4. update on non-invasive prenatal testing
Post on 09-Jan-2017
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Update Screening performance
• T21, T18 and T13
• Combined test
• Quadruple test
NIPT • Current & proposed pathway
• Changes in choice behaviour
• Modelled performance
• Positive predictive values
• Changes to the cut-off
Twins • Vanishing twins
• Quad test twin factors
DQASS reports • Reporting T13/T18
• Changes to diagnostics
NIPT
Current policy
IPD
Combined test
Offer IPD
No further testing
Offer combined test
IPD
Combined test
Offer IPD or cf DNA No
further testing
cf DNA test
Offer IPD
Offer combined test
Choice
Screening result
Proposed policy
Choice
Screening result
Change
Existing Policy New Policy
Discussion: What changes to choice behaviour would we expect
Choice
Screening result
Change
Existing Policy New Policy
Choice behaviour
Current policy
Starting with 100,000 accepting testing here
• Assume a population of 100,000 screened at 12 weeks using the combined test
• Maternal age distribution of England and Wales 2011
• Expected number of trisomies at screening • Trisomy 21 271 • Trisomy 18 116 • Trisomy 13 37
Composition of screened population
Choice behaviour after a +ve result: modelled results
RiskP
r[A
ccept|R
isk]
0.0
0.2
0.4
0.6
0.8
1.0
1/150 1/50 1/20 1/10 1/5 1/2
Outcome N +ve N %
Normal 99,576 2,104 1,236 59
T21 271 234 137 59
T18 116 97 57 59
T13 37 27 16 59
100,000 2,462 1,446
Accept IPD
Age distribution of E&W 2011
Most of the previous work assumes that the proportions accepting IPD following a high risk results are independent of outcome. In practice the pregnancies with trisomies are the ones with higher risks so they choose IPD more often.
Choice behaviour after a +ve result: modelled results
Risk
Pr[
Accept|R
isk]
0.0
0.2
0.4
0.6
0.8
1.0
1/150 1/50 1/20 1/10 1/5 1/2
Outcome N +ve N %
Normal 99,576 2,104 1,143 54
T21 271 234 198 85
T18 116 97 84 86
T13 37 27 21 80
100,000 2,462 1,446 59
Accept IPD
Outcome N +ve N %
Normal 99,576 2,104 1,236 59
T21 271 234 137 59
T18 116 97 57 59
T13 37 27 16 59
100,000 2,462 1,446
Accept IPD
Choice depends on risk
Unrealistic assumptions
Realistic assumptions
Choice behaviour after a +ve result: modelled results
Risk
Pr[
Accept|R
isk]
0.0
0.2
0.4
0.6
0.8
1.0
1/150 1/50 1/20 1/10 1/5 1/2
Outcome N +ve N %
Normal 99,576 2,104 1,143 54
T21 271 234 198 85
T18 116 97 84 86
T13 37 27 21 80
100,000 2,462 1,446 59
Accept IPD
Outcome N +ve N %
Normal 99,576 2,104 1,236 59
T21 271 234 137 59
T18 116 97 57 59
T13 37 27 16 59
100,000 2,462 1,446
Accept IPD
Fewer IPDs in normal pregnancies
Unrealistic assumptions
Realistic assumptions
Choice behaviour dependent on risk: modelled results
Risk
Pr[
Accept|R
isk]
0.0
0.2
0.4
0.6
0.8
1.0
1/150 1/50 1/20 1/10 1/5 1/2
Outcome N +ve N %
Normal 99,576 2,104 1,143 54
T21 271 234 198 85
T18 116 97 84 86
T13 37 27 21 80
100,000 2,462 1,446 59
Accept IPD
Outcome N +ve N %
Normal 99,576 2,104 1,236 59
T21 271 234 137 59
T18 116 97 57 59
T13 37 27 16 59
100,000 2,462 1,446
Accept IPD
More women with affected pregnancies choose IPD
Unrealistic assumptions
Realistic assumptions
Choice behaviour new policy
IPD
Combined test
Offer IPD or cfDNA No further testing
cf DNA test
Offer IPD
Offer combined test
Risk
Pr[
Accept|R
isk]
0.0
0.2
0.4
0.6
0.8
1.0
1/150 1/50 1/20 1/10 1/5 1/2
IPD
IPD is chosen less often. cfDNA is chosen instead. Less harm.
Cf DNA instead
Choice behaviour new policy
IPD
Combined test
Offer IPD or cfDNA No further testing
cf DNA test
Offer IPD
Offer combined test
Risk
Pr[
Accept|R
isk]
0.0
0.2
0.4
0.6
0.8
1.0
1/150 1/50 1/20 1/10 1/5 1/2
No further testing
Cf DNA
IPD
Many choose cf DNA instead of nothing. More information.
