howard cuckle nordic integrate cfdna
TRANSCRIPT
Gothenburg, April 2015 Howard Cuckle
Integration of cfDNA into current screening strategies
Traditionalscreening
7 8 9 10 11 12 13 14 15 16 17 18 19 20 Gestational age
� Quad � Combined
0%
20%
40%
60%
80%
100%
Positive rate
� Combined � Quad
0%
20%
40%
60%
80%
100% Prospective (208,000)
Positive rate
Model predicted
� Combined
0%
20%
40%
60%
80%
100% Prospective (208,000)
Positive rate
Model predicted
� Combined
0%
20%
40%
60%
80%
100%Positive rate
Down’s syndrome Edwards’ & Patau’s syndrome
Cell-free DNA
screening
v High risk pregnancies
v Thirteen large trials
v Sampled pre-CVS/amniocentesis
v T21=859
v Non-T21=10,548
0%
20%
40%
60%
80%
100%
� Combined
Positive 99.3%
0.12%
cfDNA
Ø American College of Obstetricians and Gynecologists Society for Maternal-Fetal Medicine
Ø Society of Obstetricians and Gynaecologists of Canada
Ø National Society of Genetic Counselors (USA)
Ø American College of Medical Genetics and Genomics
Ø International Society for Prenatal Diagnosis
Ø Italian College of Fetal Maternal Medicine
Ø International Society of Ultrasound in Obstetrics and Gynecology
7 8 9 10 11 12 13 14 15 16 17 18 19 20 Gestational age
cfDNA
Cost neutral or better
Down’s syndrome
Other
Sub-chromosome Whole chromosome
Sex chromosomes
Births – screen positive
Edwards’ & Patau’s
Down’s syndrome 99.3% Other whole chromosome ~75% Sub-chromosome ~10% Fetal loss 0%
Down’s syndrome 100% Other chromosomal 100% Fetal loss 0.5%
0% 20% 40% 60% 80% 100%
Chetty et al, 2013
Shah et al, 2014
Chan et al, 2015
� Combined
cfDNA
® Routine
v General risk pregnancies
v Seven trials
v Sampled at screening
v T21=231
v Non-T21=34,614
0%
20%
40%
60%
80%
100%
� Combined
Positive 100%
0.05%
cfDNA
NT scan………………...$150
PAPP-A/free-β hCG…....$50
~
CVS & PND……………$1500
~
cfDNA...………..$1500-$2500
cfDNA…...………..$300-$900
$0
$2
$4
$6
$8
$10
$12
$14
$16
T21 avoided (million)
Lifetime costs
cfDNA unit cost $1500 $900 $300 $2500 $600
® Routine
� Combined ® Routine
$0
$2
$4
$6
$8
$10
$12
$14
$16
T21 avoided (million)
Lifetime costs
cfDNA unit cost $1500 $900 $300 $2500 $600
® Routine
� Combined
cfDNA
cfDNA
Contingent [ ® Routine
82
84
86
88
90
92
94
96
98
100
10 11 12 13 14 15 16 17 18 19 20
cfDNA (%)
Detection rate (%)
Contingent [
� Combined
® Routine
82
84
86
88
90
92
94
96
98
100
10 11 12 13 14 15 16 17 18 19 20
cfDNA (%)
Detection rate (%)
Contingent [
� Combined
® Routine
$0
$2
$4
$6
$8
$10
$12
$14
$16
T21 avoided (million)
Lifetime costs
cfDNA unit cost $1500 $900 $300 $2500 $600
Contingent (20%) [
Addition of PlGF and AFP
0%
20%
40%
60%
80%
100%
� Combined � Combined Plus
Positive rate
82
84
86
88
90
92
94
96
98
100
10 11 12 13 14 15 16 17 18 19 20
cfDNA (%)
Detection rate (%)
Contingent Plus [
� Combined
® Routine
82
84
86
88
90
92
94
96
98
100
10 11 12 13 14 15 16 17 18 19 20
cfDNA (%)
Detection rate (%)
Contingent Plus [
� Combined
® Routine
$0
$2
$4
$6
$8
$10
$12
$14
$16
T21 avoided (million)
Lifetime costs
cfDNA unit cost $1500 $900 $300 $2500 $600
Contingent Plus (20%) [
$0
$2
$4
$6
$8
$10
$12
$14
$16
T21 avoided (million)
Lifetime costs
cfDNA unit cost $1500 $900 $300 $2500 $600
Contingent Plus (13%) [
cfDNA cfDNA 0.2%
20% 19.8%
7 8 9 10 11 12 13 14 15 16 17 18 19 20 Gestational age
cfDNA cfDNA 0.1%
19.9%
D 2.4% ! 5.1 business days D 1.9% & 27% ! 6.7 calendar days D 6.4% & 36% ! 6.7-9.2 calendar days
D0.1%
No-call options v Invasive PND
v No further action
v Repeat
v Deeper sequencing
v Risk assessment
98.0%
98.5%
99.0%
99.5%
100.0%False+
True-
False-
True+
Trisomy 21
Non-T21
98.0%
98.5%
99.0%
99.5%
100.0%False+
True-
False-
True+
Trisomy 21
Non-T21
T21 x900
98.0%
98.5%
99.0%
99.5%
100.0%False+
True-
False-
True+
Trisomy 21
Non-T21
not-T21 /140
Aneuploidy
Euploidy
cfDNA Prior
Z-score
FF
Depth
2.00
2.05
2.10
2.15
2.20
2.25
2.30
0 5 10 15 20 25 30
Cr21/Genome
%Fetal
3FF+2(1-FF)
2.5FF+2(1-FF) Single
Concordant twins
Discordant twins
0%
20%
40%
60%
80%
100%
NT only
Positive 95.3% (41/43)
0.00% (0/897)
cfDNA
7 8 9 10 11 12 13 14 15 16 17 18 19 20 Gestational age
Cardiac defects Down’s syndrome
cfDNA
7 8 9 10 11 12 13 14 15 16 17 18 19 20 Gestational age
Spina bifida Down’s syndrome
cfDNA
7 8 9 10 11 12 13 14 15 16 17 18 19 20 Gestational age
Pre-eclampsia Down’s syndrome
cfDNA
0%
20%
40%
60%
80%
100%
Early Late Early Late
Positive rate