Download From Primary Research to Knowledge Integration Analyses and

The Human Genome Epidemiology
Network (HuGENet)
Muin J. Khoury
Outline
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The epidemiologic approach to genomics
The challenge of integrating data:
HuGENet
HuGENet Products and Processes
Gene-Based Medicine in 2010?
“Hypothetical Genetic Test Report”
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Condition
Genes
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Prostate Ca
Alzheimer’s
Heart disease
Colon Cancer
Lung Cancer
HPC1, 2, 3
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APOE,FAD3,XAD
APOB,CETP
FCC4,APC
NAT2
RR
Lifetime
0.4
0.3
2.5
4.0
6.0
7%
10%
70%
23%
40%
Collins FC, New Engl J Med 1999;341:28-37.
Prediction of Risk of Myocardial Infarction from
Polymorphisms in Candidate Genes
Yamada et al. NEJM 2002;347:1916-1923.
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Case-Control Study (5061 MI and 2242
Controls)
Analysis of 71 candidate genes with 112
polymorphisms
A few associations were found…small odds
ratios…
Accompanying editorial
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“Findings should be used to initiate further research
Recommendations for primary prevention cannot be
based on these findings.”
“Systematic application of epidemiologic
method and approaches to assess the
impact of human genetic variation on
health and disease”
Khoury, Little and Burke, HuGE 2004
“Systematic application of epidemiologic
methods and approaches to assess the
impact of human genetic variation on
health and disease”
Khoury, Little and Burke, HuGE 2004
• Genotype prevalence
• Gene - disease association
• Gene - gene interactions
• Gene - environment interactions
• Assessment of Genetic tests
“Systematic application of epidemiologic
methods and approaches to assess the
impact of human genetic variation on
health and disease”
Khoury, Little and Burke, HuGE 2004
• Genotype prevalence
• Gene - disease association
• Gene - gene interactions
• Gene - environment interactions
• Assessment of Genetic tests
HuGE problem:
25,000 genes, their
combinations and
interactions with risk
factors
“Systematic application of epidemiologic methods
and approaches to assess the impact of human
genetic variation on health and disease”
Khoury, Little and Burke, HuGE 2004
HuGE
involves a continuum from gene discovery to
applications in health care and disease prevention
“Genetic
Epidemiology with a capital E”.
D Thomas. Genet Epidemiol 2000;19:289
Human Genome Epidemiology Network (HuGENet)
Knowledge Integration on Genetic Variation and Health
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Global
collaboration of
individuals and
organizations to
assess
population
impact of
genomics on
population health
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Information Exchange
Training and
Technical Assistance
Knowledge Base
Development
Information
Dissemination
HuGENet
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Executive Committee
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4 Coordinating Centers (Atlanta,
Cambridge, Ioannina, Ottawa)
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8 Collaborating Journals
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> 700 “Members” from > 40 Countries
Human Genome Epidemiology Network: From
Primary Research to Knowledge Integration
Guide Research
Agenda
Knowledge Base
“Genomics and
Population Health”
Guide Health
Services & Inform
Public Policy
Epidemiologic
Studies/Platforms
HuGENet
Systematic Reviews
Analyses and
Publications
Epidemiologic Studies/Platforms
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Individual Studies
Cross sectional studies
 Case-control studies
 Cohort studies/biobanks
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Consortia/Networks
P3G
 “Network of Networks”
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Human Genome Epidemiology Network: From
Primary Research to Knowledge Integration
Guide Research
Agenda
Knowledge Base
“Genomics and
Population Health”
Guide Health
Services & Inform
Public Policy
Epidemiologic
Studies/Platforms
HuGENet
Systematic Reviews
Analyses and
Publications
No. of articles in Huge Published
Literature db, 2001-2004*
4500
4079
4000
3504
3500
3160
# of articles
3000
2462
2500
2000
# Pub Lit articles
1500
1000
500
0
2001
2002
2003
2004
Year of publication
(*As of Jan 14, 2005. Count excludes review articles, m eta & pooled analyses.)
Number of Published HuGE Papers* 20012004
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Year
Prevalence Associations Interactions
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2001
308
2141
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2002
349
2799
569
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2003
323
3010
598
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2004
368
3486
604
436
•MOST ASSOCIATION STUDIES ARE CASE-CONTROL STUDIES
Rank
1
Gene
Symbol
Gene name
APOE
apolipoprotein E
481
ACE
angiotensin I converting enzyme (peptidyldipeptidase A) 1
398
MTHFR
5,10-methylenetetrahydrofolate reductase
(NADPH)
377
HLADRB1
major histocompatibility complex, class II, DR
beta 1
376
TNF
tumor necrosis factor (TNF superfamily, member
2)
346
2
3
4
5
# of
Papers
01-03
6
GSTM1 glutathione S-transferase M1
253
major histocompatibility complex, class II, DQ
beta 1
248
7
HLADQB1
8
F5
coagulation factor V (proaccelerin, labile factor)
213
GSTT1 glutathione S-transferase theta 1
9
204
Epidemiological Quality in Molecular Genetic
Research: Need for Methodological Standards
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Bogardus et al. JAMA
1999;281:1919-26.
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Methodologic
Standard
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Aim: To examine clinical
epi quality of recent
papers in molecular
genetic analysis
40 inferential articles in 4
clinical journals (1995)
38% articles passed 4 or
less methodologic
standards
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Reproducibility
38%
Objectivity
33%
Case Group
78%
Case Spectrum
88%
Comparison Group 70%
Comparison Spectrum
88%
Quantitative Summary
90%
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%
What is STROBE ?
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STROBE: international collaborative
initiative for STrengthening the Reporting
of OBservational studies in Epidemiology
Human Genome Epidemiology Network: From
Primary Research to Knowledge Integration
Guide Research
Agenda
Knowledge Base
“Genomics and
Population Health”
Guide Health
Services & Inform
Public Policy
Epidemiologic
Studies/Platforms
HuGENet
Systematic Reviews
Analyses and
Publications
The Need for Systematic Reviews:
on Genetic Variation and Health
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Unmanageable amounts of data
Small sample size of individual studies
Small effect size of gene-disease associations
Replication of associations
Publication bias
Heterogeneity
Generate and test hypotheses
Human Genome Epidemiology Network: From
Primary Research to Knowledge Integration
Guide Research
Agenda
Knowledge Base
“Genomics and
Population Health”
Guide Health
Services & Inform
Public Policy
Epidemiologic
Studies/Platforms
HuGENet
Systematic Reviews
Analyses and
Publications
HuGENet Products
(as of September 1, 2005)
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HuGE Reviews
Meta/Pooled Analyses
Fact sheets
E-journal clubs
Case studies
Genotype Prevalence Database
40
269
13
66
5
13
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Published Literature Database
17,467
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# Genes
# Risk Factors
# Outcomes
2003
656
2068
Human Genome Epidemiology Network: From
Primary Research to Knowledge Integration
Guide Research
Agenda
Knowledge Base
“Genomics and
Population Health”
Guide Health
Services & Inform
Public Policy
Epidemiologic
Studies/Platforms
HuGENet
Systematic Reviews
Analyses and
Publications