Modelling
Numbers based on a population of 100,000 accepting screening
IPD
Combined test
Offer IPD or cfDNA No further testing
cf DNA test
Offer IPD
Offer combined test
Starting with 100,000 accepting testing here
Offer choice of cfDNA or IPD: modelled results
Outcome N +ve N %
Normal 99,576 2,104 1,143 54
T21 271 234 198 85
T18 116 97 84 86
T13 37 27 21 80
100,000 2,462 1,446 59
Accept IPD
Outcome N +ve N % N % N %
Normal 99,576 2,104 702 33 1,355 64 2,057 98
T21 271 234 170 73 58 25 228 98
T18 116 97 74 76 21 21 95 98
T13 37 27 18 66 9 32 26 98
100,000 2,462 964 39 1,443 59 2,407 98
Accept IPD Accept cfDNA Accept IPD or cfDNA
Offer IPD only (Current)
Offer choice of cfDNA or IPD
Offer choice of cfDNA or IPD: modelled results
Outcome N +ve N %
Normal 99,576 2,104 1,143 54
T21 271 234 198 85
T18 116 97 84 86
T13 37 27 21 80
100,000 2,462 1,446 59
Accept IPD
Outcome N +ve N % N % N %
Normal 99,576 2,104 702 33 1,355 64 2,057 98
T21 271 234 170 73 58 25 228 98
T18 116 97 74 76 21 21 95 98
T13 37 27 18 66 9 32 26 98
100,000 2,462 964 39 1,443 59 2,407 98
Accept IPD Accept cfDNA Accept IPD or cfDNA
Offer IPD only (Current)
Offer choice of cfDNA or IPD
Fewer IPDs in unaffected pregnancies
Offer choice of cfDNA or IPD: modelled results
Outcome N +ve N %
Normal 99,576 2,104 1,143 54
T21 271 234 198 85
T18 116 97 84 86
T13 37 27 21 80
100,000 2,462 1,446 59
Accept IPD
Outcome N +ve N % N % N %
Normal 99,576 2,104 702 33 1,355 64 2,057 98
T21 271 234 170 73 58 25 228 98
T18 116 97 74 76 21 21 95 98
T13 37 27 18 66 9 32 26 98
100,000 2,462 964 39 1,443 59 2,407 98
Accept IPD Accept cfDNA Accept IPD or cfDNA
More information about trisomies
Offer IPD only (Current)
Offer choice of cfDNA or IPD
Positive predictive values
Prevalence 0.3% FPR = 0.2% DR = 100%
Screened population of 1,000 Screen positives
Positive predictive values
PPV = 3/5 = 60%
Practical Session: PPV of NIPT in the high risk group
• The prevalence of trisomies in the combined tests with risks if 1 in 150 or higher is estimated to be 7.5%
• Assume that the FPR of cfDNA is 0.2% and its DR is 99%
• What is the PPV of cf DNA?
Prevalence 7.5% FPR = 0.2% DR = 99%
Combined/Quadruple test risk ≥ 1 in 150
Practical Session: PPV of NIPT in the high risk group
PPV = 0.075×0.99/(0.075×0.99 + 0.925×0.002) = 0.976
FPR = 0.2% DR = 99%
NIPT Positive
Positive predictive values of cf DNA tests
For cfDNA test assume FPR = 0.2% DR = 99%
In the general population (E&W 2011)
In 20 year olds
In 40 year olds
In women who screen positive
In women with risks of 1 in 5
In women with risks of 1 in 150
Independent of other factors
PPV = 60%
PPV = 33%
PPV = 88%
PPV = 98%
PPV = 99%
PPV = 77%
Cf DNA testing fetal fraction
• Performance of cf DNA depends on fetal fraction
• There are differences amongst providers about the use of fetal fraction
• Some providers report inconclusive or failed test results in cases where the fetal fraction is too low (e.g. below 4%)
Sparks AB, Struble CA, Wang ET, et al. Noninvasive prenatal
detection and selective analysis of cell-free DNA obtained from
maternal blood:
evaluation for trisomy 21 and trisomy 18. Am J Obstet Gynecol
2012;206:319.e1-9.
