State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study.

OBJECTIVES: To perform individual record linkage of women undergoing screening with cell-free DNA (cfDNA), combined first-trimester screening (CFTS), second-trimester serum screening (STSS), and/or prenatal and postnatal cytogenetic testing with the aim to (1) obtain population-based estimates of utilization of prenatal screening and invasive diagnosis, (2) analyze the performance of different prenatal screening strategies, and (3) report the residual risk of any major chromosomal abnormality following a low-risk aneuploidy screening result. METHODS: This was a retrospective study of women residing in the state of Victoria, Australia, who underwent prenatal screening or invasive prenatal diagnosis in 2015. Patient-funded cfDNA referrals from multiple providers were merged with state-wide results for government-subsidized CFTS, STSS and invasive diagnostic procedures. Postnatal cytogenetic results from products of conception and infants up to 12 months of age were obtained to ascertain cases of false-negative screening results and atypical chromosomal abnormalities. Individual record linkage was performed using LinkageWizTM . RESULTS: During the study period, there were 79 140 births and 66 166 (83.6%) women underwent at least one form of aneuploidy screening. Linkage data were complete for 93.5% (n = 61 877) of women who underwent screening, and of these, 73.2% (n = 45 275) had CFTS alone, 20.2% (n = 12 486) had cfDNA alone; 5.3% (n = 3268) had STSS alone, 1.3% (n = 813) had both CFTS and cfDNA, and < 0.1% (n = 35) had both STSS and cfDNA. CFTS had a combined sensitivity for trisomies 21 (T21), 18 (T18) and 13 (T13) of 89.57% (95% CI, 82.64-93.93%) for a screen-positive rate (SPR) of 2.94%. There were 12 false-negative results in the CFTS pathway, comprising 10 cases of T21, one of T18 and one of T13. cfDNA had a combined sensitivity for T21, T18 and T13 of 100% (95% CI, 95.00-100%) for a SPR of 1.21%. When high-risk cfDNA results for any chromosome (including the sex chromosomes) and failed cfDNA tests were treated as screen positives, the SPR for cfDNA increased to 2.42%. The risk of any major chromosomal abnormality (including atypical abnormalities) detected on prenatal or postnatal diagnostic testing after a low-risk screening result was 1 in 1188 for CFTS (n = 37) and 1 in 762 for cfDNA (n = 16) (P = 0.13). The range of chromosomal abnormalities detected after a low-risk cfDNA result included pathogenic copy-number variants (n = 6), triploidy (n = 3), rare autosomal trisomies (n = 3) and monosomy X (n = 2). CONCLUSIONS: Our state-wide record-linkage analysis delineated the utilization and clinical performance of the multitude of prenatal screening pathways available to pregnant women. The sensitivity of cfDNA for T21, T18 and T13 was clearly superior to that of CFTS. While there was no statistically significant difference in the residual risk of any major chromosomal abnormality after a low-risk CFTS or cfDNA result, there were fewer live infants diagnosed with a major chromosomal abnormality in the cfDNA cohort. These data provide valuable population-based evidence to inform practice recommendations and health policies. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Follow up and evaluation of the Victorian first-trimester combined screening programme for Down syndrome and trisomy 18.

OBJECTIVE: The objective of this study was to follow up and evaluate the statewide first-trimester combined screening programme for Down syndrome and trisomy 18 at Genetic Health Services Victoria, Australia. DESIGN: Retrospective population cohort. SETTING: Maternal Serum Screening Laboratory records. SAMPLE: All women screened between February 2000 and June 2002 (16,153 pregnancies). METHODS: Screening results were matched to Victorian perinatal and birth defect data via record linkage, with an ascertainment of 96.8% of pregnancy outcomes. Manual follow up with health professionals increased ascertainment to more than 99%. MAIN OUTCOME MEASURES: Fetal Down syndrome or trisomy 18, and combined screen results, to calculate test characteristics. RESULTS: Using a risk threshold of 1 in 300 at time of ultrasound, the sensitivities for standard first-trimester combined screening and augmented 13-week combined screening for Down syndrome were 87.3 and 90.5% and the false-positive rates (FPR) were 4.1 and 3.9%, respectively. The sensitivity for trisomy 18 was 66.7% (10/15, 95% CI 42.8-90.5%) with a 0.4% FPR and 15.2% positive predictive value (1 in 250 risk threshold). CONCLUSIONS: The combined use of record linkage and manual follow-up techniques was effective in ascertaining more than 99% of pregnancy outcomes for calculations of accurate test characteristics of the combined screen. The sensitivity for Down syndrome at Genetic Health is comparable to similar populations. However, the sensitivity for trisomy 18 is lower than that elsewhere, which may reflect the overall low birth prevalence of trisomy 18 and associated small numbers in this particular cohort.

The impact of newborn screening on cystic fibrosis testing in Victoria, Australia.

Newborn screening for cystic fibrosis (CF) by examining the levels of immunoreactive trypsinogen was introduced in Victoria in 1989. This was modified by the addition of testing for the common CF gene mutation, delta F508, in 1990. Problems with the first newborn screening protocol were overcome with the addition of the DNA test as there was no need to contact the majority of families, there was a reduced number of sweat tests, and less anxiety was experienced by parents. The mode of diagnosis changed from failure to thrive, steatorrhoea, rectal prolapse, and family history to diagnosis through newborn screening. Newborn screening dramatically reduced the time of diagnosis of CF to approximately six weeks or less in the majority of cases. Since the introduction of newborn screening, the uptake of prenatal diagnosis in CF families has increased two and a quarter fold.

Effect of magnesium on passive fluxes of lithium in the human erythrocyte.

Extracellular Mg2+ is known to inhibit the passive Na+ and K+ fluxes in the human erythrocyte. In this study the effect of extracellular Mg2+ on Li+ efflux was measured in erythrocytes from 29 normotensive and essential hypertensive subjects. Magnesium produced a variable inhibition of between 0 and 47% in Li+ efflux in different subjects and this effect was unrelated to initial cell Li+, blood pressure or to an action on the co- or counter-transport pathways for this cation. A positive correlation was observed between the magnitude of the passive Li+ efflux and its inhibition (0 to 47%) by Mg2+ ions. Thus Mg2+ has an inhibitory effect on passive Li+ permeability which is unrelated to essential hypertension.

Erythrocyte cation cotransport and countertransport in essential hypertension.

We studied erythrocyte cation cotransport and countertransport systems in 21 and 27 patients with essential hypertension, respectively, all of whom were under 50 years of age, had a diastolic blood pressure level greater than 100 mm Hg, and had a family history of hypertension. The following parameters were normal in nearly all patients: total erythrocyte Na+ and K+ concentrations, the maximal rate (Vmax) of inward cotransport, the affinity of cotransport with Rb+ as the substrate, the net outward cotransport of Na+ ions, the passive "leak" influx of Rb,+ and the maximal rate of Li+-Na+ countertransport. Only four patients gave clearly abnormal results; in two the maximal rate of both cotransport and countertransport was double the normal values, while another two patients demonstrated a greater than twofold increase in passive "leak" influx to Rb+ ions. Most of the patients with moderate to severe essential hypertension in this Australian study were characterized by normal erythrocyte cation fluxes, but a few showed elevation of both cotransport and countertransport of cations.