Ramazzini Days 2016
CONFLICT OF INTEREST AND THE
OUTCOMES OF REVIEWS ON
ARTIFICIALLY SWEETENED BEVERAGES:
A SYSTEMATIC REVIEW
Daniele Mandrioli
Cesare Maltoni Cancer Research Center
Ramazzini Institute
Carpi, October 28° 2016
DECLARATION OF INTERESTS
I declare I have no actual or potential competing financial
interests, including travel funding, consultancies, board
positions, patent and royalty arrangements, stock shares, or
bonds.
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THE (ADDED) VALUE OF INDEPENDENCE
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CONFLICT OF INTEREST AND OF RISK OF BIAS
The Cochrane Collaboration authors showed that industry sponsorship is
able to affect research outcome in the medical field.
COI has been proposed as a risk of bias item by the Cochrane Collaboration
and AHRQ and is already include as an item in the assessment of the
Navigation Guide. NTP-OHAT handbook includes screening for conflict of
interest, while funding source is recommended as a factor to consider when
evaluating risk of bias of individual studies for selective reporting and then
again for evaluating the body of evidence for publication bias.
Viswanathan M, Ansari M, Berkman ND, Chang S, Hartling L, McPheeters LM, Santaguida PL, Shamliyan T, Singh K, Tsertsvadze A, Treadwell JR. 2012. Assessing the risk of bias of individual studies
when comparing medical interventions (March 8, 2012). Agency for Healthcare Research and Quality Methods Guide for Comparative Effectiveness Reviews. March 2012.
Woodruff TJ, Sutton P. 2014. The Navigation Guide systematic review methodology: a rigorous and transparent method for translating environmental health science into better health outcomes.
Environ Health Perspect 122:1007–1014; doi: 10.1289/ehp.1307175
NTP-OHAT 2015. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.
Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. 2012. Industry sponsorship and research outcome. Cochrane Database Syst Rev 12:MR000033; doi: 10.1002/14651858.MR000033.pub2. 4
CONFLICT OF INTEREST AND OF RISK OF BIAS
Questions:
Is
conflict of interest a systematic source of bias also in the field of
toxicology and environmental health?
Can
the bias induced by conflict of interest be captured by other items in
the risk of bias assessment?
Can
the peer review process prevent the potential risk of bias derived from
conflict of interest?
Viswanathan M, Ansari M, Berkman ND, Chang S, Hartling L, McPheeters LM, Santaguida PL, Shamliyan T, Singh K, Tsertsvadze A, Treadwell JR. 2012. Assessing the risk of bias of individual studies
when comparing medical interventions (March 8, 2012). Agency for Healthcare Research and Quality Methods Guide for Comparative Effectiveness Reviews. March 2012.
Woodruff TJ, Sutton P. 2014. The Navigation Guide systematic review methodology: a rigorous and transparent method for translating environmental health science into better health outcomes.
Environ Health Perspect 122:1007–1014; doi: 10.1289/ehp.1307175
NTP-OHAT 2015. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.
Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. 2012. Industry sponsorship and research outcome. Cochrane Database Syst Rev 12:MR000033; doi: 10.1002/14651858.MR000033.pub2. 5
SYSTEMATIC REVIEWS IN TOXICOLOGY

A Systematic Review is a literature review
focused on a research question that tries to
identify, appraise, select and synthesize all
high quality research evidence relevant to
that question.

Cochrane is recognized as the most
authoritative source for systematic reviews
in medicine and is official partner of WHO
for evidence-based evaluation.

Current Guidelines for Systematic Reviews
and Risk of Bias Assessment in
Environmental Health and Toxicology:
NTP-OHAT Handbook, Navigation Guide,
GRADE.
Mandrioli D, Silbergeld EK. Evidence from Toxicology: The Most Essential Science for Prevention. Environ Health Perspect. 2016 Jan;124(1):6-11.
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SYSTEMATIC REVIEW PRINCIPLES AND
METHODS

Clarity in defining the question under analysis defining populations,
exposures, comparators, outcomes, timings, and settings of interest
(PECOTS)

Transparent and replicable research strategy

Transparent data extraction and presentation

Comprehensive assessment of risk of bias

Transparent criteria for determining if quantitative data integration is
appropriate and conducting data integration, such as meta-analysis

Appropriate statistical models for integrating data

Discussion of limitations and cautions in interpretation

Disclosure of Conflicts of Interest
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RISK OF BIAS
A bias is a systematic error, or deviation from the truth, in
results or inferences
Why is risk of bias important?