Canick, Palomaki Prenatal Diagnosis 2013, 33, 667–674
DNA testing and estimated fetal fraction
Fetal fractions in high risk pregnancies
• For larger fetal fractions (10%+) cf DNA dominates other markers and is close to diagnostic
• For lower fetal fractions performance deteriorates
• Pregnancies with very high combined test risks for T13/T18 would be predicted to have low fetal fractions because of reduced PAPP-A and hCG β
Number of second stage tests 000's
Tri
so
my 2
1 p
reg
nan
cie
s c
overe
d %
(n
)
0 10 20 30 40 50 60 70 80 90 100
0
10
20
30
40
50
60
70
80
90
100
(0)
(27)
(54)
(81)
(108)
(136)
(163)
(190)
(217)
(244)
(271)
10
150
500
10002000
Trisomy 21
Proposed policy
What if we change the cut-off
Trisomy 18
Number of second stage tests 000's
Tri
so
my 1
8 p
reg
nan
cie
s c
overe
d %
(n
)
0 10 20 30 40 50 60 70 80 90 100
0
10
20
30
40
50
60
70
80
90
100
(0)
(12)
(23)
(35)
(46)
(58)
(70)
(81)
(93)
(104)
(116)
10
150
5001000
2000
Proposed policy
Trisomy 13
Number of second stage tests 000's
Tri
so
my 1
3 p
reg
nan
cie
s c
overe
d %
(n
)
0 10 20 30 40 50 60 70 80 90 100
0
10
20
30
40
50
60
70
80
90
100
(0)
(4)
(7)
(11)
(15)
(18)
(22)
(26)
(30)
(33)
(37)
10
150
500
1000
2000
Proposed policy
Screening performance
Performance of combined testing
• Predictive models
• Newcastle study
• FMF Validation study
Modelled
Age T21 T18 T13
20 0.9% 76% 70% 58%
25 1.0% 77% 70% 59%
30 1.3% 80% 71% 62%
35 2.6% 85% 84% 68%
40 8.2% 92% 91% 80%
45 24.0% 97% 97% 91%
All 2.2% 86% 84% 72%
Detection RatesFPR
Newcastle
T21 T18 T13
All ages 2.30% 84% 97% 82%
(n =10,000) (n=238) (n=72) (n=28)
Detection RatesFPR
Performance of combined testing: current policy
Term risk for T21 Term risk for T18 or T13 Risk cut-off 1 in 150 Age distribution of E&W 2011
Performance of combined testing: validation
FMF Screening cohort - crude rates; separate term risks for T21 and (T13 or T18) compared to the same risk cut-off
Risk
≥ T 21 T 18 T 13 T21+T18+T13 Turner Triploidy Other Normal All pregnancies
432 166 56 654 63 35 118 108,112 108,982
1 in 2 199 107 19 325 25 22 10 93 475
46.1 (41.3, 50.9) 64.5 (56.7, 71.7) 33.9 (21.8, 47.8) 49.7 (45.8, 53.6) 39.7 (27.6, 52.8) 62.9 (44.9, 78.5) 8.5 (4.1, 15) 0.1 (0.1, 0.1) 0.4 (0.4, 0.5)
1 in 5 270 129 28 427 43 27 18 269 784
62.5 (57.7, 67.1) 77.7 (70.6, 83.8) 50 (36.3, 63.7) 65.3 (61.5, 68.9) 68.3 (55.3, 79.4) 77.1 (59.9, 89.6) 15.3 (9.3, 23) 0.2 (0.2, 0.3) 0.7 (0.7, 0.8)
1 in 10 308 140 35 483 51 29 27 506 1,096
71.3 (66.8, 75.5) 84.3 (77.9, 89.5) 62.5 (48.5, 75.1) 73.9 (70.3, 77.2) 81 (69.1, 89.8) 82.9 (66.4, 93.4) 22.9 (15.7, 31.5) 0.5 (0.4, 0.5) 1 (0.9, 1.1)
1 in 25 346 148 40 534 59 30 43 1,093 1,759
80.1 (76, 83.8) 89.2 (83.4, 93.4) 71.4 (57.8, 82.7) 81.7 (78.5, 84.5) 93.7 (84.5, 98.2) 85.7 (69.7, 95.2) 36.4 (27.8, 45.8) 1 (1, 1.1) 1.6 (1.5, 1.7)
1 in 50 364 153 43 560 60 32 57 1,866 2,575
84.3 (80.5, 87.6) 92.2 (87, 95.8) 76.8 (63.6, 87) 85.6 (82.7, 88.2) 95.2 (86.7, 99) 91.4 (76.9, 98.2) 48.3 (39, 57.7) 1.7 (1.6, 1.8) 2.4 (2.3, 2.5)
1 in 100 383 154 45 582 62 33 61 3,227 3,965
88.7 (85.3, 91.5) 92.8 (87.7, 96.2) 80.4 (67.6, 89.8) 89 (86.3, 91.3) 98.4 (91.5, 99.96) 94.3 (80.8, 99.3) 51.7 (42.3, 61) 3 (2.9, 3.1) 3.6 (3.5, 3.8)
1 in 150 395 154 48 597 62 34 61 4,407 5,161
91.4 (88.4, 93.9) 92.8 (87.7, 96.2) 85.7 (73.8, 93.6) 91.3 (88.9, 93.3) 98.4 (91.5, 99.96) 97.1 (85.1, 99.9) 51.7 (42.3, 61) 4.1 (4, 4.2) 4.7 (4.6, 4.9)
