WHO meeting on international collaboration to reduce healthcare burden of craniofacial anomalies Gen

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WHO meeting on international collaboration to
reduce health-care burden of craniofacial
anomaliesGeneve 2-4 Dec 2004
Session 1. Update in the science and progress
with international collaboration
Epidemiology Prof Pierpaolo Mastroiacovo
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Question
How to develop epi studies in an international
setting ?
Answer
Develop a flexible International Database on
Craniofacial Anomalies
ICBD www.icbd.org
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IDCFAInternational Database of Craniofacial
Anomalies

• A world-wide initiative promoted by
• WHO Human Genetics Programme
• NIDCR National Institute of Dental and
  Craniofacial Research
• Coordinated by
• ICBD International Centre on Birth Defects
• Headquarter of the International Clearinghouse
  for Birth Defects Monitoring System

Pierpaolo Mastroiacovo and Elisabeth Robert
Gnansia Advisor Eduardo E Castilla
ICBD www.icbd.org
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What an IDCFA wants to be
Basket
ICBD www.icbd.org
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Epidemiology of CFA in an international
settingBasic needs case definition and
reliable ascertainment
ICBD www.icbd.org
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Epidemiology of CFA in an international
settingBasic needs case definition and
reliable ascertainment
ICBD www.icbd.org
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The first database
International Perinatal Database of Typical Oral
Clefts IPDTOC
ICBD www.icbd.org
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Next steps
Next presentation See session 4
ICBD www.icbd.org
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IPDTOC How it works

• Data sources
• Contacted
• Obtained
• What is requested
• Definition of cases
• Minimum dataset
• Updating
• How the information are processed at ICBD
• Miscellanea

ICBD www.icbd.org
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Data sources, contacted
ECLAMC
All, centrally
Eurocat
All, centrally
ICBDMS
All, individually
US NBDPN
All, centrally
8, individually
ICBD www.icbd.org
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Data sources, participating
ECLAMC
9 out of 9
Eurocat
15 out of 23
ICBDMS
12 out of 15
12 out of 21
US NBDPN
11 out of 52
1 out of 8
ICBD www.icbd.org
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Data sources, basic structure
60 8 ?
ICBD www.icbd.org
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IPDTOC How it works

• Data sources
• Contacted
• Obtained
• What is requested
• Definition of cases
• Minimum dataset
• Updating
• How the information are processed at ICBD
• Miscellanea

ICBD www.icbd.org
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Definitions
Cleft lip (749.1) Q36 A congenital malformation
characterized by partial or complete clefting of
the upper lip. Exclude median cleft lip part
of Holoprosencephaly Sequence rare and oblique
facial clefts
Cleft lip and palate (749.2) Q37 A congenital
malformation characterized by partial or complete
clefting of the upper lip with clefting of the
alveolar ridge and/or the hard palate. Exclude
any oral cleft part of the Holoprosencephaly
Sequence rare and oblique facial clefts
Cleft palate (749.0) Q35 A visible congenital
malformation characterized by a closure defect of
the hard palate and/or soft palate behind the
foramen incisivum without cleft lip. Exclude
submucous cleft palate, occult cleft palate,
cleft uvula. In some database cleft palate
includes Pierre Robin Sequence
Pierre Robin Sequence (756.03) Q87.08 A
congenital malformation characterized by a
closure defect of the palate behind the foramen
incisivum without cleft lip, associated to a
significant) micrognathia with or without a
clinically relevant glossoptosis (retroposition
of tongue) or respiratory distress.
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Definitions
Isolated cases Any case with only one major
defect registered. In this Database with only a
oro-facial cleft. Cases with associated
defects, multimalformed infant Any case with a
major defect registered other than the orofacial
cleft and its sequence (e.g. nose deformities).
Syndromes Any case with appropriate field
filled by a name of recognized pattern of
multiple malformations
ICBD www.icbd.org
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Please notice that

