Vision for Accelerating the Development and Dissemination of the Knowledge Base on Human Genetic...

Vision for Accelerating the Development and Dissemination of the Knowledge Base on

Human Genetic Variation and Health

Muin J. Khoury

Outline

• The Public Health Genomics Enterprise

• Evolution of Networks

• Added Value of HuGENet

• Vision for an Online Encyclopedic Distributed Knowledge Base

The “Public Health Genomics” Enterprise

– Developing and applying Genome-based knowledge for the benefit of population health

– The central role of knowledge integration

Communication and Stakeholder Engagement

Improvement

in

Population

Health

Informing Public Policy

Developing and Evaluating Health Services

Society

Research

Education and Training

Genome-based Science and Technology

KnowledgeIntegration

WithinAnd

AcrossDisciplines

Population Sciences

Humanities and Social Sciences

From the Bellagio Group

Risk Factors

Demographics

Diet

Occupation

Smoking

Alcohol

Environment

Adverse Health Outcom

es

The End of Black Box Epidemiology

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)

MMPsSusceptibilit

y to environment

al toxins

CYP1A1GSTT1

Courtesy S. Dolan Courtesy S. Dolan MD MD

Data/Sample Collection Platforms

Reports & Publications

Network

Evolution of Networks and Consortia

Data/Sample Collection Platforms

Reports & Publications

Systematic Reviews

Updated SummaryKnowledge base

Network

Evaluation of Genetic Tests inPractice & Prevention

Identify Gaps For Research

Evolution of Networks and Consortia

Data/Sample Collection Platforms Database(s)

Reports & PublicationsDatabase(s)

Systematic Reviews Database (s)

Updated SummaryKnowledge base(s) Portal

Network of

Networks

Communicate, Assist, Harmonize



Evolution of Networks and Consortia: Network of Networks



Systematic Reviews Databases

Updated SummaryKnowledge base(s)

Network of

Networks


+ HuGENet



STROBE StatementDevelop Methods Foster Research Conduct WorkshopsHuGE Journal/Portal

Evolution of Networks and Consortia HuGENet Contribution




Updated SummaryKnowledge base(s)

Network of

Networks


+ HuGENet




HuGENet ManualHuGENet SoftwareDevelop Methods FosterResearchConduct Workshops





Network of

Networks


+ HuGENet




HuGENet ManualHuGENet SoftwareDevelop Methods FosterResearchConduct Workshops

Dissemination

Methods forGrading evidence& Synthesis

Develop methods


OnlineEncyclopedia

Proposed Online Encyclopedia of Human

Genetic Variation and Health

• Succinct summary of gene-disease associations• Online and widely disseminated• Updated regularly• Peer reviewed• Distributed knowledge base• Evidence based synthesis• Grading of evidence

Clinical Evidence

• “Summarises the current state of knowledge and uncertainty about the prevention and treatment of clinical conditions, based on thorough searches and appraisal of the literature.

• It is neither a textbook of medicine nor a set of guidelines.

• It describes the best available evidence from systematic reviews, RCTs and observational studies where appropriate, and if there is no good evidence it says so.”

Diseases are Associated with Multiple Genes and Vice Versa

• Diseases

• A• B• C• D• E• F• G

• Genes/Variants

• 1• 2• 3• 4• 5• 6• 7

What could an Encyclopedia Entry Look Like?

• Health Outcome• Gene (s)• Association for each gene with outcome (RR,

AF, including gene-gene and gene-environment interactions)– Systematic reviews– Scattered studies

• Methodologic comments: Grading of evidence• Clinical and public health implication• References and link to other internet

sites/databases

Grading of Evidence?

• Size of effect– A Small effect (RR <1.5)– B Moderate effect (RR 1.5-4)– C Large effect (RR>4)

• Replication– A Single or scattered studies– B Meta analysis of group data– C Meta analysis of individual data

Modified from Ioannidis, Int J Epi 2005

Grading of Evidence?

• Methodology– A Clear presence of bias – B Uncertain of presence of bias – C Clear protection from bias

• Biology– A No or negative biologic data– B Limited or inconsistent functional data– C Biologic data supportive or consistent

Modified from Ioannidis, Int J Epi 2005

GRADING OF EVIDENCE?

Effect Size

Replica-tion

Metho-dology

Biology

A

B

C

------NO EVIDENCE------------

WEAK TO MODERATE EVIDENCE

----STRONG EVIDENCE----

Criterion&Grade



Systematic Reviews Database (s)

OnlineEncycopledia

Network of

Networks




Evolution of Networks and Consortia: Network of Networks

Vision for Accelerating the Development and Dissemination of the Knowledge Base on Human Genetic...

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