Non-invasive Prenatal Trisomy test Leon Liang BGI Health Europe A safe prenatal testing for fetal...
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Non-invasive Prenatal Trisomy test
Leon Liang
BGI Health Europe
A safe prenatal testing for fetal chromosomal aneuploidy
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Common fetal aneuploidy
• Trisomy 21 (1/700-750)• 80% reach to adulthood
Down syndrome
• Trisomy 18 (1/6000)• <10% reach to 1 year old
Edwards syndrome
• Trisomy 13 (1/10000-20000)• Most die after birth
Patau syndrome
Others: Turner syndrome (XO), Klinefelter syndrome (XXY), triple X syndrome (XXX), etc.
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Current screening & diagnostic tests
Method Invasive or Noninvasive
Pregnancy(weeks) Risks and detection rate
First-trimester serum screening Non-invasive 11-13 65%-70% detection rate*
Second-trimester serum screening Non-invasive 15-19 69%-81% detection rate*
Fetal nuchal translucency (NT) Non-invasive 11-13 64%-70% detection rate*
Serum integrated screen Non-invasive 11-13 & 15-19 85%-88% detection rate*
Serum integrated screen + NT Non-invasive 11-13 & 15-19 94%-96% detection rate*
Amniocentesis Invasive 16-21 0.5-1% miscarriagePermission required
Chorionic villi sampling (CVS) Invasive 10-13 1-2% miscarriagePermission required
Percutaneous umbilical blood sampling (PUBS) Invasive 18-24 1-2% miscarriage
Permission required
* Data present in 5% false positive rateFergal D, Jacob A, et al. The New England Journal of Medicine, 2005
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Screening tests Diagnostic tests
• Serum biochemical test; ultrasound scan
• Non-invasive• Cheap• Less accurate • Low detection rate • High false positive rate
• Karyotyping (G-banding or FISH)
• Invasive• Expensive• Highly accurate • High detection rate • Low false positive rate
NIFTY
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What’s NIFTY test?
Non-Invasive Fetal TrisomY
A superior screening test
High detection rate and low false positive rate
Non-invasive method based on NGS and bioinformatics
Analysis of fetal cell free DNA in maternal plasma
Evaluate the likelihood of fetal trisomy 21, 18, and 13
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Features of NIFTY
Accurate
Safe
Early
Optimization
Simple
New detection technology based on NGS;Sensitivity and specificity > 99%
No risks of intrauterine infection and miscarriage
Fetal trisomy risk can be evaluated as early as 12 gestational week
Reduce clinical pressure of unnecessary invasive tests
Only 5ml of peripheral blood is needed; easy to handle in clinical practice
NIFTY
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Scientific discovery
Fundamental Features of Cell-Free Fetal DNA
• Short fragments of 145-200bp, derived from placental trophocytes
• 970 times greater than fetal cells DNA in maternal blood.
• Detectable in maternal plasma from the 5th week of gestation.
• Concentration increase as the gestation age grows
• Disappears soon after childbirth.
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Sequencing revolution
TA
G
CC
TA
G
CC
1. incorporation 1. Incorporation2. Elute and scan
1. Incorporation2. Elute and scan 3. Cleavage
Sanger
NGS
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Principle of NIFTY
Chr6Chr18ChrXChr21Chr7Chr13Chr11ChrY…
..
Plasma DNA
Total cfDNA sequencing
Reads count
Normal T-21
50 bp
Bioinformatics
Reads alignment
Normal
T-21
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X YBioinformatics
analysis
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– Validation of the NIFTY in predicting the fetal risk of trisomy 21, 18, and 13 in high risk population by a double blind test
– Evaluation of sensitivity and specificity of the NIFTY by comparing to karyotyping result (clinical gold standard)
– provide supports for large-scale test in real clinical setting
Clinical validation in 3464 samples
3464 singleton pregnancies with high risk of T21, T18, T13
Plasma DNA from maternal peripheral blood
NIFTY test
Karyotyping by AF, CVS, Cord blood
Double blind
Calculate sensitivity and specificity
Bioinformatics analysis
• Study design and aim:
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NIFTY results in 3464 samples
T21 T18 T13
NIFTY positive 189 64 10
Karyotyping positive 188 63 10
False positive No. 1* 1* 0
False Negative No. 0 0 0
Sensitivity 100.00% 100.00% 100.00%
Specificity 99.97% 99.97% 100%
False Positive Rate 0.03% 0.029% 0.00%
False Negative Rate 0.00% 0.00% 0.00%Positive Predictive Rate 99.49% 98.44% 100.00%
*caused by insufficient sequencing depth
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Large scale clinical test (2009-2011)
Qualified maternal blood samples (n=11184)
Unable to produce results (n=79; failed DNA extraction, library construction, or sequencing)
Pregnant women with NIFTY results (n=11105)
Positive (n=190) Negative (n=10915)
0.7% of all samples
99.3% of all samples
• Gestational week from 9 – 28 weeks, averagely 20 weeks
• Maternal age from 18 – 45 years, averagely 31 years
• 4522 screening test high risk pregnancies
• 2426 screening test low risk pregnancies
• 2720 other high risk factors (AMA, abnormal NT, previous abnormal pregnancy, etc.)
• 1387 screening not done
Shan Dan, et al., Prenatal Diagnosis, 2012: p. 1-8.
