This document summarizes the objectives and approach of the Continuous Update Project (CUP) Mechanisms Project. The project aims to develop guidelines for systematically reviewing mechanistic studies linking exposures like diet and cancer. It will create a template protocol through expert workshops and test it on a specific exposure-outcome link. Challenges include developing generalizable methods, assessing study quality, and determining relevance to humans. The methodology could mainstream how mechanistic evidence is reviewed and inform future research directions.

1. Continuous Update Project Systematic Reviews of Animal and
Human Mechanistic Studies
Martin Wiseman
Medical and Scientific Adviser
WCRF International
London
UK
Visiting Professor of Human Nutrition
University of Southampton
UK
IUNS, Granada, 2013

2. www.dietandcancerreport.org/CUP
www.wcrf.org/ICN201

3. WCRF/AICR Reports citations

4. Global variation in cancer
incidence
Breast
Colorectal

5. Migration data Trends in
incidence (Japan)
Per 100,000, world population standard

6. Systematic reviews
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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
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Nutrition, epidemiology, systematic review, cancer biology, statistics

7. Inferring causality
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Bradford Hill
Strength
Consistency
Specificity
Timing
Dose Response
Plausibility and coherence
Experiment
Analogy

8. 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

9. GRADING THE EVIDENCE
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Convincing
Probable
Basis for
recommendations
Limited Evidence – Suggestive
Limited Evidence – No Conclusion
Substantial Effect on Risk Unlikely

12. 2007 Second Expert Report
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Information from mechanistic studiesnarrative reviews
Evidence on mechanisms-predefined
requirement for grading criteria
Considerations:
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reviews not systematic
could select a mechanism to explain
epidemiological associations

13. CO M M EN T
EARTH SY STEM S P a s t c l i m a t e s
g iv e v a lu a b le c lu e s t o f u t u r e
w a r m i n g p.5 3 7
H ISTORY OF SCI EN CE D e s c a r t e s ’
lo st le t t e r t r a c k e d u sin g
G o o g l e p.5 4 0
OBITUARY W y l i e V a l e
a n d a n e lu siv e st r e ss
h o r m o n e p.5 4 2
29 MARCH 2012 | VOL 483 | NATURE | 531
S . G S C H M E IS S N E R / S P L
AVI AN I N FLUEN ZA S h i f t e x p e r t i s e
to trac k m u t at io n s w h ere
t h e y e m e r g e p.5 3 4
M a n y l a n d m a r k fi n d in g s i n p r e c l i n ic a l o n c o l o g y r e s e a r c h a r e n o t r e p r o d u c i b le , i n p a r t b e c a u s e o f in a d e q u a t e c e l l l i n e s a n d a n i m a l m o d e l s .
R a ise st a n d a r d s fo r
p r e c lin ic a l c a n c er r e se a r c h
C . G len n B eg ley an d L ee M . E llis p ro p o se h o w m et h o d s, p u b lic at io n s a n d
in c e n t iv e s m u st c h a n g e if p a t ie n t s a r e t o b e n e fit .

