Combined screening test for trisomy 21 – is it as efficient as we believe?
Marcin WiechećAgnieszka NocuńAnna KnafelEwa WiercińskaJiri SonekWioletta Rozmus-WarcholińskaMaciej OrzechowskiD. StettnerPetr Plevak
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To compare two first-trimester screening strategies: traditional combined screening and the one based on ultrasound markers only. We investigated the effect of maternal age (MA) on the screening performance of both of these strategies.This was a prospective observational study based on a non-selected mixed-risk population of 11,653 women referred for first-trimester screening. The study population was divided in two groups: combined screening (CS) and ultrasound-based screening (US). Absolute risk was calculated to determine the influence of MA on screening performance.The CS arm comprised 5145 subjects including 51 cases of trisomy 21 (T21), and the US arm comprised 5733 subjects including 87 subjects with T21. Seven hundred and seventy-five subjects were excluded from the study. For a false positive rate (FPR) of 3%, the detection rate (DR) of T21 in CS arm was 78% vs. 90% in US arm. For 5% FPR, DR was 84% and 94% in CS and US arm, respectively. MA had an influence on DR positive rates in CS: both DR and FPR for T21 increased with advance in MA.The US protocol showed higher DR of T21 compared to the CS one. It may be considered as a viable alternative to CS for T21 where access to biochemical testing is limited.Keywords:
Trisomy
False positive rate
Medical screening
Screening test
To determine the recurrence risk of a free trisomy 21 pregnancy.Data from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all cases of Down syndrome between 1989 and 2001 in England and Wales were used. Among 11 281 women with a Down syndrome pregnancy who had had at least one previous pregnancy there were 95 women who had had a previous Down syndrome pregnancy.Women who have had a previous Down syndrome pregnancy have a constant absolute excess risk above their maternal age-related risk of having a subsequent affected pregnancy. This absolute excess risk is determined by the age at which the affected pregnancy occurred and is higher for younger than for older women. For example, after a Down syndrome pregnancy at age 20, this excess is 0.62% (95% CI: 0.24 to 1.15%) at early second trimester, and, after one at age 40, it is 0.04% (95% CI: 0.01 to 0.07%).More precise risk estimates by single year of maternal age for use in genetic counselling are provided, but they need validation from other studies before they are incorporated in the risk estimation routines used in Down syndrome screening programmes.
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Absolute risk reduction
Advanced maternal age
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Objective To assess the effectiveness of sonographic screening and discuss sonographic characteristics of Down syndrome and trisomy 18.Methods The subjects were recruited from pregnant women undergoing prenatal sonographic examinations and subsequently proven to be Down syndrome and trisomy 18 by genetic results.Results The results of ultrasound findings in 11 cases confirmed as Down syndrome and 6 cases confirmed as trisomy 18 were retrospectively reviewed.Conclusion Fetal sonography is a practical and effective prenatal screening method for detecting Down syndrome and trisomy 18.
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Prenatal ultrasound
Prenatal screening
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Second trimester screening for fetal Down syndrome and trisomy 18 is available through separate protocols that combine the maternal age-specific risk and the analysis of maternal serum markers. We have determined the extent to which additional Down syndrome affected pregnancies may be identified through trisomy 18 screening, and the extent to which additional cases of trisomy 18 may be screen-positive for Down syndrome. The combined false-positive rate, taking into consideration those pregnancies that are screen-positive by both protocols, has also been determined. Sensitivity and false-positive rates were determined by computer simulation of results that incorporated previously published statistical variables into the model. Using second trimester risk cut-offs of 1:270 for Down syndrome and 1:100 for trisomy 18, it was found that few additional cases of Down syndrome are identified through trisomy 18 screening. However, approximately 6–10% of trisomy 18 affected pregnancies will be screen-positive for Down syndrome but screen-negative for trisomy 18. For women aged 40 or more, the false-positive rate for trisomy 18 exceeds 1% and approximately half of these cases will also be screen-positive for Down syndrome. For a population with maternal ages equivalent to that in the United States in 1998, after adjusting for the cross-identification, the sensitivity for three-analyte trisomy 18 screening is 78%. If this testing is performed in conjunction with Down syndrome ‘triple’ screening, the Down syndrome sensitivity is 75% and the combined false-positive rate is 8.5%. If the three-analyte trisomy 18 screening is performed with the Down syndrome ‘quad’ screen, the trisomy 18 sensitivity remains at 78%, the Down syndrome sensitivity is 79%, and combined false-positive rate is 7.5%. Sensitivity and false-positive rates are also provided for other widely used Down syndrome and trisomy 18 risk cut-offs. Sensitivity and false-positive rates that take into consideration cross-identification and double-positives should be helpful for pre-test counseling and the evaluation of serum screening programs. Copyright © 2001 John Wiley & Sons, Ltd.
