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UOG Journal Club: Meta-analysis of second-trimester markers for trisomy 21

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  • 1. UOG Journal Club: March 2013 Meta-analysis of second-trimester markers for trisomy 21M. Agathokleous, P. Chaveeva, L. C. Y. Poon, P. Kosinksi and K. H. Nicolaides Volume 41, Issue 3, Date: March 2013, pages 247–261 Journal Club slides prepared by Dr Asma Khalil (UOG Editor for Trainees)
  • 2. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Second-trimester markers for trisomy 21• Ventriculomegaly• Absent or hypoplastic nasal bones• Increased nuchal fold thickness• Intracardiac echogenic focus• Aberrant right subclavian artery• Echogenic bowel Trachea• Mild hydronephrosis ARSA• Shortening of femur or humerus Spine
  • 3. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Calculation of risk for trisomy 21 Background risk x LR of each marker Individual risk = a priori risk × LR1 × LR2 × LR3… Normal Tr 21 LR+ LR- LRc*Mild hydronephrosis 2.6% 17.1% 6.8 0.85 1.0Echogenic foci 4.4% 30.3% 6.4 0.75 1.0Short femur 5.2% 42.0% 7.9 0.62 1.5Echogenic bowel 0.6% 17.3% 21.2 0.87 3.0Nuchal fold >6 mm 0.6% 41.1% 53.1 0.67 10.0Major defect 0.7% 21.4% 33.0 0.79 5.0LRc* = LR isolated marker Nicolaides UOG 2003, Nyberg et al. Ultrasound Med 2001
  • 4. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 ObjectiveExamine the screening performance of second trimester sonographic markers for the detection of trisomy 21
  • 5. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Methodology Inclusion criteria Eligibility criteria• Studies reporting on the 1. 2 × 2 tables for diagnostic incidence of one or more performance could be markers in trisomy 21 and constructed euploid fetuses 2. Karyotype was unknown at the time of ultrasound• 1995 – September 2012 3. Chromosomal status was confirmed by karyotype or• GA at examination14-24 wk postnatal examination• Prospective and retrospective cohort studies• Case–control studies (for ARSA and absent/hypoplastic nasal bones)
  • 6. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Methodology• Methodological quality of the studies: Newcastle–Ottawa scale• Weighted independent estimation of DR, FPR, +ve LR (sensitivity/(1−specificity)) and –ve LR ((1−sensitivity)/specificity)• Heterogeneity between studies: Higgins’ I2 and Q-test• Explore the effect of heterogeneity: analysis for the whole dataset and in the subgroups (high risk and screening)
  • 7. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Results Definitions of the markers• Ventriculomegaly: ≥ 10 mm• Increased nuchal fold thickness: ≥ 6 mm• Echogenic bowel: equal echogenicity to that of bone• Mild hydronephrosis: renal pelvis AP diameter varied from 3 to 4 or 5 mm• Hypoplastic nasal bones: cut-off varied with gestation• Short femur or humerus: cut-off varied with gestation
  • 8. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013Marker DR FPR LR LR Isolated + ve – ve markerCardiac echogenic focus 24.4 3.9 5.8 0.80 0.95Ventriculomegaly 7.5 0.2 27.5 0.94 3.81Increased nuchal fold 26.0 1.0 23.3 0.80 3.79Echogenic bowel 16.7 1.1 11.4 0.90 1.65Mild hydronephrosis 13.9 1.7 7.6 0.92 1.08Short humerus 30.3 4.6 4.8 0.74 0.78Short femur 27.7 6.4 3.7 0.80 0.61ARSA 30.7 1.5 21.5 0.71 3.94 TracheaAbsent or hypoplastic NB 59.8 2.8 23.3 0.46 6.58 ARSA No markers LR 0.13 = 7.7 fold reduction Spine Meta-analysis 47 studies 1995–2012
  • 9. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Results Estimation of combined LR of multiple markers•The LR for trisomy 21 of individual isolated markers is derived by multiplying the+ve LR for the given marker by the –ve LR of each of all other markers• The same approach when any combination of ≥ two markers are detected e.g.with mild hydronephrosis (+ve LR 7.6) and ventriculomegaly (+ve LR 27.5), thecombined +ve LR is 209 (7.6 × 27.5). This must be multiplied by the combined -veLR of all other markers that were not present (0.8 × 0.8 × 0.9 × 0.8 × 0.7 × 0.5 =0.2) to derive a final combined LR of 31.6
  • 10. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Results Excel spreadsheet (online) allowing automated calculations of the LR for any given combination of the presence and absence of markers Present/Absent (choose from drop-down:Marker Present/Absent/Not known) LRIntracardiac echogenic focus Not known 1.00Mild hydronephrosis Not known 1.00Short femur Not known 1.00Echogenic bowel Not known 1.00Increased nuchal fold Not known 1.00Aberrant right subclavian artery Not known 1.00Absent or hypoplastic nasal bone Not known 1.00Ventriculomegaly Not known 1.00 LR for combination: 1.00 http://onlinelibrary.wiley.com/doi/10.1002/uog.12364/suppinfo
  • 11. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Results a) Echogenic foci b) Ventriculomegaly c) Nuchal fold thickness d) Echogenic bowel e) Hydronephrosis f) Short humerus g) Short femur h) ARSA i) Absent nasal bone j) Absent or hypoplastic nasal bone
  • 12. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks Ashoor et al., UOG 2013 Discussion• Heterogeneity in results between the studies explained by differences indesign and focus of individual studies• The problem of high heterogeneity was not overcome by sub-analysis ofdata (screening versus high-risk populations)• Studies published before 1995 were excluded (limited awareness)• GA 14–24 weeks: potential effect of GA on the incidence of the markers• The majority of the included studies only examined the value of individualmarkers. There are no studies that systematically examined the possibleinterrelationship between markers, and it is therefore assumed that theyare independent of each other, apart from short femur and humerus
  • 13. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Implications for practice1. There is a 7.7-fold reduction in risk for trisomy 21 if a systematic second-trimester ultrasound examination demonstrates the absence of all markers2. The detection of any one of the markers during the scan should alert the sonographer to look for all other markers3. The post-test odds is derived by multiplying the pre-test odds by the +ve LR for each detected marker and the -ve LR for each marker demonstrated to be absent4. There is only a small effect on modifying the pre-test odds in the case of most isolated markers (echogenic focus, echogenic bowel, mild hydronephrosis and short femur)
  • 14. Meta-analysis of second trimester markers for trisomy 21 Agathokleous et al., UOG 2013 Conclusions• The data from this meta-analysis and their interpretationcould guide clinical practice.• However, appropriate training, certification and regular auditare essential.

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