ImmPort strategies to enhance discoverability of clinical trial data
Immunology Database and Analysis Portal ImmPort immport
description
Transcript of Immunology Database and Analysis Portal ImmPort immport
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Immunology Database and Analysis PortalImmPort
www.immport.org
Richard H. Scheuermann, Ph.D.Department of Pathology
U.T. Southwestern Medical Center
16 DEC 2010
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ImmPort Purpose and History
• NIH/NIAID/DAIT would like to:– maximize the return on the public investment in basic, translational and
clinical research
– allow investigators to more effectively extract meaningful information from the vast amounts of data generated from advanced research technologies
– => data sharing policy
• Bioinformatics Integration Support Contract (BISC) to support data sharing for all DAIT-funded programs - basic, translational and clinical research
• Immunology Database and Analysis Portal (ImmPort) - www.ImmPort.org
– Archive and manage basic and clinical research data
– Integrate these research data with extensive biological knowledge
– Support analysis of these integrated data
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Take-home messages
• ImmPort has been tailored to support the needs of the immunology research community
• Comprehensive integrated resource for the capture, support and analysis of a wide range of basic, translational and clinical research data
• Compliant with established and emerging data standards, e.g. MIAME, MIFlowCyt, Cell Ontology
• Work collaboratively with system users to develop and implement novel data processing and analysis methods
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Built by
ImmunologistsBioinformaticiansComputational BiologistsBiostatisticiansProfessional Software Developers
for Immunologists
Tailored for immunology
Built by Immunologists for Immunologists
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Vignettes
• HLA Region Genetics Consortium
– HLA typing ambiguity reduction pipeline
– HLA sequence feature definition and variant type analysis and visualization
– PyPop-based genetic analysis
• Novel methods and infrastructure for flow cytometry analysis – FLOCK
• Comprehensive support for clinical and translational research design and results data – Casale/ITN
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www.immport.org
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Reference and research data
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Visualization tools
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Analysis tools
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Workspaces
• Public– Reference data– Accessible without registration or log in
• “Semi-public”– Research data released after publication– Access to analytical tools– Registration and log in required for access– Accessible to all registered users
• Private– Pre-publication research data– Access controlled by P.I. (or P.M.)
• Collaborative– Controlled sharing of research data
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Vignettes
• HLA Region Genetics Consortium
– HLA typing ambiguity reduction pipeline
– HLA sequence feature definition and variant type analysis and visualization
– PyPop-based genetic analysis
• Novel methods and infrastructure for flow cytometry analysis – FLOCK
• Comprehensive support for clinical and translational research design and results data – Casale/ITN
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Summary of SFVT approach
• Traditional HLA allele association analysis treats entire allele as a single unit and does not capture the structural relationships between alleles
• Sequence Feature Variant Type (SFVT) approach – Define individual sequence features (SF) in HLA proteins (genes)
– Determine the extent of polymorphism for each sequence feature by defining the observed variant types (VT)
– Re-annotate HLA typing information with complete list of VT for each SF
– Examine the association between every sequence feature variant type and disease or other phenotype
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Representative Sequence Features
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A*0201 - ‘CD8 binding’ &‘TCR binding’ SF
CD8 Binding
TC
R B
inding
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Summary of SFs defined
1775 total
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Variant Types for Hsa_HLA-DRB1_beta-strand 2_peptide antigen binding
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Publication
67F 70D
71R
86V
26F
37Y
30Y28D
67I 70D
71R
86G
26F
37F
30L28E
protective risk
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ImmPort HLA SFVT Workflow
Table of subject vs. HLA 4-digit typing data Table of subject vs. SFVT feature vector
Table of p-values, adj. p-values, odds ratio, confidence intervals
CD8 Binding
TC
R B
inding
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HLA Typing Platforms and Ambiguity
• HLA Typing Platforms– SSOP – single-stranded oligonucleotide probe– SSP – sequence-specific priming– SBT – sequence-based typing– SSCP – single-stranded conformation polymorphism
• Allelic Ambiguity– Typing methodology cannot distinguish between sets of
alleles– Polymorphisms that distinguish these alleles are not
interrogated by the method• Outside of exon 2 (class II) or exons 2 and 3 (class I)• Sections of these exons not covered by the probes/primers
• Genotypic Ambiguity– Inability to determine phase in heterozygous samples
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Ambiguity in HLA Typing Data
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Allelic Ambiguity Reduction
Eliminate others
Eliminate others
Are any of the alleles reg-CWD?
