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The Human Genome Epidemiology NetworkThe Human Genome Epidemiology Network(HuGE Net)(HuGE Net)

Muin J. Khoury, MD, Ph.D.Muin J. Khoury, MD, Ph.D.

Director,Director,

CDC Office of Genomics and Disease PreventionCDC Office of Genomics and Disease Prevention

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“Welcome to the Genomics Era”(NEJM Dec 2003)

”Genetic Testing for Sale” Vineis, P, Christiani, D. Epidemiology Jan 2004

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“Welcome to the Genomics Era”(NEJM Dec 2003)

”Genetic Testing for Sale” Vineis, P, Christiani, D. Epidemiology Jan 2004

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Gene-Based Medicine in 2010?Gene-Based Medicine in 2010?“Hypothetical Genetic Test Report”“Hypothetical Genetic Test Report”

• ConditionCondition Genes RRGenes RR Lifetime Lifetime

• Prostate Ca Prostate Ca HPC1, 2, 3HPC1, 2, 3 0.4 0.4 7% 7%• Alzheimer’s Alzheimer’s APOE,FAD3,XADAPOE,FAD3,XAD 0.3 10% 0.3 10%• Heart disease Heart disease APOB,CETPAPOB,CETP 2.5 70% 2.5 70%• Colon CancerColon Cancer FCC4,APCFCC4,APC 4.0 23% 4.0 23%• Lung CancerLung Cancer NAT2NAT2 6.0 6.0 40% 40%

Collins FC, New Engl J Med 1999;341:28-37.Collins FC, New Engl J Med 1999;341:28-37.

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• 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

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• 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 HuGE problem: HuGE problem: 25,000 genes, 25,000 genes,

their combinations their combinations andand

interactions with interactions with risk factorsrisk factors

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Risk FactorsRisk Factors

DemographiDemographicscs

DietDiet

OccupationOccupation

SmokingSmoking

AlcoholAlcohol

EnvironmentEnvironment

Adverse Adverse Health Health OutcomOutcom

eses

The End of Black Box Epidemiology?The End of Black Box Epidemiology?

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proteases

Preterm Delivery

Uterine Contractions

Cervical change

• Infection: - Chorion-Decidual - Systemic

DecidualHemorrhageAbruption

CRHE1-E3

Prothrombin G20210AFactor V LeidenProtein C, Protein SType 1 PlasminogenMTHFR

PathologicalUterine

Distention

• Multifetal Pregnancy• Polyhydramnios• Uterine abnormalities

Inflammation

• Maternal-Fetal Stress

•Premature Onset of Physiologic Initiators

Activation of Maternal/Fetal

HPA Axis

CRH

+

+ChorionDecidua

uterotonins

Mechanical stretch

Gap jct

IL-8 PGE2

Oxytocin recep

PROM

InterleukinsTNF-α Fas L

Adapted from: C. J. Lockwood, Paediatr Perinat Epidemiol 15, 78 (2001) & X. Wangl. Paediatr Perinat Epidemiol 15, 63 (2001)

MMPs

Susceptibility to

environmental toxins

CYP1A1GSTT1

Courtesy S. Dolan Courtesy S. Dolan MD MD

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Primary HuGE Research Agenda and Funding

Study Design Single studies (case-control, cohort biobanks) Consortia

Implementation Candidate gene selectionRisk factor dataOutcome data

Analysis: G-G, G-E

InterpretationCausal inferenceRisk estimation

DisseminationAppraisalSynthesis

ReviewsMeta-analysis

Policy &Practice

Identify Knowledge gapsMethodologic problemsResearch Priorities

(Single study)

From HuGE Research to Synthesis & Dissemination for Policy and Practice

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Primary HuGE Research Agenda and Funding

Study Design Single studies (case-control, cohort biobanks) Consortia

Implementation Candidate gene selectionRisk factor dataOutcome data

Analysis: G-G, G-E

InterpretationCausal inferenceRisk estimation

DisseminationAppraisalSynthesis

ReviewsMeta-analysis

Policy &Practice

Identify Knowledge gapsMethodologic problemsResearch Priorities

(Single study)

From HuGE Research to Synthesis & Dissemination for Policy and Practice

HuGE Net

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Human Genome Epidemiology Network Human Genome Epidemiology Network (HuGE Net)(HuGE Net)

• Global collaboration Global collaboration of individuals and of individuals and organizations to organizations to assess population assess population impact of genomics impact of genomics and how it can be and how it can be used to improve used to improve health and prevent health and prevent disease disease (~700 (~700 collaborators, 43 collaborators, 43 countries)countries)

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Human Genome Epidemiology Network Human Genome Epidemiology Network (HuGE Net)(HuGE Net)

• Information Information ExchangeExchange

• Training and Training and Technical Technical AssistanceAssistance

• Knowledge Base Knowledge Base Development Development

• Information Information DisseminationDissemination

• Policy Policy DevelopmentDevelopment

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Primary HuGE Research Agenda and Funding

