transmart community meeting 5-7 nov 13 - session 5: advancing transmart analytical capabilities with...
DESCRIPTION
tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content Sirimon Ocharoen, Thomson Reuters To effectively analyze data in tranSMART, biological analysis/knowledge-based approach is needed. Through a case study, we will demonstrate how system biology content can be integrated in tranSMART to enable functional analysis and biological interpretation. We will also share our experience and user feedbacks from various projects.TRANSCRIPT
![Page 1: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/1.jpg)
ADVANCING TRANSMART ANALYTICAL CAPABILITIES WITH KNOWLEDGE CONTENT
tranSMART Community Meeting
Sirimon O’[email protected]
November 6th, 2013
![Page 2: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/2.jpg)
2
4 EXAMPLES OF tranSMART USE CASES
• Use case 1: Leveraging public datasets
• Use case 2: Finding information on variant and mutation
• Use case 3: Biological interpretation
• Use case 4: Implementing classification model
• Feedbacks from tranSMART users
![Page 3: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/3.jpg)
3
Leveraging Public Datasets
USE CASE 1
![Page 4: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/4.jpg)
4
Where else is IL-33 gene significantly expressed?
Up-regulated in an asthma study
![Page 5: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/5.jpg)
5
What are other genes significantly expressed in Ulcerative Colitis?
![Page 6: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/6.jpg)
6
REG1A
![Page 7: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/7.jpg)
7
SLC6A14
![Page 8: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/8.jpg)
8
MICROARRAY REPOSITORY:PROCESSING PROCEDURE
A. Search for Datasets in public databases & Data loading
B. Quality Control (QC) testing of Raw Assays (filtering out of unsuitable defective Assays)
C. GCRMA Processing of QC-approved Assays
D. Assays Annotation: i. Assignment of experimental
meta-data values to the Assays
ii. Assignment of experimental Assays Groups and their Comparisons
E. Statistical analysis of defined Comparisons:
i. Differential expression testingii. Calculation of Fold Changesiii. Functional Descriptors
calculation
(A)(B)
(C)
(D)
(E)
Optional: cutoffs
![Page 9: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/9.jpg)
9
MICROARRAY REPOSITORY:QC PROCEDURE
• Datasets undergo rigorous quality control during processing
• An assay is removed from the dataset if it’s identified as an outlier by the majority of qc metrics
• Users are able to see which tests the datasets passed/failed
![Page 10: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/10.jpg)
MICROARRAY REPOSITORY: ANNOTATION PROCEDURE
10
METACORE
Additional manual annotation of datasets increases granularity & numbers of groups and comparisons
![Page 11: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/11.jpg)
11
Finding Information on Variant and Mutation
USE CASE 2
![Page 12: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/12.jpg)
12
How does 17p13 deletion correlated to thalidomide response in chronic lymphocytic leukemia (CLL) patients?
WBC Reduction at Day 7
No abberation vs. 17p13 deletion
![Page 13: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/13.jpg)
13
What are other diseases or drugs that 17p13 deletion is associated to?
![Page 14: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/14.jpg)
14
GENE VARIANT RECORD
![Page 15: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/15.jpg)
15
GENE VARIANT ASSOCIATIONS
![Page 16: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/16.jpg)
GENE VARIANT API
16
Significance of genotype-phenotype relationships across the translational pipeline
OH
O
O
O
DISEASEDRUGVARIANTDISEASEVARIANT
IDENTIFY ACTIONABLE GENE VARIANTS
A. Establish variant significance B. Characterize the variantC. Asses the utility of the
variant:• Understanding Disease
Mechanism • Treatment & Response
DISEASE RECORD RESPONSE RECORD
Disease ProfilingDiagnosisPrognosis
Screening, Risk
Predicting Efficacy / ToxicityMonitoring Efficacy / Toxicity
Selection for TherapyResistance
DISCOVERY VALIDATION APPLICATION
Preclinical in vitro & animal studies Clinical studies in patient segments
FDA approvals Clinical guidelines
HTP StudiesCandidate Studies
MANUALLY CURATED CONTENT FROM A RANGE OF SOURCES
![Page 17: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/17.jpg)
GENE VARIANT API: PROCEDURE
17
SOURCES
SOURCE SELECTION
VS. REJECTION
SELECTION CRITERIA BY THE ANALYST
conference abstracts, patents, peer reviewed journal articles, clinical trial registries, clinical guidelines, and
authority approval documents (ex. FDA)
• Retrospective selection or prospective screening for frontfile. Items are screened by a text-mining tool to identify and remove items that have no relevance to the Gene Variant API.