More rigorous studies are more likely to yield results that are
closer to the truth

Results may be consistent among studies but all the studies
may be flawed
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RISK OF BIAS ITEMS
Items accepted and proposed for risk of bias assesment and other methodological
criteria of interest for nonhuman models in toxicology*:
Treatment
allocation/randomization.
Concealment
of allocation.
Blinding.
Inclusion/exclusion
Selective
Reporting
Incomplete
Financial
Outcome Data
conflict of interest.
Dose–response
Optimal
criteria.
model.
time window investigated.
*David Krauth,1 Tracey J. Woodruff,2,3 and Lisa Bero1,4 Instruments for Assessing Risk of Bias and Other Methodological Criteria of Published Animal Studies: A Systematic Review.
Environ Health Perspect; DOI:10.1289/ehp.1206389
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SYSTEMATIC REVIEW ON COI AND RISK OF BIAS
Background
Several reviews examining the effects of artificially sweetened beverages on
obesity have discrepancies in their results and conclusions.
Objectives
To determine whether risk of bias, results, and conclusions of reviews of
effects of artificially sweetened beverage consumption on weight outcomes
differ depending on review sponsorship, authors’ financial conflicts of interest
and journal funding.
Characteristics
Risk of bias performed according to Cochrane methods.
Conflict of interest assessed according to ICMJE criteria.
Over 900 records screened (31 reviews met our inclusion criteria)
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TRANSPARENCY

Authors of 42% (13/31) of reviews had conflicts of interest
that were not disclosed in the article;

Most of these (n = 8) were in reviews that also had no
disclosed funding sources
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REVIEW FUNDING AND REVIEW OUTCOMES

Artificial sweetener industry sponsored reviews were more
likely to have favorable results (3/4) than non-industry
sponsored reviews (1/23), RR: 17.25 (95% CI: 2.34 to
127.29), as well as favorable conclusions (4/4 vs. 15/23), RR:
1.52 (95% CI: 1.14 to 2.06).

All reviews funded by competitor industries reported nonfavorable results and conclusions (4/4).
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COI OF THE AUTHORS AND REVIEW OUTCOMES

Reviews performed by authors that had a financial conflict of
interest with the food industry were more likely to have
favorable conclusions (18/22) than reviews performed by
authors without conflicts of interest (4/9), RR: 7.36 (95% CI:
1.15 to 47.22).
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JOURNAL FUNDING AND REVIEW OUTCOMES

Almost all the reviews published in industry or mixed funded
journals reported favorable conclusions (11/12), while the
majority of the reviews published in non-industry funded
journals did not reported favorable conclusions (8/19) RR:
2.18 (95% CI: 1.25 to 3.79).
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RISK OF BIAS

Risk of bias of the reviews was generally high

No difference in risk of bias among study funded by different
sources or performed by conflicted authors
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PEER-REVIEW

Almost all the reviews were published in peer-reviewed
journals (27/31). No difference in peer-review process among
review funded by different sources or performed by conflicted
authors.
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CONCLUSIONS

Financial conflicts of interest introduced a bias at all levels of
the research and publication process (author financial ties,
review sponsorship and journal funding), affecting the
outcomes of reviews

The bias introduced by financial interests could not be
ascribed to the overall risk of bias of the reviews and was not
prevented by the peer review process.

Our results confirm the need for including conflict of interest
as an item in risk of bias assessment
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CONCLUSIONS

The opposite direction of bias in the outcomes of reviews
funded by producers and competitors. Fair evaluations of
safety and effectiveness of products might be potentially
undermined by reviews performed by competitors.

Need for increased transparency and accountability in
policies for declaration of interest
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Acknowledgments
Fiorella Belpoggi and the Ramazzini Institute Staff
Ellen Silbergeld, Johns Hopkins
Lisa Bero, University of Sydney
Cristin Kearns, University of California
Elizabeth Waters, Cochane Collaboration
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REMEMBERING CESARE MALTONI
Maltoni-1974-La cancerogenesi ambientale e professionale. Nuove prospettive alla luce della cancerogenesi da cloruro di vinile.
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REMEMBERING CESARE MALTONI
“The reward of great men is that, long after they have died, one is
not quite sure that they are dead”
Jules Renard , 1864 -1910