Non-Invasive prenatal testing (NIPT)

and impact on antenatal screening

Stephanie Allen
Consultant Clinical Scientist
West Midlands Regional Genetics
Laboratory

Oct 2014
Overview

Background to NIPT (NIPS)

ffDNA / cfDNA
Applications
Technology - NGS
NIPT and situation worldwide
Antenatal screening in UK
RAPID study
Free Fetal DNA - background
Lo et al (1997) - free Plasma
fetal DNA (ffDNA) in the
plasma of pregnant
women

Derived from trophoblast

(cfDNA)

Represents up to 20% of
cell free DNA in maternal
plasma

Useful source of material

for genetic prenatal
diagnosis
Cell free maternal DNA
Cell free fetal DNA
Clearance of cell free fetal nucleic acids after delivery
Applications

Fetal sexing
Detection of Y chromosome

Fetal Rhesus D status

Detection of RhD in RhD ve mother

Single gene disorders

Paternal or de novo mutations

NIPT for aneuploidy

 Landmarks in Genetics

Cost of
Draft sequencing
Mendel Sanger sequence of a human
publishes sequencing human genome
work on first genome reduced to
inheritance reported Cost: $2.7 bn < $10,000

1866 1953 1977 1983 2001 2005 2012

The Kary Mullis Next
structure of invented generation
DNA is Polymerase sequencing
described Chain invented
Reaction
 Next Generation Sequencing /
Massively Parallel Sequencing

Capillary 2005 MiSeq HiSeq

60,000 bases 150,000,000 bases 6,000,000,000 bases
0.002% of genome 2% of genome 2 whole genomes
10 genes >20,000 genes
NIPT for aneuploidy (=NIPS)
Lots of money invested in development NIPT for aneuploidy
Prenatal testing for Down syndrome (trisomy 21), Edwards
syndrome (trisomy 18), Patau syndrome (trisomy 13)
Extend to other aneuploidies
Potential to include subchromosomal aberrations
A number of companies offering testing worldwide
Not currently available on NHS or any other state-funded
healthcare system
155,000
135,000
67,500
Commercially available tests
Test Performance

Quoted sensitivity and specificity data for one of the commercially

available tests, based on their clinical validation study
Screening and not Diagnosis

False positives
Vanishing twin
Placental mosaicism
Maternal factors (mosaicism, tumours)
False negatives
Insufficient cfDNA
Placental mosaicism
Technical issues

Confirmation of abnormal results prior to TOP

Cost!!!!
Antenatal screening in the UK

Advises Ministers and the NHS in the four UK countries about all aspects
of screening and supports implementation of screening programmes
Part of Public Health England (PHE),
Combined Screening test
10 - 14+1 weeks
DR 85%, FPR 2.5%
(cut off 1:150)
http://www.rapid.nhs.uk/
 NIPT for aneuploidy RAPID study

Study to evaluate NIPT in screening pathway in NHS

led by Prof Lyn Chitty, RAPID project
Are looking at women who are screen risk of 1:1,000 or
greater (15% women having DSS) Health Economics
dictates that cost needs to be 250 to break even.
They also have a separate arm to the study where they
are considering additional serum markers improve
current screening test.
1 year study started Nov 2013, finishes Dec 2014,
hope to recruit 4,000 women (London centres).
Study has been extended to spring 2015
Will establish a user group and are feeding back to the
NSC
NIPT for Aneuploidy Evaluation Study

Barriers and facilitators to implementing NIPT in

the NHS
Compare uptake of screening, NIPT and
diagnostic testing
Economic factors
Develop educational materials for women and
professionals
Acceptability to service users and providers
Sensitivity and specificity in a medium risk
population
Current DSS Pathway

Screening and risk assessment

Detects1:150
85% of Downs
risk for <1:150 risk syndrome
for
T21, T13, T18 T21, T13, T18
cases for a 3% false positive rate.

Standard
Invasive testing
antenatal care
Possible models for integrating NIPT
into pathway
Three most likely:
1. An alternative to invasive PND NIPT only
offered to women with a high risk result
2. A first line screening test to replace the
current DSS programme
3. Contingent screening where all women with a
DSS risk above a pre-specified level are offered
NIPT
Possible models for integrating NIPT
into pathway
1. An alternative to invasive PND NIPT only
offered to women with a high risk result

Slight decrease in DS cases detected

IPD still required for confirmation of abnormal
results
Possible models for integrating NIPT
into pathway
2. A first line screening test to replace the
current DSS programme

Increase in cases DS detected

Reduction in miscarriages
Much more expensive!!
Identification of other abnormalities,
preeclampsia, IUGR by current DSS lost
Possible models for integrating NIPT
into pathway
3. Contingent screening where all women with a
DSS risk above a pre-specified level are offered
NIPT

Same or better than current DSS

Fewer miscarriages
Less costly

1:1,000 is a good balance between cost,

improved detection, decrease in invasive testing
Study Pathway
Screening and risk assessment Additional markers

1:1000 risk <1:1000 risk

for T21, T13, for T21, T13,
T18 T18
Detects 94% of Downs syndrome
NIPT
cases.
sequencing
test

T21, T13 or T18 T21, T13 or T18

predicted highly unlikely

Potential to reduce the need

Invasive Standard for invasive tests by >90%
testing antenatal care
 Testing pathways: options for women

Declines DSS
o No further testing, not eligible for study

DSS result of 1 in 2 1 in 150

o No further testing
o NIPT and await result before deciding on further invasive testing
o Invasive test and NIPT
o Invasive test

DSS result of 1 in 151 1 in 1000

o No further testing
o NIPT with option for invasive test if NIPT predicts the baby is affected

DSS result of less than 1 in 1001

o No further testing, not eligible for NIPT
Current situation in UK

Awaiting study results and possible amendments

to screening policy by NSC (? 2015-2016)
NIPT available privately and in a patchy way by
sending samples to USA / Hong Kong through
private labs 300-600
NHS and private labs in UK setting this up
Any Questions?