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Second trimester
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Objective To assess the effectiveness of sonographic screening and discuss sonographic characteristics of Down syndrome and trisomy 18. Methods The subjects were recruited from pregnant women undergoing prenatal sonographic examinations and subsequently proven to be Down syndrome and trisomy 18 by genetic results. Results The results of ultrasound findings in 22 cases confirmed as Down syndrome and 8 cases confirmed as trisomy 18 were retrospectively reviewed. Conclusion Fetal sonography is a practical and effective prenatal screening method for detecting Down syndrome and trisomy 18.
Trisomy
Prenatal ultrasound
Prenatal screening
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Second trimester screening for fetal Down syndrome and trisomy 18 is available through separate protocols that combine the maternal age-specific risk and the analysis of maternal serum markers. We have determined the extent to which additional Down syndrome affected pregnancies may be identified through trisomy 18 screening, and the extent to which additional cases of trisomy 18 may be screen-positive for Down syndrome. The combined false-positive rate, taking into consideration those pregnancies that are screen-positive by both protocols, has also been determined. Sensitivity and false-positive rates were determined by computer simulation of results that incorporated previously published statistical variables into the model. Using second trimester risk cut-offs of 1:270 for Down syndrome and 1:100 for trisomy 18, it was found that few additional cases of Down syndrome are identified through trisomy 18 screening. However, approximately 6-10% of trisomy 18 affected pregnancies will be screen-positive for Down syndrome but screen-negative for trisomy 18. For women aged 40 or more, the false-positive rate for trisomy 18 exceeds 1% and approximately half of these cases will also be screen-positive for Down syndrome. For a population with maternal ages equivalent to that in the United States in 1998, after adjusting for the cross-identification, the sensitivity for three-analyte trisomy 18 screening is 78%. If this testing is performed in conjunction with Down syndrome "triple" screening, the Down syndrome sensitivity is 75% and the combined false-positive rate is 8.5%. If the three-analyte trisomy 18 screening is performed with the Down syndrome "quad" screen, the trisomy 18 sensitivity remains at 78%, the Down syndrome sensitivity is 79%, and combined false-positive rate is 7.5%. Sensitivity and false-positive rates are also provided for other widely used Down syndrome and trisomy 18 risk cut-offs. Sensitivity and false-positive rates that take into consideration cross-identification and double-positives should be helpful for pre-test counseling and the evaluation of serum screening programs.
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Abstract Objectives To develop a reliable and specific technique for rapid prenatal diagnosis of Down syndrome. Methods High throughput real‐time PCR technique was used to measure the DSCR3 gene dosage of genomic DNAs from uncultured amniocytes of fetuses, lymphocytes of trisomy 21 syndrome patients, and normal people, compared to conventional cytogenetic karyotype analysis. Results The DSCR3/GAPDH ratio of uncultured amniocytes in trisomy 21 syndrome fetuses to normal fetuses was 1.69 ± 0.17 to 1.06 ± 0.14, respectively ( p < 0.001); and the DSCR3/GAPDH ratio of lymphocytes in trisomy 21 syndrome children to normal people was 1.67 ± 0.13 to 0.99 ± 0.10, respectively ( p < 0.001). Real‐time PCR technique effectively differentiates the normal fetuses from the trisomy 21 syndrome fetuses; therefore, compared to the results of the conventional cytogenetic karyotype analysis, the DSCR3 / GAPDH ratios of trisomy 21 syndrome fetuses are significantly higher than those of normal fetuses. Conclusion Because the DSCR3/GAPDH ratio of trisomy 21 syndrome fetuses is significantly higher than that of normal fetuses, the genomic DNA real‐time PCR technique may be a reliable and specific method for the rapid prenatal diagnosis of Down syndrome. Copyright © 2004 John Wiley & Sons, Ltd.
