Anita de Waard

1. Closing the Loop:
Towards Claim-Evidence
Networks in Clinical Practice
Anita de Waard
VP Research Data Collaborations, Elsevier

2. Clinical Communication
Has Many Loose Ends…
Case
Reports
Case
Reports
About.comAbout.com
WikipediaWikipedia
Patient
Forums
Patient
Forums
Patient.co.ukPatient.co.uk
Papers and
Papers and
Papers and
Papers…
Papers and
Papers and
Papers and
Papers…

3. • Data2Semantics Project: Linking clinical guidelines to evidence in a
linked data form
• Goal: improve speed of integration of research > practice
• Issue: citations seem to provide evidence… or do they?
Studies have demonstrated inconsistent results regarding the use
of such markers of inflammation as C-reactive protein (CRP),
interleukins- 6 (IL-6) and -8, and procalcitonin (PCT) in neutropenic
patients with cancer [55–57].
Studies have demonstrated inconsistent results regarding the use
of such markers of inflammation as C-reactive protein (CRP),
interleukins- 6 (IL-6) and -8, and procalcitonin (PCT) in neutropenic
patients with cancer [55–57].
[55]: …PCT and IL-6 are more reliable markers
for neutropenia than CRP for predicting
bacteremia in patients with febrile
[55]: …PCT and IL-6 are more reliable markers
for neutropenia than CRP for predicting
bacteremia in patients with febrile
[56] In conclusion, daily measurement of PCT or
IL-6 could help identify neutropenic patients with a
stable course when the fever lasts >3 d. …, it would
reduce adverse events and treatment costs.
[56] In conclusion, daily measurement of PCT or
IL-6 could help identify neutropenic patients with a
stable course when the fever lasts >3 d. …, it would
reduce adverse events and treatment costs.
[57] Our study supports the value of PCT as
a reliable tool to predict clinical outcome in
febrile neutropenia.
[57] Our study supports the value of PCT as
a reliable tool to predict clinical outcome in
febrile neutropenia.
Why Is That A Problem?
1. From Trials to Guidelines

4. Why is that a problem? 2.
44

5. 5

6. Karen Dineen Wagner, M.D., Ph.D.; Adelaide S. Robb, M.D
Robert L. Findling, M.D.; Jianqing Jin, Ph.D.; Marcelo M
Gutierrez, Ph.D. William E. Heydorn, Ph.D.
A Randomized, Placebo-Controlled Trial of Citalopram f
the Treatment of Major Depression in Children and
Adolescents
Am J Psychiatry 2004;161:1079-1083.
10.1176/appi.ajp.161.6.1079
Karen Dineen Wagner, M.D., Ph.D.; Adelaide S. Robb, M.D.
Robert L. Findling, M.D.; Jianqing Jin, Ph.D.; Marcelo M.
Gutierrez, Ph.D. William E. Heydorn, Ph.D.
A Randomized, Placebo-Controlled Trial of Citalopram fo
the Treatment of Major Depression in Children and
Adolescents
Am J Psychiatry 2004;161:1079-1083.
10.1176/appi.ajp.161.6.1079
Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S.
Escitalopram in the treatment of adolescent depression: a
randomized placebo-controlled multisite trial.
J Am Acad Child Adolesc Psychiatry. 2009 Jul;48(7):721-9.
Disclosure: Dr. Emslie has received grants from the National
Institute of Mental Health, Eli Lilly and Company, Forest
Laboratories, …. Drs. Ventura, Korotzer, and
Tourkodimitris are employees of Forest Research Institute.
Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S.
Escitalopram in the treatment of adolescent depression: a
randomized placebo-controlled multisite trial.
J Am Acad Child Adolesc Psychiatry. 2009 Jul;48(7):721-9.
Disclosure: Dr. Emslie has received grants from the National
Institute of Mental Health, Eli Lilly and Company, Forest
Laboratories, …. Drs. Ventura, Korotzer, and
Tourkodimitris are employees of Forest Research Institute.
http://clinicaltrials.gov/ct2/show/NCT00107120
Emslie Study:
The Safety and Efficacy of Escitalopram in Pediatric Patients With Major
Depressive Disorder
Sponsor: Forest Laboratories
Information provided by: Forest Laboratories
ClinicalTrials.gov Identifier: NCT00107120
http://clinicaltrials.gov/ct2/show/NCT00107120
Emslie Study:
The Safety and Efficacy of Escitalopram in Pediatric Patients With Major
Depressive Disorder
Sponsor: Forest Laboratories
Information provided by: Forest Laboratories
ClinicalTrials.gov Identifier: NCT00107120
The citalopram trial (Wagner et al., 2004) that formed part of the basis for
escitalopram FDA approval was alleged to have been written and
submitted by a medical “ghost-writer” on behalf of Forest Laboratories,
Inc. [...] Drs. Wagner, Robb, and Findling reported that they had received
an initial draft from Dr. Heydorn to which they contributed through several
drafts. . Drs. Wagner, Robb, and Findling report that they contributed with
Dr. Heydorn to the resubmission and that they were not aware that Dr.
Heydorn was working with a commercial writer. Dr. Heydorn did not
respond to our request for comment.
The citalopram trial (Wagner et al., 2004) that formed part of the basis for
escitalopram FDA approval was alleged to have been written and
submitted by a medical “ghost-writer” on behalf of Forest Laboratories,
Inc. [...] Drs. Wagner, Robb, and Findling reported that they had received
an initial draft from Dr. Heydorn to which they contributed through several
drafts. . Drs. Wagner, Robb, and Findling report that they contributed with
Dr. Heydorn to the resubmission and that they were not aware that Dr.
Heydorn was working with a commercial writer. Dr. Heydorn did not
respond to our request for comment.
The research groups that have studied citalopram and escitalopram for pediatric depression in
RCTs are not independent groups, with the exception of the von Knorring group from Sweden
(von Knorring et al., 2006). However, the RCT by this group was a negative trial. The other
principal investigators on the studies analyzed here are co-authors on each others studies
(Wagner et al., 2006; Wagner et al., 2004) and one group performed the double blind extension
(Findling et al., 2008) of the other group’s RCT (Emslie et al., 2009). From these data,
escitalopram and citalopram should not be considered for first-line treatment of adolescent
depression, given the lack of replication of positive studies by independent groups. […]
Each positive RCT lasted for only 8 weeks duration (Wagner et al., 2004; Emslie et al., 2009),
and there was only one 16 week extension (Findling et al., 2008). Hence, the indication for
escitalopram for maintenance treatment of adolescent depression is premature. […]
While not required for licensing approval, a glaring omission is the lack of head to head trials
of escitalopram or citalopram with fluoxetine, the gold-standard treatment for pediatric
depression.
The research groups that have studied citalopram and escitalopram for pediatric depression in
RCTs are not independent groups, with the exception of the von Knorring group from Sweden
(von Knorring et al., 2006). However, the RCT by this group was a negative trial. The other
principal investigators on the studies analyzed here are co-authors on each others studies
(Wagner et al., 2006; Wagner et al., 2004) and one group performed the double blind extension
(Findling et al., 2008) of the other group’s RCT (Emslie et al., 2009). From these data,
escitalopram and citalopram should not be considered for first-line treatment of adolescent
depression, given the lack of replication of positive studies by independent groups. […]
Each positive RCT lasted for only 8 weeks duration (Wagner et al., 2004; Emslie et al., 2009),
and there was only one 16 week extension (Findling et al., 2008). Hence, the indication for
escitalopram for maintenance treatment of adolescent depression is premature. […]
While not required for licensing approval, a glaring omission is the lack of head to head trials
of escitalopram or citalopram with fluoxetine, the gold-standard treatment for pediatric
depression.
Conclusion
In conclusion, the available evidence does not support
first-line treatment of adolescent depression with either
escitalopram or citalopram. It is our opinion that the US
FDA approval of escitalopram was premature, given the
available evidence.
Conclusion
In conclusion, the available evidence does not support
first-line treatment of adolescent depression with either
escitalopram or citalopram. It is our opinion that the US
FDA approval of escitalopram was premature, given the
available evidence.

