Meeting Notes - September 10, 2009

PENTACON GLUE Grant Consortium Meeting, Penn Sept 10th 2009.

This meeting reviewed the draft revision of the planning grant due for submission on September 16th.
Several major points emerged from the day’s discussion.

• A major feature of this endeavor could be taking advantage of new approaches to communication – Goggle; PLOS systems, NCBI initiatives) to establish a new paradigm for “group science” where issues like communication, training, dissemination and authorship across the consortium might be continuously refined. List new mechanisms of collaboration as an output.
• It was suggested that the pitch be adjusted to facilitate more the “lay” reader. Examples would be putting numbers on the people exposed and the CV consequences of the coxibs; the (retrospective) predictive power of Zak’s approach to pharmacovigilance; charting how different data silos were ignored and how that contributed to delay in recognizing or interpreting hazard and how different types of data only made sense when integrated. Perhaps a table of such synergies ( or a posting of the upcoming Ann Rev of Medicine article on Googlegroups). Integration of data could be a bullet point in the high level assessment of outcomes.
• Somewhere there should be a list of likely new technologies including some that cant be stated explicitly at this time – e.g. new informatics tools.
• Post on google a table of specific responses to the reviewers’ concerns.
• Multiple Venn diagrams of investigators might replace original table 1 and this could be web posted.
• Front end emphasis on data curation should be listed as a high level output . Maybe promise a subcommittee specifically targeted on annotation. Propose workshop on this specific issue early given the experience of how each model has its own syntax and how ortholog mapping can be hazardous. Adopt common approach to network construction across species. (Olga will draft a paragraph here for potential inclusion).
• Presentation from Rick Bushman on microbiome prompted much enthusiasm. Ideally this could immediately become part of the first book end ( together with assessment in patients undergoing joint replacement to look at gut floral impact of high dose antibiotic interaction with NSAIDs) and a translational study in ~300 humans where we would in a randomized manner apply the same analyses as in the first book end to validate drug impact on measurements. Integration of metabolomics signatures in urine where Jules is the key person with stool analysis would be nice in the human studies. Ideally gnotobiotic mice and zebrafish (ref from Calum) can be used to assess the impact of NSAIDs on microbiome and microbiome on NSAID metabolism and action across species. Zak and Tilo can come up with a questionnaire to get some handle on diet in these studies. However we could expand on this in the phase II grant as we are already conduction controlled evaluation of dietary substrate manipulations (EPA/DHEA) where we could gather preliminary data.
• Precedent paper already on acetaminophen disposition in people:
  Clayton TA, Baker D, Lindon JC, Everett JR, Nicholson JK. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14187-8. PMID: 19667173 (pdf)
• Some discussion of the ethnicity hypothesis raised by the studies in B lymphocytes. Scott provides some suggestion that there might be an impact on events in his overview of celecoxcib trials. Perhaps this might intersect with ethnic differences in microbiome attributable to dietary
  preferences. There was discussion of including immortalization studies in the first book end but it was thought contingent on evidence for the functional importance of the B lymphocyte mRNA variability from ongoing studies in relatively small numbers with extreme phenotypes before
  justifying the expense of moving to scale.
• Considerable discussion on yeast in response to reviewers concerns. Yeast will afford us the chance to discuss two aspects of “off target” drug effects assuming that we validate reported absence of COXs (we will seek PG formation).  
  • Firstly, COX inhibition might have a secondary distant effect on a net work that is functionally relevant (e.g. thrombomodulin regulation by prostacyclin contributing to the effects of NSAIDs on hemostasis).
  • Secondly, NSAIDs might interact directly with another signaling system that impacts on functional outcome. (e.g. inhibition of elements of NFkB signaling).
  • Thirdly, the drugs might affect cytotoxicity (e.g hepatotoxicty from diclofenac or lumiracocoxib). Yeast are set up to probe all 3. While the latter is not a feature of the major NSAID CV and GI adverse effects (of celecoxib, naproxen or ibuprofen), hepatotoxicty is the basis for the most common drug AEs and probing this aspect is particularly relevant to the generalizability of the paradigm that we will establish. In this regard cautious integration of GWAS in first bookend should be prompted by detection in very small numbers by GWAS of a MHC II haplotype signal for lumiracoxib hepatotoxicity (pdf) (ref also Evan JAMA paper on drug metabolism and GWAS) and PharmGKB .
• New approaches to on vs off target effects could be an bullet output.
• A table should be presented with a timeline and metrics of progress.
• We should discuss how our human data will be compliant with the highest standards of confidentiality. Commitment to sharing has had a very beneficial effect on genome community so to this we are committed. Here we could play a leadership role in establishing standards for sharing other types of data. Identify a subset of human investigators across institutions that establish shared IRB approval. Lazy evaluation approach to IP. Russ to revise expand the final para although more detail is provided on the website.