Are any of the alleles reg-CWD?
Elimination of less-probable alleles by CWD statusReduction of multiple alleles to G- or P-codes
yes
no
Eliminate others
Eliminate others
Are any of the alleles
CWD?
Are any of the alleles
CWD?
yes
no
Eliminate others
Eliminate others
Are any of the alleles reg-Rare?
Are any of the alleles reg-Rare?
yes
Combine to G-code
Combine to G-code
Do any alleles belong to a common G-
code?
Do any alleles belong to a common G-
code?
yes
no
Combine to P-code
Combine to P-code
Do any alleles or G-codes belong to a common P-
code?
Do any alleles or G-codes belong to a common P-
code?
yes
Eliminate rare alleles
Eliminate rare alleles
Do the alleles contain any
G- or P-codes?
Do the alleles contain any
G- or P-codes?
yes
no
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Outcome of HLA Ambiguity Reduction
Allelic Ambiguity Reduction
Genotypic Ambiguity Reduction
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Vignettes
• HLA Region Genetics Consortium
– HLA typing ambiguity reduction pipeline
– HLA sequence feature definition and variant type analysis and visualization
– PyPop-based genetic analysis
• Novel methods and infrastructure for flow cytometry analysis – FLOCK
• Comprehensive support for clinical and translational research design and results data – Casale/ITN
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Flow Cytometry Analysis
FLOCK is an algorithmic application for the identification of unique cell populations in multi-dimensional flow cytometry data
N1-3
UM1-2
UM3-4PB GSM
GNSM
DNM
CD27
IgD
A
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Population statistics
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Summary Statistics
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B cell component of the Cell Ontology
http://www.obofoundry.org/
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FlowCAP
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Vignettes
• HLA Region Genetics Consortium
– HLA typing ambiguity reduction pipeline
– HLA sequence feature definition and variant type analysis and visualization
– PyPop-based genetic analysis
• Novel methods and infrastructure for flow cytometry analysis – FLOCK
• Comprehensive support for clinical and translational research design and results data – Casale/ITN
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5+ DAIT-funded Programs
Immune Function and Biodefense in Children, Elderly, and Immunocompromised Populations Program
Population Genetics Analysis Program: Immunity to Vaccines/Infections Program
HLA Region Genetics in Immune-Mediated Diseases Program
Other Consortium Projects
Immune Modeling Centers
ImmPort Research Data | My Work Bench
Browse Data/ ImmPort Research Data/ ImmPort Supported Programs
Reagent Development for Toll-like and other Innate Immune Receptors
DMID-funded Centers of Excellence for Influenza Research and Surveillance
GlaxoSmithKline – COPD trial
34 Projects, >100,000 subjects, terabytes of FCM, microarray, SNP genotype, ELISA, ELISPOT, etc. data
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PopGen
Grants/Contracts/Projects:
Population Genetics Analysis Program: Immunity to Vaccines/Infections Program
Project Title Institute Principle
Investigator Objective Number of Subjects Mechanistic Assays Status
Immunity to Vaccinia Virus Infection Mayo Clinic Gregory A. Poland,
M.D .
To correlate variability in humoral and cell-mediated immune responses to vaccinia virus immunization with genetic variation in the HLA, cytokine and cytokine receptor genes and the broader genome.
1,076ELISA, ELISPOT, HLA genotype, GWAS, Microarray, Flow Cytometry
Completely loaded in PPW
Population Genetics Program on West Nile Virus Project
McMaster University Mark Loeb, Ph.D.
Gene analysis using Illumina Human NS-12 and Omni 1, single nucleotide polymorphisms (SNPs) to compare gene frequencies between individuals with meningoencephalitis and those with West Nile Fever using a case-control study design.
1,346Infinium assay, sequenom, whole-genome expression
Completely loaded in PPW
Immunity to Vaccines/Infections Immune Response Polymorphisms: Smallpox, Tuberculosis, Influenza and Common Encapsulated Bacteria Infections
deCODE Genetics Jeffrey Gulcher,
M.D., Ph.D.
To map, isolate and validate human host genes that confer risk of either adverse reactions to smallpox vaccination or lack of specific immune response to the vaccine.