• Orofacial clefts associated to holoprosencephaly
  are excluded
• Cleft uvula and submucous cleft palate are
  excluded
• Pierre Robin is revised and defined at central
  level
• Multimalformed infant are revised, defined and
  coded at central level
• Syndromes are validated as much as possible

ICBD www.icbd.org
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Information dataset case by case

• Subject code ()
• Date of birth (at least month and year)
• Sex, BW, GA, singleton/twin
• Living status at registration (ToP, SB, LB)
• Code (and) verbatim description of OFC and
  associated anomalies, including syndrome code
  when recognized
• Any information available
• () All codes are hidden centrally, key available
  only locally

Updating requested every 6 months 1 year
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IPDTOC How it works

• Data sources
• Contacted
• Obtained
• What is requested
• Definition of cases
• Minimum dataset
• Updating
• How the information are processed at ICBD
• Miscellanea

ICBD www.icbd.org
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What ICBD does before processing data

• Data arrive in heterogeneous format as locally
  stored, must be converted in an homogeneous
  format
• General checking of all data
• Create the appropriate variables needed (e.g.
  date of birth by yy/mm/dd specific field for
  OFC country code gravidity)
• Code the final diagnosis
• Isolated
• Multimalformed infants, coded by number of
  associated unrelated malformations (e.g. 3333)
• Cases with syndromes, coded with OMIM
• Request of information when needed
• Interact with local registries

An algorithm is applied and a review is performed
centrally, to define more uniformely cases with 2
or more major unrelated malformations, the so
called multi-malformed infants (MMI). See
Guidelines for MMI used at ICBD since 2001
ICBD www.icbd.org
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Request informationWhen ?

• Median cleft lip (holoprosencephaly ? Syndrome ?)
• Cleft lip / palate in
• chromosomal syndromes (holoprosencephaly ?)
• so called amniotic band syndrome (atypical ?)
• Pierre Robin with cleft lip
• Any syndrome
• with a too generic name (eg. first arch
  syndrome)
• without a commonly available lab confirmation
  please what is the evidence ?

ICBD www.icbd.org
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IPDTOC How it works

• Data sources
• Contacted
• Obtained
• What is requested
• Definition of cases
• Minimum dataset
• Updating
• How the information are processed at ICBD
• Miscellanea

ICBD www.icbd.org
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Some organizational aspects

• The database is anonymous at the central level
• Key code available only to the local
  organizations
• The databases is located at ICBD and within the
  WHO Human Genetics Programme
• Aggregated results are available through the web
  site http//www.who.int/genomics/anomalies/idcfa/e
  n/
• The access to the case by case database is
  possible for any contributing researchers group
  according to specific rules developed by the
  IDCFA Steering Committee

ICBD www.icbd.org
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Steering Commitee

• WHO Human Genetics Programme Victor
  Bouljchenkov
• NIDCR - National Institute of Dental and
  Craniofacial Research Kevin Hardwick
• Craniofacial Project of the WHO Human Genetics
  Programme Peter Mossey
• ICBD International Centre on Birth Defects
  Pierpaolo Mastroiacovo
• ECLAMC Estudio Collaborativo Latino-Americano
  Malformaciones Congenitas Eduardo E Castilla
• EUROCAT European Registry of Congenital Anomaly
  Helene Dolk
• ICBDMS International Clearinghouse of Birth
  Defects Monitoring Systems John Harris
• US-NBDPN National Birth Defects Prevention
  Network US Robert Meyer

ICBD www.icbd.org
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International Perinatal Database Typical Oral
CleftIDPTOC