Study Design Single studies (case-control, cohort biobanks) Consortia

Implementation Candidate gene selectionRisk factor dataOutcome data

Analysis: G-G, G-E

InterpretationCausal inferenceRisk estimation

DisseminationAppraisalSynthesis

HuGEMeta-analysis

Policy &Practice

Identify Knowledge gapsMethodologic problemsResearch Priorities

(Single study)

From HuGE Research to Synthesis & Dissemination for Policy and Practice

HuGE Net

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HuGE Net Products HuGE Net Products (as of January 10, 2005)(as of January 10, 2005)

• ReviewsReviews 3333• Fact sheetsFact sheets 1313• E-journal clubsE-journal clubs 5353• Case studiesCase studies 4 4• Genotype Prevalence DatabaseGenotype Prevalence Database 1313• Methods workshop/guidelines 2Methods workshop/guidelines 2• Training workshopsTraining workshops 6 6• Book Book 1 1

• Published Literature Database 14,127Published Literature Database 14,127– # Genes# Genes 1710 1710– # Risk Factors# Risk Factors 559 559– # Outcomes# Outcomes 1797 1797

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HuGE ReviewsHuGE Reviews“Systematic Reviews of Gene-Disease Associations”“Systematic Reviews of Gene-Disease Associations”

• Full ReviewsFull Reviews– AbstractAbstract– GeneGene– Gene variants PrevalenceGene variants Prevalence– Disease/Health outcomeDisease/Health outcome– AssociationsAssociations– InteractionsInteractions– Laboratory TestsLaboratory Tests– Population Testing and other applicationsPopulation Testing and other applications– Recommendations for further researchRecommendations for further research

• Mini-ReviewsMini-Reviews• Gene-Disease Association ReviewsGene-Disease Association Reviews• Prevalence ReviewsPrevalence Reviews

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HuGE Reviews by TopicHuGE Reviews by TopicJan 10, 2005Jan 10, 2005

• CancerCancer 1313• CardiovascularCardiovascular 4 4• Birth DefectsBirth Defects 4 4• Single Gene DsSingle Gene Ds 4 4• ExposuresExposures 3 3• OthersOthers 5 5

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Systematic Reviews of Gene-Disease Associations:Systematic Reviews of Gene-Disease Associations:GDP Info: Oct 2000-Aug 2004GDP Info: Oct 2000-Aug 2004

Category Number %________________________________________________Cancer 34 23.9

Cardiovascular diseases 27 19.0Mental Health 25

17.6Neurologic diseases 12 8.5Osteoporosis 6 4.2

Pregnancy/Reproduction 5 3.5 Infectious diseases (all HIV) 4 2.8Diabetes 3 2.1

Autoimmune diseases 3 2.1

Obesity 2 1.4Arthritis 2 1.4 Asthma 2 1.4______________________________________________

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No. of articles in Huge Published Literature db, 2001-2004*

2462

3160

3504

4079

0

500

1000

1500

2000

2500

3000

3500

4000

4500

2001 2002 2003 2004

Year of publication(*As of Jan 14, 2005. Count excludes review articles, meta & pooled analyses.)

# o

f ar

ticl

es

# Pub Lit articles

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Number of Published HuGE Papers* Number of Published HuGE Papers* 2001-20042001-2004

• YearYear PrevalencePrevalence Associations InteractionsAssociations Interactions

• 20012001 308308 2141 4362141 436

• 20022002 349349 27992799 569 569

• 20032003 323323 30103010 598 598

• 20042004 368368 34863486 604 604

* Data from CDC’s GDP Info 1/2005* Data from CDC’s GDP Info 1/2005

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HuGE Net Next StepsHuGE Net Next Steps

• Knowledge base developmentKnowledge base development– Develop tools for synthesis (“Cochrane” manual) Develop tools for synthesis (“Cochrane” manual) – Develop research agenda and Pilot projectsDevelop research agenda and Pilot projects

• Enhance collaborations and information Enhance collaborations and information SharingSharing– ““Network of Networks”Network of Networks”– Collaboration with BiobanksCollaboration with Biobanks

• Training and technical assistanceTraining and technical assistance• Electronic journal (forum for negative Electronic journal (forum for negative

studies)studies)• Use in public health genetics policy and Use in public health genetics policy and

practicepractice

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Primary HuGE Research Agenda and Funding

Study Design Single studies (case-control, cohort biobanks) Consortia

Implementation Candidate gene selectionRisk factor dataOutcome data

Analysis: G-G, G-E

InterpretationCausal inferenceRisk estimation

DisseminationAppraisalSynthesis

HuGEMeta-analysis

Policy &Practice

Identify Knowledge gapsMethodologic problemsResearch Priorities

(Single study)

From HuGE Research to Synthesis & Dissemination for Policy and Practice

HuGE Net

HuGE Journal