90,037genotyping, mRNA expression, GWAS
Partially loaded in PPW
Immune Response Polymorphisms: Typhoid/Cholera Vaccines
RTI International Diane Wagener,
Ph.D.
To understand role of polymorphisms in genes of innate and adaptive immunity in modulating the response to typhoid vaccine.
2000
Sequencing , ELISA, Mass spectrometry, multiplex bead assay, gel electrophoresis, shotgun proteomics, vibriocidal assay
Completely loaded in PPW
Genetic Risk for Smallpox Vaccine Related to Myocarditis
University of Washington Christopher B. Wilson, M.D.
To identify genetic differences that increase the risk for a major adverse event associated with smallpox vaccination - myocarditis - and to determine the mechanism by which these genetic differences confer risk
Unknown? SNP Array Genotyping, HLA genotyping
Completely loaded in PPW
Genetic Factors and Immune Response to Anthrax Vaccine
Univerity of Alabama at Birmingham, Birmingham
AL
Richard Kaslow, M.D.
To investigate variability in host genes predicting variation in antibody responses and adverse reactions to Anthrax Vaccine Adsorbed (AVA).
1453ELISA, Flow Cytometry, Pyrosequencing, Gene expression
Completely loaded in PPW
ImmPort Research Data | My Work Bench
Browse Data/ ImmPort Research Data/ ImmPort Supported Programs
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Special Pops
Grants/Contracts/Projects:
Immune Function and Biodefense in Children, Elderly, and Immunocompromised Populations Program
Project Title InstitutionPrinciple
Investigator ObjectiveNumber of
Subjects Mechanistic Assays Status
An Improved Influenza A Vaccine for Rapid Protection of the Elderly
The Wistar InstituteHildegund C. J. Ertl, M.D.
To conduct pre-clinical studies needed to develop a vaccine for the elderly that would provide protection in the event of a bioterror attack with influenza A virus.
600ELISA, ELISPOT, Flow Cytometry
Partially loaded in PPW
Protective Immunity in Transplant Recipients
Emory Transplant Center
Larsen, Christian, Ph.D.
To determine the effects of chronic immunosuppressive therapies on adaptive, innate and specific immunity
90ELISA, ELISPOT, Microarry, RT - PCR
Partially loaded in PPW
Kinetic analysis of immunologic repletion and influenza vaccine responsiveness
Children´s Hospital of Philadelphia
Sullivan, Kathleen, Ph.D.
To propose a comprehensive analysis of the immunologic response to killed trivalent influenza vaccine in different immunocompromised populations in order to understand how to improve vaccine responses
54ELISPOT, Sequencing, Flow Cytometry
Partially loaded in PPW
Immune Function and Biodefense in Children, Elderly, and Immunocompromised Populations: TLRs in Innate Immunity and the Induction of Adaptive Immunity in the Neonate and Infant
University of Washington
Hajjar, Lynn, M.D.
To define comprehensively and in molecular and cellular detail differences in recognition and response to microbe-derived danger signals between adults, neonates and infants, and how these, in turn, contribute to differences in innate immunity and the induction of antigen-specific (adaptive) immunity
17 adults, 17 neonates
RT-PCR, ELISA, Flow Cytometry, Microarray
Partially loaded in PPW
Responses to Influenza Vaccination in Systemic Lupus
Oklahoma Medical Research Foundation (OMRF)
Thompson, Linda, Ph.D.
To understand why many patients with systemic lupus erythematosus (SLE) fail to make adequate responses to immunization with the influenza vaccine.
60ELISPOT, ELISA, multiplex RT-PCR
Partially loaded in PPW
Immune function and Biodefense in Children, Elderly and Immunocompromised Populations
Oregon Health and Science University
Nikolich-Zugich, Janko, M.D., Ph.D.
To characterize immune markers and mechanisms in the elderly that determine their vulnerability to infectious and bioterrorism agents in categories A-C.
130Flow Cytometry, ELISA, RT-PCR, Gene expression,
Partially loaded in PPW
Immune Response to Virus Infection During Pregnancy
Mt. Sinai School of Medicine
Moran, Thomas, Ph.D.