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NIFTY results in 11105 samples
No. of casesPositive Results
Negative resultsT21 T18 T13
NIFTY 11,105 140 42 0 10915
Karyotyping 182 + 2818 139 41 0 2818
False positive rate 0.03% 0.03% n/a
False negative rate 0% 0% n/a
Detection rate 100% 100% n/a
Specificity 99.96% 99.96% n/a
Shan Dan, et al., Prenatal Diagnosis, 2012: p. 1-8.
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A T21 case was missed by biochemical screening
Sample ID: PDP10003761
Age: 31
Screening test: 1/510( Low
risk)NIFTY: T21
Karyotyping: 47, XX, +21
15
Other rare aneuploidies
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T9
Sample ID: PDB11AJ00026
Age: 41
NIFTY: T9
Karyotyping: T9
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T16
Sample ID: PDB11AJ00783
Age: 30
NIFTY: T16
FISH: T16
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Mosaic T21
Sample ID: PDB12AO00267
Age: 38
NIFTY: T21
Karyotyping: 47, XX, +21 (88%)
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T21-T7-XXY complex placental mosaic
Sample ID: PDB12AL00732
Age: 37
NIFTY: T21-T7-XXY/XY
Karyotyping: CVS T21-T7-XXY/XY; AF euploid
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NIFTY clinical pipeline
AMA, Previous affected fetus,Recurrent miscarriage,Aneuploidy background
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Test workflow
Pre-test counseling
Blood collection Bar-coding Plasma
preparation
Laboratory testing
Bioinformatics analysis
Report delivery
Post-test counseling
Hospital
BGI Clinical Laboratories: 10 days
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22
Sample Management System
Unique Identification Sample Location Storage Capability
Effective lab space separation
Progressively decreased pressure
Restricted traffic flow
Laboratory System
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NIFTY is not suitable for
Detection of balanced rearrangements and low level of mosaicism
The pregnant woman is a chromosomal aneuploidy carrier
If either of the parent has chromosomal structural abnormalitiese.g. duplication, deletion, translocation, etc.
If the pregnant woman receives allogenic DNA importation prior to NIFTYe.g. blood transfusion, transplantation, stem cell therapy, etc.
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Report
Genetic testing report
Low risk: the fetus is unlikely to be T21, T18, or T13. No special medical procedure is recommended. Routine prenatal checks is suggested.
High risk: the fetus is likely to be T21, or T18, or T13. diagnostic procedure such as amniocentesis or cordocentesis is recommended.
More than 98% of cases
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Delay notification
QC: Caused by either the experiment or blood sample quality; need to repeat the experiment
Data fluctuation: Caused by high data deviation; need to repeat the experiment
cfDNA concentration low:Need to repeat the experiment
If repeating experiment still cannot solve the problem, blood re-sampling is required.
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Re-sampling notification
QC: Caused by poor blood sample quality
cfDNA concentration low
Previous NIFTY failed to produce informative result, and gestational age is more than 22 weeks
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Sample requirement
Blood sampling• 5ml in EDTA tube• Clearly labeled
Plasma preparation• Immediately extract plasma• Stored at 4 , extract in 4 hours℃
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Packing for delivery• Strong support in case of damage• Enough dry ice to keep frozen
Sample storage• -20 for a week, -80 for long ℃ ℃
term• Avoid room temperature and
repeated thaw
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BGI papers
30
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More Choice
NIFTY express NIFTY NIFTY plus
Detection of T21, T18, T13 √ √ √Gender √ √ √Twin pregnancies √ √ √Sex chromosome abnormality
× √ √
Microdeletion & Microduplication
× × √
Monogenic disease × × √Turn around time 6 days 14 working days 14 working days
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NIFTY express
DataChr21(61 T21 cases)
Sensitivity 96.7% (59/61)
Specificity 98.4% (1561/1586)Chr18(16 T18 cases)
Sensitivity 100% (16/16)
Specificity 98.7% (1610/1631)Chr13(13 T13 cases)
Sensitivity 92.3%(12/13)
Specificity 99.1%(1619/1634)
Performed on Ion Proton platform, extremely fast
Performed in Czech Republic BGI-GENNET co-lab. EU based service.
Similar price
Validated on 1647 samples
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NIFTY plus
Detection of Microdeletion syndromes
Non-invasive Monogenic disease detection
Results of other prenatal tests such as biochemical and ultrasound tests should be considered. Diagnostic procedure such as amniocentesis/cordocentesis is suggested.
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Summary
Non-invasive • 5ml maternal
blood• No risk of
intrauterine infection and miscarriage
Accurate • Sensitivity
>99%• Specificity
>99%
Turnaround time• 10 days
Early detection• As early as
12 weeks
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About BGI
• Largest genomics research center in the world – 137 Hiseq2000, 27 AB Solid, 1 Roche 454, 1 Ion Torrent, 30 AB 3730
• Strong leader board and qualified employees– More than 4000 employees including 1500 bioinformaticians
• Extraordinary super computer and cutting-edge cloud computing technique– 102T flops/ 10PB storage/ 20TB memory
• Numerous high-quality publications on top academic Journals– Nature/ Science/ …
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Selected Top Publications of BGI
38
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Milestones of BGI
BGI-HZ, 2001
BGI-Beijing, 1999
BGI-WH, 2010
BGI-SZ, 2007
BGI-HK, 2009
BGI-Americas, 2010
BGI-Europe, 2010
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Platforms of BGI
40
Computing and bioinformatics platform
Sequencing platform
Agricultural genomics platform
Cloning platform
Healthcare platform
Microbiology platform
Proteomics platform
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Research collaborators worldwide