Plenary 3 Cochairs: Sally Green and Helen Whelton Pembroke

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Plenary 3Co-chairs Sally Green and Helen
WheltonPembroke
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The Human Genome Epidemiology Network (HuGENet)
making sense of 10,000,000 postulated genetic
risk factors

• John P.A. Ioannidis
• Department of Hygiene and Epidemiology
• University of Ioannina School of Medicine,
  Ioannina, Greece
• and Tufts University School of Medicine, Boston,
  USA

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Human Genome Epidemiology Network (HuGENet)

• Global collaboration of individuals and
  organizations to assess population impact of
  genomics and how it can be used to improve health
  and prevent disease

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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
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From Genetics to Genomics

• Genetic Disorders
• Mendelian Disorders
• Disease burden 5
• Mutations/One Gene
• High Disease Risk
• Environment /-
• Genetic Services

• Genetic Information
• All Diseases
• Disease Burden 95
• Variants/MultiGenes
• Low Disease Risk
• Environment
• General Practice

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Counting fish in the sea of gene-disease
associations
Ioannidis, Trends Mol Med 2003
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Major postulated problems of human genome
epidemiology

• Small sample sizes
• Small effect sizes
• Large number of biological factors
• Main effects vs. interactions of genes
• Interaction with environmental exposures
• Potential variability across populations
• Old-epidemiology problems confounding
  (population stratification), misclassification
• Questionable replication validity

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Background issues

• Assay development
• Minimizing measurement error
• Minimizing design error
• Standardization and harmonization
• Validation
• Biological rationale and plausibility
• Clinical and public health use

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Small sample size
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Small genetic effects
Ioannidis, Trikalinos, and Khoury, Am J Epidemiol
2006
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Number of Published Human Genome Epidemiology
(HuGE) Papers 2001-2005

• Year Prevalence Associations Interactions
• 2001 308 2141 436
• 2002 349 2799 569
• 2003 328 3021 600
• 2004 430 3772 664
• 2005 418 4569 911

Data from HuGE Published Literature Database
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The HuGENet Road Map

Guide Research Agenda
Epidemiologic Studies/Platforms

Analyses and Publications
Knowledge Dissemination
Network of Networks/P3G

Knowledge Integration
Guide Health Services Inform Public Policy

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HuGENet Network of Networks
Nat Genet Jan 2006
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Examples of Network-based HuGE Study Platforms

• Disease Consortium Teams Subjects
• Parkinson GEO-PD 18 10,000
• Osteoporosis GENOMOS 10 30,000
• Preterm birth PREGENIA 10 20,000
• Lymphoma INTERLYMPH 15 20,000
• Lung cancer ILLCO 30 51,000
• Head Neck INHANCE 13 28,000
• Melanoma GENOMEL 12 3,000
• Pancreatic Ca PACGENE 10 5,000

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Study Platforms Methodologic Implications

• Assembling Teams
• Overall Project Design
• Harmonization vs standardization
• Outcome definitions and ascertainment
• Risk factor definitions and ascertainment
• Gene Selection and Measurement of genotypes
• Other biological markers
• Integrating and understanding the environmental
  variables (see. Davey-Smith et al. IJE 2006)

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Non-replicated diminishing effects
Ioannidis et al, Nature Genetics 2001
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Breast cancer a null field for common genetic
variants?
Ioannidis, JNCI 2006 and Pharoah et al. JNCI 2006
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The other side dont give up early
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H heterogeneityR/F difference in first vs.
subsequentD1-D3 small-study bias
diagnosticsRS/FS significant findings
(with/without first studies)
Ioannidis et al, Lancet 2003
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Succession of early extremes the Proteus
phenomenonIoannidis and Trikalinos, J Clin
Epidemiol 2005
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Language bias and global science
Pan et al. PLoS Med 2005
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Measurement error insight from a collaborative
analysis

• Of 18 teams of investigators participating in the
  collaborative analysis of alpha-synuclein REP-I
  variation and Parkinsons disease risk, we found
  that 7 had to be excluded from the main analyses
  because of laboratory error exceeding 10 and/or
  overt violation of HWE in the controls
• Two other teams who had published an inverse
  association apparently had miscoded the alleles
  in their databases.

Maraganore et al, JAMA 2006
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Let us add the environment
Hunter D. Nat Rev Genet 2005
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Genomic Tests a Public Health Issue

• Can potentially affect a lot of people
  (especially pharmacogenomics)
• Potential for enhancing and targeting prevention
  efforts
• Implementation and access
• Provider and public education
• Monitoring impact on population health

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Genomic profiling to promote a healthy
lifestyle not ready for prime time Haga S et
al. Nat Genet 2003
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Knowledge Integration Across Disciplines
Evaluation of Genetic Tests

• For each intended use
• Analytic Validity
• Clinical Validity
• Clinical Utility
• Define test, disorder, and setting

http//www.cdc.gov/genomics/activities/fbr.htm
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Research on genetic risk factors

• Single studies purely hypothesis-generating,
  important to register data, regardless of results
• Meta-analyses of group data increasing
  certainty when several thousand subjects
  available
• Large-scale evidence from consortia or
  meta-analysis of individual-level data evolving
  gold standard?

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Plenary 3Co-chairs Sally Green and Helen
WheltonPembroke