Transcript Document

Improving test properties for neonatal
cystic fibrosis screening
in the Netherlands before the nationwide start by May 1st 2011
Geneva
30.08.2011
International
Society for
Neonatal
Screening
Martina Cornel, MD, PhD
Professor of Community Genetics & Public
Health Genomics,
Dept Clinical Genetics
Quality of Care
EMGO Institute for Health and Care Research
Cystic fibrosis
• Mucoviscidosis
• Lung infections
• Nutritional problems
www.nhlbi.nih.gov/.../Diseases/cf/cf_signs.html
• Chronic obstructive pulmonary disease, pancreatic
fibrosis, hepatic fibrosis, diabetes, azoospermia,
etc.
Life expectancy improved: now ± 40 y
Dankert-Roelse, Lancet 1986
Autosomal recessive
• 2 mutations in CFTR gene: infant develops disease
• Most parents (80-90%) do not know in advance
that they are (healthy) carriers
Neonatal screening for cystic fibrosis?
•First studies decades ago
•IRT (dried blood spots)
•Less days in hospital
Wilcken & Chalmers 1985
•Wisconsin: Pseudomonas Aeruginosa in children
diagnosed through newborn screening
Sir Muir Gray (Nat Scr Comm UK)
All screening programmes do harm. Some
do good as well and, of these, some do
more good than harm at reasonable cost.
Pros and cons need to be evaluated
• Live longer & healthier
• Less days in hospital
• Life expectancy increases?
• False positives (referral for sweattest; in majority
of cases this concerns healthy infants)
• Uncertainty for days or weeks
• # carriers and false positives
New technological possibilities
– Attunement between parties
Achterbergh et al. Health Policy 2007; 83: 277-286.
Neonatal screening for cystic fibrosis?
Health Council report NL 2005:
• 50-60 patients per year
• 600 infants referred for sweat test
• 400 heterozygotes diagnosed (carriers of CF)
• prognosis improved after screening
• Advice to perform Pilot Study: CHOPIN
(Cystic fibrosis Heelprick screening in a newbOrn Population
In the Netherlands).
Balancing pros and cons
Good test available?
• False positives :
550/179.450
• Specificity (1-FP): 99,7%
• False negatives
• Sensitivity (1-FN)
• Positive predictive value
Disease
→
Present
Absent
Test
Result↓
Positive
Negative
A
B
C
D
CHOPIN
• PI Jeanette Dankert-Roelse
• Publications submitted
• Three provinces of NL
• Protocols in parallel (IRT/PAP or IRT/DNA)
• Summary of results in Health Council Report
Four step protocol proposed:
1. IRT
<60 µg/l: negative, otherwise
2. PAP
< 1,0 µg/l if IRT < 100 µg/l or
< 1,8 µg/l if IRT 60-100 µg/l : negative,
otherwise
3. DNA panel of 36 most common mutations in NL
• INNO-LiPA CFTR 19 and INNO-LiPA 17+Tn
if 1 mutation or IRT ≥ 100 µg/l :
4. DNA sequencing of CFTR gene
Screening protocol diagram
www.gr.nl neonatal screening CF 2010
Expected to be reported to parents
• 25 infants with cystic fibrosis
– excl 4 with earlier diagnosis: meconium ileus
• 12 carriers (heterozygotes)
• Ministry of Health accepted Health Council advice
and implementated by 1 May 2011
Preliminary results NL 3 months 11 patients
sequencing:
LiPA:
8 CF patients
in 3 months
3 CF patients
in 3 months
www.gr.nl neonatal screening CF 2010
Benefits of screening
• Better feeding status, prevention of an often
protracted and aggravating diagnostic process and
decrease in hospital admissions
• Specificity 100%
– Few referrals to pediatrician
• Sensitivity
– Panel: only 44% for Turkish migrants and 69%
for North African migrants (Lakeman 2008)
– Higher due to sequencing and failsafe in
IRT≥100µg/l
Additional benefits of screening
Is carrier status information a benefit?
• Complicating pre-test counseling:
“If the newborn child is a carrier, then it follows that one, or
both, parents (and possibly other children) are carriers. The
parents should be alerted to these possible outcomes prior
to screening. Information of this kind can, in practice, give
rise to misunderstandings with regard to the health of the
carriers. etc”
“One problem lies in the fact that it is not always possible to
determine for certain whether only one parent is a carrier
(as is the case with, for example, cystic fibrosis, where not
all mutations are known).”
Phases of life & genetic screening
• Preconceptional
• Antenatal
• Neonatal
• Later in life
Carrier screening – when?
• Before pregnancy (in preconceptional screening)
more reproductive options:
– No children (adoption)
– Preimplantation genetic diagnosis (embryo
selection)
– Prenatal diagnosis and termination of affected
fetuses
– Different partner
– Donor gametes (artificial insemination donor
sperm)
– etc
A CF carrier identified in NBS
A
a
A
A
AA
Aa
A
AA
a
Aa
aa
a
Aa
?
If child is carrier, at least one of parents is carrier
as well. If 1:30 is carrier, the allele frequency is
1:60, and for each next pregnancy the risk of of CF
affected infant is 1/4X1/60=1/240.
Report carrier information from NBS?
• Relevant for some parents in connection with
future family planning
• Secondary finding rather than objective
• CF is a severe disorder – if requested, it would be
necessary to provide genetic advice and treatment
options.
• Certainly, parents must be able to make an
informed and conscious choice and the consent of
parents is required for the provision of information
on being a carrier.
Opting out of carrier status information
Conclusion
• In the new program as of 1.5.2011 100%
specificity is achieved
• Sensitivity will be very high,
further evaluation is needed,
esp. for infants with migrant ancestors.
• Carrier status information is provided to small #,
if parents do not opt out,
and clinical geneticist can provide counseling to
carriers upon request.
Thank you!