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Mental Retardation (MR), also referred as ‘Intellectual Disability’, ‘Mental Deficit’, ‘Mental Subnormality’ or ‘Mental Handicap’ means delay in mental development; it means an impairment of the intellectual processes of the mind, making it difficult for the person to cope with environment in which they find themselves. The prevalence rate of mental retardation in the general population is estimated to be approximately 1% to 3%. It has been estimated that environmental factors and genetic factors play equal role. Chromosomal abnormalities (numerical and structural) are responsible for up to 28% in mental retardation with the high prevalence of Down Syndrome (DS). In general, over 95% of Down syndrome individuals possess free trisomy 21. Translocations of chromosome 21 (D or G group) were found in 2-4% while 1-2% are mosaics. The present study was aimed to investigate the chromosomal abnormalities in 100 mentally retarded cases. The frequency of regular trisomy was 18 (18%). The frequency of Robertsonian translocations 46, XY, t (21;21) +21 and 46, XY, t (14;21), +21 were 3 (3%) and 1 (1%) respectively. The frequency of mosaic 46, XY/47, XY, + 21 was 2 (2%). Since the study is already published without detailed case studies, the present paper discusses each case in detail.
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Amniocentesis
Chorionic villus sampling
False positive rate
Screening test
False Negative Reactions
Prenatal screening
Triple test
Second trimester
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Abstract Combined first trimester screening using pregnancy associated plasma protein‐A (PAPP‐A), free β‐human chorionic gonadotrophin, and nuchal translucency (NT), is currently accepted as probably the best combination for the detection of Down syndrome (DS). Current first trimester algorithms provide computed risks only for DS. However, low PAPP‐A is also associated with other chromosome anomalies such as trisomy 13, 18, and sex chromosome aneuploidy. Thus, using currently available algorithms, some chromosome anomalies may not be detected. The purpose of the present study was to establish a low‐end cut‐off value for PAPP‐A that would increase the detection rates for non‐DS chromosome anomalies. The study included 1408 patients who underwent combined first trimester screening. To determine a low‐end cut‐off value for PAPP‐A, a Receiver–Operator Characteristic (ROC) curve analysis was performed. In the entire study group there were 18 cases of chromosome anomalies (trisomy 21, 13, 18, sex chromosome anomalies), 14 of which were among screen‐positive patients, a detection rate of 77.7% for all chromosome anomalies (95% CI: 55.7–99.7%). ROC curve analysis detected a statistically significant cut‐off for PAPP‐A at 0.25 MoM. If the definition of screen‐positive were to also include patients with PAPP‐A<0.25 MoM, the detection rate would increase to 88.8% for all chromosome anomalies (95% CI: 71.6–106%). This low cut‐off value may be used until specific algorithms are implemented for non‐Down syndrome aneuploidy. Copyright © 2001 John Wiley & Sons, Ltd.
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To evaluate the potential of maternal serum A Disintegrin And Metalloprotease 12-S (ADAM12s) as an additional marker for the combined test in the Dutch first-trimester national Down syndrome (DS) screening program.Serum samples were collected between 2004 and 2007 as part of the national program. A total of 218 singleton cases of trisomy 21 (DS), 62 trisomy 18 (Edwards syndrome) and 29 trisomy 13 (Patau syndrome) were identified. All cases were matched with controls for gestation, maternal weight and maternal age. The serum concentration of ADAM12s was determined 'blind' to outcome and expressed in multiples of the gestation-specific median for controls (MoM).The median ADAM12s was 1.00 MoM in controls and in the DS cases at 8, 9, 10, 11, 12, 13 weeks it was 0.45 (n = 3), 0.73 (22), 0.74 (53), 0.85 (37), 0.92 (71), 1.06 (32) MoM, respectively. The median for trisomy 18 was 0.85 MoM and for trisomy 13 0.63 MoM.The ADAM12s MoM values were clearly reduced in early first-trimester for all trisomies. However, the screening performance for DS did not greatly improve adding ADAM12s. ADAM12s could be an additional biochemical marker for first-trimester screening for trisomies other than DS.
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