNA screening according to the additional markers used, the proportion of women with the highest initial test risks reflexed to DNA testing and the gestational age at the time of blood collection.Results If 10% of women are reflexed, the addition of the three biochemical markers to the Combined test increases the DR from 90.8% to 92.3% (FPR 0.025% to 0.027%) with markers measured at 11 completed weeks' gestation. With markers measured at 13 completed weeks' gestation the DR increases from 87.7% to 95.2% (FPRs both 0.027%). The further addition of the two ultrasound markers increases the DR to 96.8% and 97.5% at 11 and 13 weeks' respectively (FPR to 0.024% and 0.022% respectively).Conclusion Adding the specified markers to the Combined test can maintain or improve screening performance with a lower proportion of women reflexed. Our results can be used to determine the most cost-effective reflex DNA screening policy.

Differentially expressed miRNAs in trisomy 21 placentas

“…38 Three additional biochemical markersinhibin-A (INHA), placental growth factor (PIGF) and alfafetoprotein (AFP)are currently added to enhance the conventional combined test for Down syndrome detection. 39 DS placenta's elevated miRNAs potentially regulate four out of five markers mentioned: PAPPA (let-7c-5p, miR-654-5p and miR-10b-5p target the 3′-UTR, miR-615-5p target the CDS, miR-542-5p targets the promoter region), PIGF (validated target of miR-125b-5p), INHA (miR-654-5p and 615-5p target CDS, miR-10b-5p target the promoter region) and AFP (miR-125b-5p targets the CDS region). We tried to correlate levels of biochemical markers detected in the first trimester screening test with the miRNA levels (see Results section).…”

“…The first trimester screening test (combined test) usually includes hCG and PAPPA next to the ultrasound markers . Three additional biochemical markers – inhibin‐A (INHA), placental growth factor (PIGF) and alfafetoprotein (AFP) – are currently added to enhance the conventional combined test for Down syndrome detection . DS placenta's elevated miRNAs potentially regulate four out of five markers mentioned: PAPPA (let‐7c‐5p, miR‐654‐5p and miR‐10b‐5p target the 3′‐UTR, miR‐615‐5p target the CDS, miR‐542‐5p targets the promoter region), PIGF (validated target of miR‐125b‐5p), INHA (miR‐654‐5p and 615‐5p target CDS, miR‐10b‐5p target the promoter region) and AFP (miR‐125b‐5p targets the CDS region).…”

Prenatal genetic testing 1: screening tests

“…New horizons: reflex cell-free DNA carrier screening Carrier screening which reflexes to fetal cell-free DNA (cfDNA) is an expanding area of technologic promise. In this method, a positive maternal carrier screen during pregnancy is reflexed to test fetal cfDNA in maternal circulation to provide the mother with an estimate of fetal risk based on fetal DNA analysis [16]. This is useful as it does not require a paternal blood sample to provide an estimate of fetal risk and can help patients in their decision to undergo diagnostic testing [16].…”

“…This test screens for 16 conditions associated with five genes ACOG recommends screening for including HBA1, HBA2, HBB, CFTR, and SMN1 genes using NGS, MLPA, and PCR [17]. If the patient is a carrier for a certain condition, the test then reflexively moves to cfDNA testing to get a fetal risk assessment [16]. For instance, the assessment of the HBB gene has been described to be 97.4% (75 out of 77 patients) in comparison to 42% with traditional screening [18 ▪ ].…”