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9/28/2004 REMBRANDT Empowering Translational Research… RE M BRA N DT REpository of Molecular BRAin Neoplasia DaTa HL7 Clinical Genomics SIG Atlanta, September04.

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Presentation on theme: "9/28/2004 REMBRANDT Empowering Translational Research… RE M BRA N DT REpository of Molecular BRAin Neoplasia DaTa HL7 Clinical Genomics SIG Atlanta, September04."— Presentation transcript:

1 9/28/2004 REMBRANDT Empowering Translational Research… RE M BRA N DT REpository of Molecular BRAin Neoplasia DaTa HL7 Clinical Genomics SIG Atlanta, September04

2 9/28/2004 Agenda Translational Research – Why do we care? GMDI – How we got here? Conceptual Model Gene Expression Use Case analysis Gene Expression Data analysis Wire Frames System Architecture Object Model Data warehouse design

3 9/28/2004 Translational Research – Why do we care? Iressa Drug Case Study ( at Harvard Medical School ) Targeted towards lung cancer Phase II trial – A minority of patients showed dramatic tumor shrinkage Phase III randomized trial – No survival improvement. Patients with mutations in Iressas target, EGFR, showed response to the drug. Pharmacogenomics future is based on translational research Reference: Clinical Pharmacogenomics: Almost a reality; Modern Drug Discovery, August 2004

4 9/28/2004 Scientific goals of GMDI Develop a molecular classification schema that is both clinically and biologically meaningful, based on gene expression and genomic data from tumors (Gliomas) of patients who will be prospectively followed through natural history and treatment phase of their illness

5 9/28/2004 Rembrandt Knowledgebase Better understanding Better treatments Expression array data Clinical data SNPArray data Proteomics data

6 9/28/2004 REMBRANDT Project Goals Produce a national molecular/genetic/clinical database of several thousand primary brain tumors that is fully open and accessible to all investigators (including intramural and extramural) Provide informatics support to molecularly characterize a large number of adult and pediatric primary brain tumors and to correlate those data with extensive retrospective and prospective clinical data

7 9/28/2004 Functional genomics data in the knowledge-base RNA 100K SNP array Protein Tissue Arrays for ISH Gene Expression Analysis Affy/Oligo Arrays cDNA/GenePix Arrays Real time RTPCR LOH Copy No. DNA Proteomics (Mass Spec) Tissue Arrays (IHC) Array CGH

8 9/28/2004 Conceptual Model UserInputUserInput Sample SNP Abnorm_Status SNP_Expt Call Gene Change_Status Expr_Expt E-value BAC_ID Map_Location CGH_Expt Abnorm_Status Patient Survival Prior_Therapy Outcome Demographics Pathology Trial Time course C3D CaCore caArray

9 9/28/2004 REMBRANDT will Leverage NCICB and caBIG Infrastructure Components Aligns with caBIG principles: Open source Open access Syntactic and Semantic interoperability Federated data NCICB Infrastructure caARRAY gene expression data repositories and analysis tools Cancer Genome Anatomy Project (CGAP) genomic tools C3D Clinical Informatics System caCORE Infrastructure (caBIO, EVS, caDSR) caBIG Infrastructure being delivered by caBIG workspaces

10 9/28/2004 Typical Rembrandt Search Show me the tumors (Tumor samples) that have amplification and over-expression of Genes EGFR & Cyclin D1. Restrict the search to cases with amplification confirmed by SNP Chip and CGH, and over-expression confirmed by Oligo and cDNA Arrays Presentation of Results Which genes are under-expressed respect to normal? Do this subset of tumors have a better survival? Do they segregate to a certain age group, geographical area or ethnicity?