• Recent data
• 2001 2002 (2003)
• Up dated to July 15, 2004

Strengths International Very large data
set Recent Revised centrally
Weakness Small sample size in some areas Quality
of diagnosis should be improved at local registry
level, mainly for the MMI and syndromes
ICBD www.icbd.org
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5 areas 3 countries2 ml births per year
ICBD www.icbd.org
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Number of Typical Oral Clefts
Total cases
Time period 2001-2002-(2003)
ICBD www.icbd.org
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Variability in All oral clefts rates is
mainly due to CLP rates variations.Cleft lip and
Cleft palate has less variability.
24.0
23.8
23.8
All Oral Clefts
20.0
17.4
17.4
16.0
15.9
15.9
15.7
14.8
14.8
13.6
12.0
Cleft lip and palate
9.5
8.9
8.0
7.0
6.5
Cleft palate
6.4
6.3
5.8
5.5
5.6
5.0
4.0
3.9
3.7
3.6
Cleft lip
2.9
3.1
3.2
2.9
2.0
Total cases
Japan
EU South
US Canada
EU North
EU Central
Mex SAM
ICBD www.icbd.org
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The 7 Areas with gt 10,000 births and highest
rates of CL/-P
No heterogeneity among registries in the same
area
ICBD www.icbd.org
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The 7 Areas with gt 10,000 births and lowest
rates of CL/-P
No heterogeneity among registries in the same
area
ICBD www.icbd.org
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Correlation between Latitude and Isolated CL/-
P rates in European Countries
25 Registries gt 10.000 births 18 Countries
Isolated cases
CL/-P rates per 10,000
r 0.61 Plt0.01
Latitude degrees
No correlation for Cleft Palate, r 0.31 p 0.10
ICBD www.icbd.org
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Higher rates of CL/ P are associated to higher
proportion of CLP which are the more severe
types of primary palate defects
Isolated cases

• 46
• Registries
• gt10,000 births
• 28
• Countries

Proportion of CLP out of CLCLP
r 0.60 P lt 0.01
Rates x 10,000 of CL/-P
ICBD www.icbd.org
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Maternal age and isolated TOC
R A T E R A T I O
South Europe Xx cases from Italy
Central Europe XX casi .
ICBD www.icbd.org
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Proportion of isolated cases
North Europe
Central Europe
South Europe
US - Canada
South America - Mexico
Japan

plt0.05





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Male sex proportion
Isolated cases

• No (not yet ?) heterogeneity for
• cleft lip vs cleft lip palate
• isolated vs MMI vs syndromic
• ToP vs births
• among registries
• No correlation with rates

MF 1.70
0.63
MF 0.78
0.48
MF 0.91
0.44
C L / P n 2 549
C P n 1 069
Pierre Robin n 160
ICBD www.icbd.org
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Proportion of termination of pregnancies
21.3
9.8
0
2.7
MMI Synd
Isolated
MMI Synd
Isolated
US
Europe
ICBD www.icbd.org
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More information and updating onwww.who.int/geno
mics/anomalies/idcfa/en/
ICBD www.icbd.org
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ICBD www.icbd.org
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Aknowledgments
Alessandra Lisi Simonetta Zezza Mauro Di
Lisio Antonin Sipek Blanca Gener Brian Lowry
Bridget S. Mosley Carmen Mosquera-Tenreiro 
Catherine De Vigan  Csaba Siffel/Julia Metneki
Dave Erickson David Bourne-Rauf Sayed David J.
Law Diana Wellesley Eduardo E Castilla Elena
Szabova Elisabeth Robert-Gnansia Ester Garne
Fabrizio Bianchi Gioacchino Scarano Glenn
Copeland Guido Cocchi Helen Dolk Hermien de
Walle Ingeborg Barisic Joyce M. Robl Kathryn
G. Cummons Kay A. Pearson Lenore Abramsky
Lihadh Al Gazali Ludmila Joutchenko Marcia
Lynn Feldkamp Maria Feijoo Marie-Claude Addor
Martin Haeusler Miriam Gatt Osvaldo Mutchinick
Patricia Boyd Paul Merlob Peg Hilliard Robert
Mc Donnell Romano Tenconi Ruth D. Merz Samara
Viner-Brown Sebastiano Bianca Trish Egler
Volker Steinbicker Wladimir Wertelecki Yoshio
Sumiyoshi Yves Gillerot
ICBD www.icbd.org
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Thanks
ICBD www.icbd.org