14. CO M M EN T
29 MARCH 2012 | VOL 483 | NATURE | 531
EART H SYST EM S P a s t c l i m a t e s
g iv e v a lu a b le c lu e s t o f u t u r e
w a r m i n g p.5 3 7
HI STORY OF SCI ENCE D e s c a r t e s ’
lo st le t t e r t r a c k e d u sin g
G o o g l e p.5 4 0
OB ITUA RY W y l i e V a l e
a n d a n elu siv e st r e ss
h o r m o n e p.5 4 2
S . G S C H M E IS S N E R / S P L
AVI AN IN FLUEN Z A S h i f t e x p e r t i s e
to t rac k m u t at io n s w h ere
t h e y e m e r g e p.5 3 4
M a n y la n d m a r k fi n d i n g s i n p r e c l in i c a l o n c o l o g y r e s e a r c h a r e n o t r e p r o d u c ib l e , i n p a r t b e c a u s e o f i n a d e q u a t e c e l l l i n e s a n d a n i m a l m o d e l s .
R a ise st a n d a r d s fo r
p r e c lin ic a l c a n c er r e se a r c h
C . G len n B eg ley a n d L ee M . E llis p r o p o se h o w m e t h o d s, p u b lic a t io n s a n d
in c e n t iv e s m u st c h a n g e if p a t ie n t s a r e t o b e n e f it .
E
ffo rts o v er th e p a st d e c a d e to
c h a r a c t e r iz e t h e g e n e t ic a lte r a t io n s
in h u m a n c a n c e r s h a v e le d to a b e tte r
u n d e r s t a n d in g o f m o le c u la r d r iv e r s o f t h is
c o m p le x s e t o f d is e a s e s . A lt h o u g h w e in t h e
c a n c e r f ie ld h o p e d t h a t th is w o u ld le a d to
m o r e e f f e c t iv e d r u g s , h is t o r i c a lly , o u r a b i lit y
to t r a n s l a t e c a n c e r r e s e a r c h t o c li n i c a l s u c c e s s h a s b e e n r e m a r k a b ly lo w 1. S a d ly , c lin i c a l
tr ia ls in o n c o lo g y h a v e t h e h ig h e s t fa ilu r e
r a te c o m p a r e d w it h o t h e r t h e r a p e u tic a r e a s .
G iv e n t h e h ig h u n m e t n e e d in o n c o lo g y , it
is u n d e r s t a n d a b le t h a t b a r r ie r s to c lin ic a l
d e v e lo p m e n t m a y b e lo w e r t h a n f o r o t h e r
d is e a s e a r e a s , a n d a la r g e r n u m b e r o f d r u g s
w it h s u b o p t i m a l p r e c li n i c a l v a li d a t io n w i ll
e n te r o n c o lo g y t r i a ls . H o w e v e r, t h is lo w s u c c e s s r a te is n o t s u s t a in a b le o r a c c e p t a b le , a n d
© 2 0 12 M a c m il l a n P u b li s h e r s L i m i t e d . A l l r ig h t s r e s e r v e d
in v e s t ig a to r s m u s t r e a s s e s s th e ir a p p r o a c h to
tr a n sla tin g d is c o v e r y r e s e a rc h in to g r e a te r
c lin ic a l s u c c e s s a n d im p a c t .
M a n y fa c to r s a r e r e s p o n s ib le fo r t h e h ig h
fa ilu r e r a te , n o tw ith s t a n d in g t h e in h e r e n t ly d iff ic u lt n a tu r e o f t h is d is e a s e . C e r ta in ly, th e lim ita tio n s o f p re c lin ic a l to o ls
s u c h a s in a d e q u a te c a n c e r - c e ll- lin e a n d
m o u s e m o d e ls 2 m a k e it d if fic u lt fo r e v e n
2 9
M A R C H
2 0 1 2
|
V O L
4 8 3
|
N A T U R E
|
5 3 1
• Reproducibility
• Relevance of model
• Relevance of exposure
• Relevance of dose
• Route of administration
• Publication bias

15. 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.

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

17. 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

18. CUP Mechanisms Project
Objectives
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Two Phases (18 month project)
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Develop draft template protocol to stage where
it can be tested using specific exposureoutcome link (Phase 1)
Carry out feasibility test of developed template
protocol for conducting systematic reviews of
mechanistic evidence for specific exposurecancer link (Phase 2)

19. WCRF International Continuous Update Project
Systematic review method for mechanistic evidence
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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

20. Systematic reviews of mechanisms
Conditions
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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…

21. Overall approach
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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

22. Challenges
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Developing a one size fits all template
Finding the relevant studies
Determining study quality
Determining the strength of evidence for different
study types
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Determining the relevance to humans
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Publication bias
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Collating and synthesising the evidence
Displaying the results

23. Potential Impact
Recommendations based on most robust
science
Beyond CUP
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New methodology-mainstream approach
to review mechanistic studies
 Inform direction of future research in area
of diet/PA/body fatness and cancer
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24. Thank you!
www.dietandcancerreport.org/CUP
www.wcrf.org/ICN2013