1 in 200 401 155 49 605 62 34 63 5,523 6,287
92.8 (90, 95.1) 93.4 (88.5, 96.6) 87.5 (75.9, 94.8) 92.5 (90.2, 94.4) 98.4 (91.5, 99.96) 97.1 (85.1, 99.9) 53.4 (44, 62.6) 5.1 (5, 5.2) 5.8 (5.6, 5.9)
1 in 300 407 156 49 612 62 34 65 7,548 8,321
94.2 (91.6, 96.2) 94 (89.2, 97.1) 87.5 (75.9, 94.8) 93.6 (91.4, 95.3) 98.4 (91.5, 99.96) 97.1 (85.1, 99.9) 55.1 (45.7, 64.3) 7 (6.8, 7.1) 7.6 (7.5, 7.8)
1 in 500 413 160 51 624 62 34 71 10,898 11,689
95.6 (93.2, 97.3) 96.4 (92.3, 98.7) 91.1 (80.4, 97) 95.4 (93.5, 96.9) 98.4 (91.5, 99.96) 97.1 (85.1, 99.9) 60.2 (50.7, 69.1) 10.1 (9.9, 10.3) 10.7 (10.5, 10.9)
1 in 1,000 422 162 53 637 63 34 81 17,457 18,272
97.7 (95.8, 98.9) 97.6 (93.9, 99.3) 94.6 (85.1, 98.9) 97.4 (95.9, 98.5) 100 (94.3, 100) 97.1 (85.1, 99.9) 68.6 (59.5, 76.9) 16.1 (15.9, 16.4) 16.8 (16.5, 17)
Abnormal Karyotype
Performance of quadruple testing
Term risk for T21 Risk cut-off 1 in 150 Age distribution of E&W 2011
Age FPR T21 T18 T13
20 1.2% 64% 1% 12%
25 1.3% 66% 2% 13%
30 2.0% 71% 2% 16%
35 4.7% 80% 4% 23%
40 13.1% 91% 10% 37%
45 32.2% 97% 24% 56%
All 3.3% 82% 8% 29%
Detection Rates
Discussion: Vanishing Twins
Prevalence 21-30% (Sampson & de Crespigny, 1992)
First trimester vanishing twins
All Vanishing Twins Empty Twin Sac Singleton Controls
n 193 76 1,361
Free ß-hCG Median MoM 1.024 0.968 0.983
PAPP-A Median MoM 1.317 1.04 0.964
Sampson A, de Crespigny LC. Vanishing twins: the frequency of spontaneous fetal reduction of a twin pregnancy. Ultrasound Obstet
Gynecol. 1992 Mar 1. 2(2):107-9.
Suppose risks are calculated without any adjustments for twins.
What might be expected to happen to the risks of trisomies in a vanishing twin?
Is the biochemistry useful?
If so, how should the biochemistry be interpreted?
Data from Spencer.
Second trimester twin effects
1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4
Cycle 18
Cycle 19
Pooled
Second trimester twin effect: AFP
MoM
Spencer 2005 – Multiple Pregnancy: Epidemiology, Gestation & Perinatal Outcome (Blickstein & Keith eds.)
Spencer, 2005
1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4
Cycle 18
Cycle 19
Pooled
Second trimester twin effect: hCG
MoM
1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4
Cycle 18
Cycle 19
Pooled
Second trimester twin effect: hCG β
MoM
1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4
Cycle 18
Cycle 19
Pooled
Second trimester twin effect: uE3
MoM
MoM
1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 3 3.2 3.4
Cycle 18
Cycle 19
Pooled
Second trimester twin effect: Inhibin
MoM
DQASS Reports: Reference distribution
DQASS Reports: Trisomies 18 and 13
Reporting
Laboratory reports
• Choice of test (Table/Bar Chart/Pie Chart)
• Screen positive rate overall (+ve = Any risk ≥ 1 in 150)
Cycle reports • SPRs by choice of test and overall
DQASS Reports: MoM diagnostics
Spot the difference
Robust DQASS diagnostics Geometric Mean Sample Median Trimmed geometric mean
Discussion
• The current diagnostics (geometric means) are affected by outliers and skewness
• The difference between DQASS diagnostics and the sample medians has been a source of considerable discussion with some laboratories
• We need to use mean log MoMs (i.e. geometric means) for CUSUM charts and flags
• Should we start using trimmed MoM diagnostics?
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