Meeting Notes - June 8, 2009

GLUE 4 - PENTACON (Personalized NSAID Therapeutics Consortium ).

Informatics Meeting. June 8th 2009.

September 2009 Planning grant submission
May 2010 Full grant submission
Review December 2010
Funding cycles; March/May 2011 – 2016-2021.

ATTENDEES; ALTMANN, KOHANE, WISHART, BLAIR, HOGENSESCH, PIZARRO, FITZGERALD

SEVERAL GRANTS WERE SUBMITTED IN RESPONSE TO STIMULUS FUNDING OF RELEVANCE TO THE GLUE PROPOSAL. THESE AY SUPPORT GATHERING CONSIDERABLE PRELIMINARY DATA BEFORE A FULL SUBMISSION AND WILL BE A NICE OPPORTUNITY TO START POPULATING DATA MATRICES THAT WE ESTABLISH AND TO INITATE ANNOTATION ETC UNDER KARA’S DIRECTION.

ARRA responses:

(i) to perform studies in mice and humans to determine whether heterogeneity of COX-2 expression in EBV transformed lymphocytes ex vivo is related to variability in NSAID response [NIGMS Challenge];

(ii) to utilize novel mouse models to explore the mechanism by which NSAIDs predispose to heart failure [NCI Challenge];

(iii) to determine genetic modifiers of the hypertensive response to NSAIDs involving studies in inbred mice and humans and the development of a related systems network [GO];

(iv) limited studies in humans to explore potential variability in analgesic efficacy of NSAIDs [CTSA supplement]

(v) cloud computing [CTSA supplement].

(vi) NMR bioinformatics recruitment [ARRA p30 supplement]

FOLLOWING GLUE 3 WE CAME UP WITH THESE QUANTITATIVE VARIABLES [ A FEW
MORE WERE ADDED AT THIS MEETING] AND THE IDEA WAS TO DEVELOP A MATRIX
ACROSS THE 5 SYSTEMS – YEAST,MAMALIAN CELLS, FISH, MICE, HUMANS – TO LINK
INDIVIDUAL VARIABLES IN INDIVIDUAL SYSTEMS

Matrix of Quantitative Variables:
Blood pressure (salt loading/deprivation; pressor infusion)
Renal function (GFR, urine biomarkers, osmolarity etc)
Analgesic response (self rated VAS, fMRI, arterial spin labeling estimate of blood flow)
Potential PET readouts
Thermal response
Drug and metabolite exposure
Hepatic function (enzymes)
GI – Hgb in zebrafish
Markers of on target action (urine metabolites, whole blood assays)
Markers of off target action ( lipidomics [PL turnover], proteomics, metabolomics)
Arrhythmias
CNS effects in model organisms

DISCUSSION CENTERED ON THE HIGH PRINCIPLES RELATED TO INFOMRATICS ENUNCIATED AT GLUE 1 ( IN LOWER CASE) AND ELABORATED ON HERE IN HIGHER CASE INFORMATICS

Distributed network; build only when needed. Loose on standards in order not to strangle innovation, but high quality, curated data made available to the public upon publication.

(i) Common MOU on data sharing – NIGMS review of PharmGkB document
THIS IS A HIGH PRIOIRITY ; THE IDEA IS FOR THE INFORMATICS GROUP TO DRAFT THIS AND ATTENDANT MATERIALS FOR A JULY 15TH DEADLINE AS A PRELUDE TO INCLUSION IN THE PLANNING GRANT HAD THE IDEA TO ESTABLISH APROVISIONAL PENTACON WEBSITE WHERE WE COULD LIST ALL THESE MATERIALS AND PROGRESS THAT LETS US GET BEYIND PAGE RESTRICTIONS IN THE PLANNING GRANT OBJECTIVES TO FORGE AGGREMENT ON IP ISSUES AMONGST PIS. YOU HAVE TO BE WILLING TO POSTPONE IP AGREEMENTS UNTIL RELAIZATION OF ACTUAL VALUE AND
THEN THE PRINCIPLE WILL BE TO DIVIDE UP BETWEEN PARTICIPATING PLAYERS. SOME VERSION OF THIS WOULD BE A CONDITION OF ENTRY INTO THE CONSORTIUM DON’T PLAY UNLESS YOU ARE WILLING TO SHARE IDEA TO HAVE STUDIES AT SCALE AS BOOKENDS TO THE PROJECT INITALLY MAYBE A THOUSAND PEOPLE ON 2-3 DIFFERENT NASAIDS AND COLLECT OMICS DATA ON THEM; UNBIASED SURVEY OF DRUG DISTINCTIONS THEN DO ALL THE PARTICULATE STUDIES THAT WE PLAN AND GENERATE HYPOTHESES THEN PROJECT TO SCALE IN RANDOMIZED TRIALS WHERE THESE HYPOTHESES ARE TESTED BUT ALSO DISCOVERIES THAT MIGHT HAVE DERIVED FROM THE UNBIASED ANALYSES IN THE FIRST BOOKEND

(ii) Development of a questionnaire for participating researchers on their informatics requirements.

(iii) Common IRB approaches for specimen collection and storage for future unknown analyses
ZAK HAS TEMPLATES ; NEED TO GO BEYOND BEYOND DEIDENTIFICATION

(iv) Two levels of information access anticipated. High level curation co-ordinated by Kara Dolinski from Princeton.
A GENERAL PRINCIPLE:
BIOINFORMATICS GUYS HAVE TO INVOLVE EXPERIMENTALISTS IN PUBLICATION REASSURE THEM ON NOT BEING SCOOPED ON THEIR OWN DATA DATA CONDITIONER AT EACH SITE REPORTING TO KARA

(v) A restricted wiki with password for uploading data sets, presentations, and curation notes for data sets so that all can understand them. Web site for dissemination contents of wiki as things are published.

(vi) Formalize reporting structure from nodes.

(vii) Perhaps an iterative tool for accumulating data and using it for in silico predictions prior to next round of experimental perturbations.

OUTPUTS BY JULY 15TH:
DRAFT MOU;
QUESTIONAIRRE,
WIKI;
KARA OPERTAING RULES;
IP AND PUB RULES;
PARTNERS EST HOW MANY ON CELECOXIB , NAPROXEN , IBUPROFEN.
RECRUIT RICK BUSHMAN – GUT MICROBIOME
OLGA AND CAROLYNE THORNE

RELATIONSHIPS WITH EXTERNAL NETWORKS
(i) PharmGkB -Russ
(ii) I2b2-Zak
(iii) DrugBank, FDA
(iv) National Biomedical Computation Centers
(v) indigobio.com

ULTIMATE OUTPUTS
• new quantitative models of drug response ;
• new technologies;
• new ideas about how drugs might be developed and approved;
• new exposures for trainees.