To determine whether the different trimesters of pregnancy, characterized by unique hormonal environments, are associated with (a) identifiable, discrete changes in maternal systemic immunity and/or (b) recognizable alterations in susceptibility to select bio-defense pathogens and/or (c) differential responses to influenza vaccination
75Flow Cytometry, multiplex ELISA, RT-PCR
Partially loaded in PPW
Rochester Biodefense University of Rochester Sanz, Ignacio, M.D.To identify the specific immune defects that make immunocomprised populations specially susceptible at bioterrorists attack.
280 Flow CytometryPartially loaded
in PPW
Innate Immune Responsiveness in the Elderly and the Immunosuppressed
Yale School of Medicine
Montgomery, Ruth, M.D.,Erol Fikrig, MD
This proposal will explore the hypothesis that altered innate immune responsiveness in the elderly and the immunosuppressed contributes to vaccine unresponsiveness or disease susceptibility.
1160SNP genotyping, Flow Cytometry, ELISA
Partially loaded in PPW
ImmPort Research Data | My Work Bench
Browse Data/ ImmPort Research Data/ ImmPort Supported Programs
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Consortium Projects
Grants/Contracts/Projects:
Other Consortium Projects
ImmPort Research Data | My Work Bench
Browse Data/ ImmPort Research Data/ ImmPort Supported Programs
Project Title InstitutePrinciple
Investigator ObjectiveNumber of
Subjects Mechanistic Assay Status
Allergen immunotherapy Co-administered with Omalizumab shared to Semi-Public Workspace (SPW) Project
Immune Tolerance Network Group (ITN)
Thomas Casale
To determine whether taking a drug called omalizumab (also known as Xolair) before getting the allergy shots is more effective than allergy shots alone or other treatments, such as prescription antihistamines.
159 Flow cytometry, ELISACompletely
available in SPW
Atopic Dermatitis and Vaccinia Network (ADVN ) many Donald Leung many 2761
Flow cytometry, ELISA, ELISPOT, RT-PCR, Microarry gene expression, Genotyping
Partially loaded in PPW
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Study summary
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Study schematic
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Study download packages
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Summary of records for download
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Download folder of data
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Links to external resources
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Data sets - Demographics
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ImmPort-calculated summary statistics
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Data sets - Assessments
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Assessment summaries and links to complete
results sets
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Diastolic Blood Pressure
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Data sets – Adverse events
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ELISA and FCM
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Results, protocols, reagents, biological samples
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Download of FCM sample sets
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Complete representation of a clinical trial in ImmPort
Access data through advanced query interface as well
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Take-home message
• ImmPort has been tailored to support the needs of the immunology research community
• Comprehensive integrated resource for the capture, support and analysis of a wide range of basic, translational and clinical research data
• Compliant with established and emerging data standards, e.g. MIAME, MIFlowCyt, Cell Ontology
• Work collaboratively with system users to develop and implement novel data processing and analysis methods
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Human Immune Phenotype
Dependent on:age, race gender, genetic background
disease status, therapeutic and vaccine interventions
Genetic predispositionsSNP, CNV, HLA typeGenetic predispositionsSNP, CNV, HLA type
Cellular componentsFCM, ELISPOT, CyTOFCellular componentsFCM, ELISPOT, CyTOF
Serum antibodyELISA, HAISerum antibodyELISA, HAI
Serum cytokine/chemokineELISA, CBA, MSSerum cytokine/chemokineELISA, CBA, MS
Antigen receptor repertoireSequencing, spectrotypingAntigen receptor repertoireSequencing, spectrotyping
Gene expressionMicroarray, QPCR, RNASeqGene expressionMicroarray, QPCR, RNASeq
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UT SouthwesternDavid KarpMegan KongDiane XiangYu (Max) QianJie HuangNishanth MarthandanYoung Bun KimPaula GuidryDavid Dougall
CollaboratorsKaren Kessler (Rho)Keith Boyce (ITN)Dave Parrish (ITN)Ignacio Sanz (Rochester)Michael Feolo (NCBI)Glenys Thomson (UC Berkeley)Steven G. E. Marsh (ANRI)Bjoern Peters (LIAI)Effie Petersdorf (FHCRC)Steve Mack (CHORI)DAIT-funded programs
Supported by NIH N01AI40076
Northrop GrummanCarl DahlkeVincent DesboroughJohn CampbellYue LiuPatrick DunnLiz ThompsonTom SmithJeff WiserMike Attasi
Acknowledgments
Dedicated to Carl Dahlke In Memorium