• All articles not removed are sent to manual selection by trained annotators who follow the policy.
• A clear study design, and valuable results are required by the analyst. The item must satisfy requirements of evidence-based medicine in order to be taken into consideration.
• Statistics and / or statement by the author of the variant effect on health are required. If both components are absent, the item is rejected.
![Page 18: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/18.jpg)
18
Biological Interpretation
USE CASE 3
![Page 19: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/19.jpg)
19
INVASIVE BREAST CANCER STUDY
Find predictors for treatment response
![Page 20: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/20.jpg)
20
RCB 0/I RCB III
MARKER SELECTION WORKFLOW
![Page 21: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/21.jpg)
21
NFIB nuclear factor IB type- a potential biomarker in breast neoplasmsSTK24 –induction of apoptosisESR1- Estrogen receptor 1PGR – Progesteron receptorCDKN2A Cyclin-dependent kinase inhibitor 2A Geminin – DNA replication inhibitorMCM2/5- a regulatory subunit inhibiting the helicase complexCDC45L- Cell cycle control proteinMSH6 and MSH2 - MutS homologues, proteins involved in DNA repairRAD50 – DNA repair protein (homologues recombination-dependent repair)DNMT1 – DNA methylation enzymeEZH2- Histone methylation enzymeHDAC2- Histone acetylation enzyme
Significant signaling pathways enriched with differentially expressed genes in Responders vs. Non-responders
Estrogen/Progesteron signalingCell Cycle regulationDNA damage repairEpigenetic regulation of gene expression
ENRICHMENT ANALYSIS
![Page 22: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/22.jpg)
22
PATHWAY MAPS
Brca1 and Brca2 in breast cancer Cell cycle: Start of DNA replication in early S phase
![Page 23: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/23.jpg)
23
PATHWAY MAPS
Epigenetic alterations in ovarian cancer
PR action in breast cancer -stimulation of cell growth and proliferation
![Page 24: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/24.jpg)
24
Implementing Classification Model
USE CASE 4
![Page 25: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/25.jpg)
25
PATIENT STRATIFICATION MODEL
![Page 26: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/26.jpg)
IMPLEMENTING MODEL IN tranSMART
Sample Molecular Subtype
Associated clinical phenotype
ModelBiomarkers
Stratification rule
Mechanism
Drug target
Standard tranSMART
MetaCore Cytoscape
Pathways
SubnetworksAdditional functionality in tranSMART
Applicable for both One Mind and Orion projects
![Page 27: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/27.jpg)
SYSTEMS BIOLOGY TOOLS
Network/Pathways based Approach–
OMICs data + other data types including clinical response
Statistical Approach
• Drug Targets
• Drug Repositioning
• Biomarker Identification
• Biological Mechanism
Reconstruction
• Drug Combinations
• Prognostic Biomarkers
• Predictive Biomarkers
SYSTEMS BIOLOGY TOOL LIBRARYState of the art methods
METABASEThe most comprehensive data available
![Page 28: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/28.jpg)
Systems Biology(Zhang et al., 2011)
Probabilistic Inference(Su et al., 2009)
Pathway Activity(Lee et al., 2007)
RRFE(Johannes et al., 2010)
Subnetworks(Chuang et al., 2012)
EXAMPLES OF NETWORK APPROACHES
Pathway Based(Kim et al., 2012)
![Page 29: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/29.jpg)
29
FEEDBACKS FROM tranSMART USERS
![Page 30: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/30.jpg)
30
STATISTICAL ANALYSIS QUESTIONS
• How to control Type 1 error rate?– Testing set vs. Validation set
• How to perform longitudinal analysis?– Regression models
• How to identify covariance variables? Which variable has the highest correlation with the outcome?– Multivariate analysis
• Other analysis methods/workflows
![Page 31: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/31.jpg)
31
SCIENTIFIC QUESTIONS
• How to set QC framework around uploaded data? Community developed QC standard?
• How to do across study analysis (easier)?
• How to do across species analysis?
• How to the community report these (and bugs)?
![Page 32: tranSMART Community Meeting 5-7 Nov 13 - Session 5: Advancing tranSMART Analytical Capabilities with Knowledge Content](https://reader035.vdocuments.mx/reader035/viewer/2022070304/54bbf1b94a795952248b4569/html5/thumbnails/32.jpg)
32
FEATURE WISH LIST
• Multiple improvement to R advance workflows
• Sending results (gene list, patient subsets) from an advanced workflow back to summary statistics
• Saving a workflow (history/output)
• Using gene expression data to create subsets
• Viewing specific subject records
• Adding data types (i.e. date, longitudinal measurement)
• Improving exported tables
and many more ….