howard cuckle nordic integrate cfdna

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