Martin Wiseman

Medical and Scientific AdviserWCRF InternationalLondonUK

Visiting Professor of Human NutritionUniversity of SouthamptonUK

IUNS, Granada, 2013

Continuous Update Project -Systematic Reviews of Animal and Human Mechanistic Studies

www.dietandcancerreport.org/CUP

www.wcrf.org/ICN2013

WCRF/AICR Reports citations

Global variation in cancer incidence

Breast

Colorectal

Per 100,000, world population standard

Migration data Trends in incidence (Japan)

Expert international Task Force for method Nine centres - USA, UK, NL, Italy SLR centre coordinator Test of reproducibility Standardised search, analysis and display Epidemiology and mechanisms Quality assessment Peer review - protocol, report Defined expertise required

Nutrition, epidemiology, systematic review, cancer biology, statistics

Systematic reviews

• Strength• Consistency• Specificity• Timing• Dose Response• Plausibility and coherence• Experiment• Analogy

Bradford Hill

Inferring causality

GRADING CRITERIA

Predefined requirements for:

–Number and types of studies–Quality of exposure and outcome assessment–Heterogeneity within and between study types–Exclusion of chance, bias or confounding–Biological gradient–Evidence of mechanisms–Size of effect

Convincing Probable

Limited Evidence – Suggestive Limited Evidence – No Conclusion

Substantial Effect on Risk Unlikely

Basis for recommendations

GRADING THE EVIDENCE

2007 Second Expert Report

Information from mechanistic studies-narrative reviews

Evidence on mechanisms-predefined requirement for grading criteria

Considerations: reviews not systematic could select a mechanism to explain

epidemiological associations

29 MARCH 2012 | VOL 483 | NATURE | 531

29 MARCH 2012 | VOL 483 | NATURE | 531

• Reproducibility• Relevance of model• Relevance of exposure• Relevance of dose• Route of administration

• Publication bias

Meta-analysis of the association between TP53 status and the risk of death at 2 years

Kyzas P A et al. JNCI J Natl Cancer Inst 2005;97:1043-1055

© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org.

• Systematic reviews • Allow objective appraisal of evidence • Reduce false-positive & false-negative results• Identify sources of bias, improving study quality

• Extensive mechanistic data from animals & cell lines linking diet & cancer

• Rigorous methods for conducting & reporting SRs of mechanistic studies are lacking

• This project should increase the value of mechanistic data:

• Enable more rigorous systematic reviews • Increased precision of estimated effects • Identify gaps in the research evidence• Reduce selective citation of mechanistic evidence• Inform generalisability to humans (e.g. heterogeneity across species &

models)• A potential tool in the translation of basic sciences into

policy & practice

Importance

Mechanisms Protocol Development Group

• Stephen Hursting (chair)

• Andrew Dannenberg

• Johanna Lampe

• Henry Thompson

• Steven Clinton

• Nikki Ford - associate member

Task: develop guidelines on how review of mechanisms could be approached

CUP Mechanisms Project Objectives

Two Phases (18 month project)

Develop draft template protocol to stage where it can be tested using specific exposure-outcome link (Phase 1)

Carry out feasibility test of developed template protocol for conducting systematic reviews of mechanistic evidence for specific exposure-cancer link (Phase 2)

University of Bristol Multidisciplinary team (informatics, statistics,

epidemiology, systematic reviews, cancer biology, pathology, nutrition)

Search terms/inclusion-exclusion criteria How to manage vast number of papers What information to be extracted How to analyse/display results Identify criteria for grading the evidence

WCRF International Continuous Update Project Systematic review method for mechanistic evidence

Reviews to be systematic and peer reviewed

Reviews conducted by exposure Feasibility test of final draft protocol by

external group, including peer review Molecular, cellular, physiological…

Systematic reviews of mechanismsConditions

Overall approach Four workshops with experts within group at

University of Bristol, UK

Regular meetings between workshops refine the protocol carry out searches investigate quality criteria determine inclusion/exclusion criteria consider methods to investigate publication bias consider methods to report/display results

External reference groups CUP Panel Mechanisms PDG

Developing a one size fits all template Finding the relevant studies

Determining study quality

Determining the strength of evidence for different study types

Determining the relevance to humans

Publication bias

Collating and synthesising the evidence Displaying the results

Challenges

Potential Impact Recommendations based on most robust

science

Beyond CUP New methodology-mainstream approach

to review mechanistic studies Inform direction of future research in area

of diet/PA/body fatness and cancer

Thank you!

www.dietandcancerreport.org/CUP

www.wcrf.org/ICN2013