The Human Genome Epidemiology Network (HuGENet)

Muin J. Khoury Muin J. Khoury

Outline

The epidemiologic approach to genomicsThe epidemiologic approach to genomics The challenge of integrating data: The challenge of integrating data:

HuGENetHuGENet HuGENet Products and ProcessesHuGENet Products and Processes

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

ConditionCondition Genes RR Genes 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.

Prediction of Risk of Myocardial Infarction from Polymorphisms in Candidate GenesYamada et al. NEJM 2002;347:1916-1923.

Case-Control Study (5061 MI and 2242 Case-Control Study (5061 MI and 2242 Controls)Controls)

Analysis of 71 candidate genes with 112 Analysis of 71 candidate genes with 112 polymorphisms polymorphisms

A few associations were found…small odds A few associations were found…small odds ratios…ratios…

Accompanying editorialAccompanying editorial ““Findings should be used to initiate further researchFindings should be used to initiate further research Recommendations for primary prevention cannot be Recommendations for primary prevention cannot be

based on these findings.”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

• 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

“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

“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 HuGE involves a continuum from gene discovery to applications in health care discovery to applications in health care and disease preventionand disease prevention

““Genetic Epidemiology with a Genetic Epidemiology with a capital E”.capital E”. D Thomas. Genet D Thomas. Genet Epidemiol 2000;19:289Epidemiol 2000;19:289

Human Genome Epidemiology Network (HuGENet)

Knowledge Integration on Genetic Variation and Health

Global Global collaboration of collaboration of individuals and individuals and organizations to organizations to assess assess population population impact of impact of genomics on genomics on population health population health

Information ExchangeInformation Exchange Training and Training and

Technical AssistanceTechnical Assistance Knowledge Base Knowledge Base

Development Development Information Information

DisseminationDissemination

HuGENet

Executive CommitteeExecutive Committee

4 Coordinating Centers (Atlanta, 4 Coordinating Centers (Atlanta, Cambridge, Ioannina, Ottawa)Cambridge, Ioannina, Ottawa)

8 Collaborating Journals8 Collaborating Journals

> 700 “Members” from > 40 Countries > 700 “Members” from > 40 Countries

Epidemiologic Studies/Platforms

Human Genome Epidemiology Network: From Primary Research to Knowledge Integration

Analyses and Publications

Systematic Reviews

Knowledge Base“Genomics and Population Health”

HuGENet

Guide HealthServices & InformPublic Policy

Guide ResearchAgenda

Epidemiologic Studies/Platforms

Individual Studies Individual Studies Cross sectional studiesCross sectional studies Case-control studiesCase-control studies Cohort studies/biobanks Cohort studies/biobanks

Consortia/NetworksConsortia/Networks P3GP3G ““Network of Networks”Network of Networks”

Epidemiologic Studies/Platforms

Human Genome Epidemiology Network: From Primary Research to Knowledge Integration

Analyses and Publications

Systematic Reviews

Knowledge Base“Genomics and Population Health”

HuGENet

Guide HealthServices & InformPublic Policy

Guide ResearchAgenda

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

Number of Published HuGE Papers* 2001-2004

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•MOST ASSOCIATION STUDIES ARE CASE-CONTROL STUDIESMOST ASSOCIATION STUDIES ARE CASE-CONTROL STUDIES

Rank GeneSymbol

Gene name # of Papers01-03

1 APOE apolipoprotein E 481

2ACE angiotensin I converting enzyme (peptidyl-

dipeptidase A) 1398

3MTHFR 5,10-methylenetetrahydrofolate reductase

(NADPH)377

4HLA-DRB1

major histocompatibility complex, class II, DR beta 1

376

5TNF tumor necrosis factor (TNF superfamily, member

2)346

6 GSTM1 glutathione S-transferase M1 253

7HLA-DQB1

major histocompatibility complex, class II, DQ beta 1

248

8 F5 coagulation factor V (proaccelerin, labile factor) 213

9GSTT1 glutathione S-transferase theta 1 204

10 IL10 interleukin 10 177

Epidemiological Quality in Molecular GeneticResearch: Need for Methodological Standards

Bogardus et al. JAMA 1999;281:1919-26.

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

Methodologic % Standard

Reproducibility 38% Objectivity 33% Case Group 78% Case Spectrum 88% Comparison Group 70% Comparison Spectrum

88% Quantitative Summary

90%

What is STROBE ?

STROBE: international collaborative STROBE: international collaborative initiative for initiative for STSTrengthening the rengthening the RReporting eporting of of OBOBservational studies in servational studies in EEpidemiologypidemiology

Epidemiologic Studies/Platforms

Human Genome Epidemiology Network: From Primary Research to Knowledge Integration

Analyses and Publications

Systematic Reviews

Knowledge Base“Genomics and Population Health”

HuGENet

Guide HealthServices & InformPublic Policy

Guide ResearchAgenda

The Need for Systematic Reviews:on Genetic Variation and Health

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

Epidemiologic Studies/Platforms

Human Genome Epidemiology Network: From Primary Research to Knowledge Integration

Analyses and Publications

Systematic Reviews

Knowledge Base“Genomics and Population Health”

HuGENet

Guide HealthServices & InformPublic Policy

Guide ResearchAgenda

HuGENet Products (as of September 1, 2005)

HuGE Reviews HuGE Reviews 4040 Meta/Pooled AnalysesMeta/Pooled Analyses 269 269 Fact sheetsFact sheets 1313 E-journal clubsE-journal clubs 6666 Case studiesCase studies 5 5 Genotype Prevalence DatabaseGenotype Prevalence Database 1313

Published Literature Database 17,467Published Literature Database 17,467 # Genes# Genes 2003 2003 # Risk Factors# Risk Factors 656 656 # Outcomes# Outcomes 2068 2068

Epidemiologic Studies/Platforms

Human Genome Epidemiology Network: From Primary Research to Knowledge Integration

Analyses and Publications

Systematic Reviews

Knowledge Base“Genomics and Population Health”

HuGENet

Guide HealthServices & InformPublic Policy

Guide ResearchAgenda