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UOG Journal Club: March 2013
     Meta-analysis of second-trimester markers for trisomy 21

M. 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)
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
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           1.0
Echogenic foci              4.4%        30.3%                6.4           0.75           1.0
Short femur                 5.2%        42.0%                7.9           0.62           1.5
Echogenic bowel             0.6%        17.3%                21.2          0.87           3.0
Nuchal fold >6 mm           0.6%        41.1%                53.1          0.67          10.0
Major defect                0.7%        21.4%                33.0          0.79           5.0

LRc* = LR isolated marker
                                                    Nicolaides UOG 2003, Nyberg et al. Ultrasound Med 2001
Meta-analysis of second trimester markers for trisomy 21
                      Agathokleous et al., UOG 2013




                           Objective

Examine the screening performance of second trimester
  sonographic markers for the detection of trisomy 21
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)
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)
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
Meta-analysis of second trimester markers for trisomy 21
                        Agathokleous et al., UOG 2013

Marker                          DR    FPR        LR      LR    Isolated
                                                + ve    – ve   marker
Cardiac echogenic focus        24.4    3.9      5.8     0.80    0.95
Ventriculomegaly                7.5    0.2      27.5    0.94    3.81
Increased nuchal fold          26.0    1.0      23.3    0.80    3.79
Echogenic bowel                16.7    1.1      11.4    0.90    1.65
Mild hydronephrosis            13.9    1.7      7.6     0.92    1.08
Short humerus                  30.3    4.6      4.8     0.74    0.78
Short femur                    27.7    6.4      3.7     0.80    0.61
ARSA                           30.7    1.5      21.5    0.71    3.94
                                                                                  Trachea
Absent 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
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), the
combined +ve LR is 209 (7.6 × 27.5). This must be multiplied by the combined -ve
LR 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
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)                 LR
Intracardiac echogenic focus                    Not known                 1.00
Mild hydronephrosis                             Not known                 1.00
Short femur                                     Not known                 1.00
Echogenic bowel                                 Not known                 1.00
Increased nuchal fold                           Not known                 1.00
Aberrant right subclavian artery                Not known                 1.00
Absent or hypoplastic nasal bone                Not known                 1.00
Ventriculomegaly                                Not known                 1.00

      LR for combination:                           1.00
        http://onlinelibrary.wiley.com/doi/10.1002/uog.12364/suppinfo
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
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 in
design and focus of individual studies
• The problem of high heterogeneity was not overcome by sub-analysis of
data (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 individual
markers. There are no studies that systematically examined the possible
interrelationship between markers, and it is therefore assumed that they
are independent of each other, apart from short femur and humerus
Meta-analysis of second trimester markers for trisomy 21
                          Agathokleous et al., UOG 2013


                  Implications for practice
1. There is a 7.7-fold reduction in risk for trisomy 21 if a systematic
   second-trimester ultrasound examination demonstrates the absence
   of all markers
2. The detection of any one of the markers during the scan should alert
   the sonographer to look for all other markers
3. 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 absent
4. 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)
Meta-analysis of second trimester markers for trisomy 21
                        Agathokleous et al., UOG 2013




                         Conclusions
• The data from this meta-analysis and their interpretation
could guide clinical practice.
• However, appropriate training, certification and regular audit
are essential.

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

  • 1. UOG Journal Club: March 2013 Meta-analysis of second-trimester markers for trisomy 21 M. 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 1.0 Echogenic foci 4.4% 30.3% 6.4 0.75 1.0 Short femur 5.2% 42.0% 7.9 0.62 1.5 Echogenic bowel 0.6% 17.3% 21.2 0.87 3.0 Nuchal fold >6 mm 0.6% 41.1% 53.1 0.67 10.0 Major defect 0.7% 21.4% 33.0 0.79 5.0 LRc* = 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 Objective Examine 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 2013 Marker DR FPR LR LR Isolated + ve – ve marker Cardiac echogenic focus 24.4 3.9 5.8 0.80 0.95 Ventriculomegaly 7.5 0.2 27.5 0.94 3.81 Increased nuchal fold 26.0 1.0 23.3 0.80 3.79 Echogenic bowel 16.7 1.1 11.4 0.90 1.65 Mild hydronephrosis 13.9 1.7 7.6 0.92 1.08 Short humerus 30.3 4.6 4.8 0.74 0.78 Short femur 27.7 6.4 3.7 0.80 0.61 ARSA 30.7 1.5 21.5 0.71 3.94 Trachea Absent 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), the combined +ve LR is 209 (7.6 × 27.5). This must be multiplied by the combined -ve LR 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) LR Intracardiac echogenic focus Not known 1.00 Mild hydronephrosis Not known 1.00 Short femur Not known 1.00 Echogenic bowel Not known 1.00 Increased nuchal fold Not known 1.00 Aberrant right subclavian artery Not known 1.00 Absent or hypoplastic nasal bone Not known 1.00 Ventriculomegaly 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 in design and focus of individual studies • The problem of high heterogeneity was not overcome by sub-analysis of data (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 individual markers. There are no studies that systematically examined the possible interrelationship between markers, and it is therefore assumed that they are 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 practice 1. There is a 7.7-fold reduction in risk for trisomy 21 if a systematic second-trimester ultrasound examination demonstrates the absence of all markers 2. The detection of any one of the markers during the scan should alert the sonographer to look for all other markers 3. 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 absent 4. 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 interpretation could guide clinical practice. • However, appropriate training, certification and regular audit are essential.