7. 7
Lexapro under performing in the under 20 age segment (9%)Lexapro under performing in the under 20 age segment (9%)

8. So How Do We Connect
These Loose Ends?
Case
Reports
Case
Reports
About.comAbout.com
WikipediaWikipedia
Patient
Forums
Patient
Forums
Patient.co.ukPatient.co.uk
Papers and
Papers and
Papers and
Papers…
Papers and
Papers and
Papers and
Papers…

9. So How Do We Connect
These Loose Ends?
WikipediaWikipedia
Cancer
Commons
Cancer
Commons
WebsitesWebsites

10. Scientists Clinical Researchers Physicians Patients
Guidelines Data Case ReportsTrials Treatments Journals
One Example of a Closed Loop:
Cancer Commons
© Marty Tenenbaum
Reference
Models

11. Another example of a closed loop:
the Cochrane Collaboration*
•Our mission is to promote evidence-informed health decision-making by
producing high-quality, relevant, accessible systematic reviews and other
synthesized research evidence.
•Cochrane Reviews are systematic reviews of primary research in human
health care and health policy, and are internationally recognised as the highest
standard in evidence-based health care.
(*) Thanks to Chris Borgman for reminding me of Cochrane”s!

12. Trying to find evidence in papers:
Big Mechanism
1. Identify epistemic values (v.1 completed):
– Problem (Value = 0.25): “Until now, it has been unclear how RAS could affect ASPP2 to
enhance p53 function.”
– Hypothesis (Value = 0.5): “It is likely that this possible feedback loop leads to an
amplified pro-apoptotic signal.”
– Implication (Value = 0.75): “We show here that ASPP2 is phosphorylated by the
RAS/Raf/MAPK pathway..”
– Fact (Value = 1.0): “ASPP2 is a haploinsufficient tumor suppressor [15] [16] and it can
cooperate with p53 to suppress tumour growth in vivo [15].”
1. Identify source of statements (in progress):
– Result (Source=Author): “Here we show that monoubiquitination decreases the
sensitivity of Ras to GAP–mediated hydrolysis. ”
– Others-Result (Source=Citation): “It has recently been shown that oncogenic RAS can
enhance the apoptotic function of p53 via ASPP1 and ASPP2. [2]”
1. Identify basis of statements (in progress):
– Result (Basis=Data): “…we observed two conserved putative MAPK phosphorylation
sites in ASPP1 and ASPP2.”
– Hypothesis (Basis=Reasoning): “If RAS is only temporarily active, as happens in natural
growth conditions, one could hypothesize that ASPP2 would bind active RAS, potentiate
its downstream pathways, and MAPK-mediated phosphorylation of ASPP2 would lead to
increased binding to p53.”

13. In Summary:
• Having all clinical trials available is GREAT – but it’s
not enough:
– Example: guideline does not summarize trials
– Example: marketing drugs enables sketchy evidence to look
strong
• What we need: better relations between claims and
evidence:
– Example: Cancer Commons
– Example: Cochrane Collaboration
– Example: finding epistemics in text
• Better tools to link to evidence
• More cries for evidence!