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NIPT – an update
JORDANIAN SOCIETY OF OBSTETRICIAN AND GYNECOLOGISTS
AMMAN, JORDAN
September 1st, 2016
Bo Jacobsson
Professor, MD, PhD,
Department of Obstetrics and Gynecology
Sahlgrenska University Hospital
Gothenburg, Sweden
Senior Reseracher
Norwegian Institute of Public Health
Oslo, Norway
Overview of
of the
Overview
thetalk
talk
1. General population results
2. Reduce the price; different methods
3. More than trisomies?
4. Some important points we already knew 2015
5. Future
Overview of
of the
Overview
thetalk
talk
1. General population results
Identify T21
Postive test rate
that need
invasive test
1
Maternal age ≥ 35y
2
Combiend test (nuchal translusency +
PAPP-A and S-HCG)
90%
3
Cellfree fetal DNA NIPT
>99%
30%
100%
5%
<0.1%
T21
T18
T13
Positive predictive value on the
incidence of the condition
100%
Prevalence = 1.00%
90%
Sensitivity is set to
99% in all examples
80%
Prevalence = 0.5%
70%
60%
50%
Prevalence = 0.1%
40%
30%
20%
Prevalence = 0.01%
10%
0%
97%
98%
Specificity%
99%
99.9%
The New England Journal of Medicine 2015
The New England Journal of Medicine 2015
The New England Journal of Medicine 2015
Systematic search
Evidence grading according to GRADE
882 abstracts
429 abstracts
excluded
453 articles
reviewed in full text
399 papers
excluded
Low quality
23 articles
Intermediate
quality
31 articles
High quality
0 articles
Moderate scientific support
Moderate scientific support
Moderate scientific support
Limitied scientific support
NIPT
How
good is
the test?
Sensitivity
What
does this
mean?
Positive predictive value
Overview of
of the
Overview
thetalk
talk
2. Reduce the price; different methods
Overview
of the
talkwas expected
Not the decrease
in costs
that
1. Expensive technology
2. One dominating company
3. Technique development
© Bo Jacobsson
Counting principle of DNA
sequencing for aneuploidy
Maternal and fetal
DNA fragments
Sequencer
”reads”
the DNA
21
x
Genome map
21
y
x
”Reads” mapped to
reference genome and
assigned a chromosome of
origin
Counting principle of DNA
sequencing for aneuploidy
Maternal and fetal
DNA fragments
Sequencer
”reads”
the DNA
21
x
After millions
of reads…..
Genome map
21
y
x
”Reads” mapped to
reference genome and
assigned a chromosome of
origin
SMART NIPT - VANADIS
No amplification
No PCR
No consumables
No bioinformatics
Cheaper
SMART
NIPT -–
VANADIS
Smart
NIPT
No PCR
No Pre-PCR or post PCR requirements
SMART NIPT - VANADIS
SMART NIPT - VANADIS
Proof of principle
presented
Clinical trail
Finland, Sweden
Including Sahlgrenska
Overview of
of the
Overview
thetalk
talk
3. More than trisomies?
Deletions and Duplications
Be very careful when offered on the NIPT panel
– take it out from the offer of the companies.
Spectrum of Genetic Disease
Autosomal
recessive
Autosomal
dominant
X-linked
Chromosomal
Congenital
malformations
European Journal of Human Genetics (2012) 20, 521-526
Spectrum of chromosomal disorders
Others
45X
TXY
T21
T13
T18
European Journal of Human Genetics (2012) 20, 521-526
© Bo Jacobsson
© Bo Jacobsson
© Bo Jacobsson
© Bo Jacobsson
Snp-based Microdeletion & Aneuploidy RegisTry
The Panorama 22q11.2 Screening Registry
August 2016
Bo Jacobsson
22q11
10 000 women should be recruited
Sahlgrenska about to enter
© Bo Jacobsson
Registry Design
•
Multi-center prospective observational study/Registry
•
Track birth outcomes and perinatal correlates to the Panorama prenatal screening
test in the general population among ten thousand women.
•
Primary objective: To determine prospectively the performance of SNP based NIPT for the 22q11.2
microdeletion syndrome (PPV, specificity, and sensitivity)
•
Sample types collected: maternal blood samples, placenta, baby samples (blood
spots or buccal swab)
Current Study Progress
•
•
•
Launched April 2015
12 sites currently
recruiting across many
countries
>3000 participants
recruited
Enrollment
Current
To be recruited
Overview of
of the
Overview
thetalk
talk
4. Some important points we already knew 2015
Three parallel developments:
1.
NIPT with higher sensitivity, specificity and PPV
2.
Combiende test (KUB) cover more the trisomies
3.
Invasive procedures might be performed to a lover risk
than we believed
23.4% not
decteced by NIPT
Ultrasound Obstet Gynecol 2014; 43: 265-271
Obstet Gynecol 2014; 124:979-86
16.9% not
detected by NIPT
Response time and response rate
Response time:
5-9 working days
Response rate:
2 – 6 % no response rate at first sampling
50-75% additional responses at the second
What to do with the rest?
Intention to diagnose!!
Intension to diagnose example
TEST +
TEST -
Test 0
True +
9
1
2
12
True -
5
950
33
988
951
35
1000
14
Sensitivity (standard): 1/10=90%
Sensitivity (intension to diagnose): 3/12=75%
Proportion of Samples Returning a
Result by Gestational Age
Pergament et al (Obstet Gynecol 2014;124:210-8)
For sex determination very high test
performance
For sex chromosomal aberrations
not so good
Monogenic disease
Positive development
Potential problems with NIPT
Week 10
Week 12
Amniocentensis might be recommended
Week 15
Overview of
of the
Overview
thetalk
talk
5. Future
Three perspectives
Today
Fetal rhesus factor (dD)
Fetal gender
cffDNA (Cell free fetal DNA) in maternal plasma for fetal T 21 and T 18 (high risk)
Short Perspective – 2-5 years
Better T18 and T13 test
cffDNA in maternal blood for detection of fetal syndromes and monogenic
diseases
Somewhat longer perspective – 5-15 years
Cancer screening
Diagnostic tool
Don’t forget!!!
ALL POSITIVE NIPT SHOULD
BE FOLLOWED UP BY
AN INVASTIVE PROCEDURE
Thanks
Overview
of the talk
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Bo Jacobsson #BoJacobsson