11 9/28/2004 True Measure of Translation Research To present the all DOWN Regulated Genes within each sample in the result set, we have to pivot the result set on its Gene Expression axis. All Translational Queries should allow the ability to easily pivot between: Disease View Patient / Sample View Experiment/ Annotations View Time Course View

12 9/28/2004 High-level Search Use cases

13 9/28/2004 Gene Expression Search Use cases

14 9/28/2004 Gene Expression data analysis Binary chp files from GCOS Convert chp files to txt files Using GDAC SDK Calculate ratio of individual tumor intensity to Normal pool Calculate ratio of average intensities between tumor pool and Normal pool Calculate statistical significance for comparison, using Permax R module

15 9/28/2004 cDNA data handling Technical Replicates Pearson Correlation between one spot across all arrays and another spot for the same clone across all arrays Is Correlation > 0.7 Yes No For each array, calculate the average of expression measurement inconsistent call is made and no e-value Computed for that clone

16 9/28/2004 UI Wire Frames

17 9/28/2004 UI Wire Frames

18 9/28/2004 Architecture

19 9/28/2004 Object Model DomainElement Represents the basic elements involved in translational research space. All queries, views and presentation objects are composed of domain elements Provides strong type checking and validations

20 9/28/2004 Database Schema Star schema Is a generic, query optimized schema A star schema consists of Fact tables and dimensions Provides a highly de-normalized view of the data Provides a data neutral framework from which queries can be executed with very fast results Prototype usage will help us validate our approach

21 9/28/2004 Database Schema Fact Table Contains key performance indicators Helps eliminate expensive joins from queries In the future, if multi-dimensional measures are required, then our schema is extensible to allow us to perform OLAP queries Dimension Dimensions are the categories of data analysis When a report is requested "by" something, that something is usually a dimension. For example, in a gene expression query, the two dimensions needed are genes (GENE_DM) and samples (BIOSPECIMEN _DM)

22 9/28/2004 Database Schema

23 9/28/2004 Problem we are trying to solve A typical Rembrandt data portal search: Show me all tumor samples that have amplification of 13q11.3, deletion of 10p21, D7S522 and the FHIT region confirmed by SNP chips and CGH analysis. Display regions with LOH for these samples. Which genes are under-expressed in these tumor samples with respect to normal? Do this subset of tumors have a better survival? Do they segregate to a certain age group, geographical area or ethnicity?

24 9/28/2004 Fact: Cancer develops as a result of Chromosomal aberrations Duplications Deletions Somatic Mutations We need to measure chromosomal aberrations To solve this problem Chrom N, Copy 1 Chrom N, Copy 2 LOH Complete Loss Duplication

25 9/28/2004 How to measure aberrations? CGH SNP Arrays Have higher resolution than CGH Analyze chromosomal copy number and genotype in one experiment SNP arrays help determine the following between normal blood sample and Tumor sample Heterozygous to Homozygous: Loss of one allele Heterozygous to No Call: Partial Loss of one allele/No Call Homozygous to Homozygous: Unchanged/Loss of one allele

26 9/28/2004 Genotype model for Rembrandt Model basic science Model SNPs in relation to chromosomal aberrations and as markers on the genome Model to include annotations and external cross-references Model Experimental observations Capture observations such as LOH in relation to SNPs and chromosomal aberrations (CGH data) Capture expression value for SNP elements on arrays to correlate with DNA copy number

27 9/28/2004 Translational Research use case The Clinical Genomics model should serve the translational research use case Model should allow for associations between: Basic science / molecular observations (Gene expression, SNP, pathway etc) Clinical science (Prior therapy, outcome, demographics etc) data.

28 9/28/2004 Translational Research Space Genotype Model Clinical Trial Model caBIOEVS caDSR caMOD MAGE-OM /caArray

29 9/28/2004 Next Steps Reviewing the HL7 Re-usable genotype R-MIM as a starting point to build a clinical genomics object model Translating the genotype R-MIM into UML to establish relationships and cardinalities between various scientific observations For REMBRANDT, Extending the caBIO Object Model Developing a data warehouse infrastructure for REMBRANDT to define relevant translational spaces and relationships between them Future: We plan to merge our clinical objects with the HL7 Clinical model

30 9/28/2004 The Rembrandt Team! Ram Bhattaru James Luo Alex Jiang Prashant Shah Ryan Landy Kevin Rosso Jyotsna Chilukuri Dana Zhang Nick Xiao Smita Hastak Himanso Sahni Subha Madhavan Internal Advisors Ken Buetow Peter Covitz Sue Dubman Mervi Heiskanen Carl Schaefer Christo Andonyadis Scott Gustafson Sharon Settnek External Advisors Jean-Claude Zenklusen Yuri Kotliarov Howard Fine Tracy Lugo Bob Finkelstein

31 9/28/2004 I am done Questions

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