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Richard H. Scheuermann, Ph.D. Department of Pathology U.T. Southwestern Medical Center 19 JAN 2011 PowerPoint Presentation
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Genetic and Human Phenotype Data Support in the Immunology Database and Analysis Portal ImmPort www.immport.org. Richard H. Scheuermann, Ph.D. Department of Pathology U.T. Southwestern Medical Center 19 JAN 2011. Outline. Summary of project data in ImmPort

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slide1

Genetic and Human Phenotype Data Support in the Immunology Database and Analysis PortalImmPortwww.immport.org

Richard H. Scheuermann, Ph.D.

Department of Pathology

U.T. Southwestern Medical Center

19 JAN 2011

outline
Outline
  • Summary of project data in ImmPort
  • First complete dataset available – ITN Casale
  • Collaborative ImmPort development projects
    • HLA Genetics Consortium and HLA typing data
    • PopGen and genetic analysis
    • Special Pops and FCM analysis
  • Data from previous PopGen projects
  • Data submission support
immport purpose and history
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
5 dait funded programs
5+ DAIT-funded Programs

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Population Genetics Analysis Program: Immunity to Vaccines/Infections Program

HLA Region Genetics in Immune-Mediated Diseases Program

Immune Function and Biodefense in Children, Elderly, and Immunocompromised Populations Program

Immune Modeling Centers

Other Consortium Projects

Reagent Development for Toll-like and other Innate Immune Receptors

DMID-funded Centers of Excellence for Influenza Research and Surveillance

GlaxoSmithKline – COPD trial

Human Immune Phenotyping Centers

34 Projects, >100,000 subjects, terabytes of FCM, microarray, SNP genotype, ELISA, ELISPOT, etc. data

popgen
PopGen

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Population Genetics Analysis Program: Immunity to Vaccines/Infections Program

Grants/Contracts/Projects:

special pops
Special Pops

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Immune Function and Biodefense in Children, Elderly, and Immunocompromised Populations Program

Grants/Contracts/Projects:

immune modeling centers
Immune Modeling Centers

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Immune Modeling Centers

Grants/Contracts/Projects:

hla genetics consortium
HLA Genetics Consortium

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

HLA Region Genetics in Immune-Mediated Diseases Program

Grants/Contracts/Projects:

consortium projects
Consortium Projects

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Other Consortium Projects

Grants/Contracts/Projects:

slide10
ADVN

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Other Consortium Projects

Atopic Dermatitis and Vaccinia Network (ADVN ):

human immune phenotype
Human Immune Phenotype

Dependent on:

age, race gender, genetic background

disease status, therapeutic and vaccine interventions

Cellular components

FCM, ELISPOT, CyTOF

Genetic predispositions

SNP, CNV, HLA type

Antigen receptor repertoire

Sequencing, spectrotyping

Serum antibody

ELISA, HAI, and neutraliz.

Serum cytokine/chemokine

ELISA, CBA, MS

Gene expression

Microarray, QPCR, RNASeq

complete representation of itn casale
Complete representation of ITN Casale

Complete support for ITN Casale

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Other Consortium Projects

Grants/Contracts/Projects:

complete representation of a clinical trial in immport
Complete representation of a clinical trial in ImmPort

Access data through advanced query interface as well

collaborative immport development projects
Collaborative ImmPort Development Projects
  • HLA Region Genetics Consortium
    • HLA typing ambiguity reduction pipeline
    • HLA sequence feature definition and variant type analysis and visualization
    • PyPop-based genetic analysis
  • Population Genetics Program
    • Haploview implementation
    • Ped file generation
    • LD Select implementation
  • Special Populations Program
    • Novel methods and infrastructure for flow cytometry analysis – FLOCK
summary of sfvt approach
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
publication
Publication

67F

67I

70D

70D

71R

71R

protective

risk

28D

28E

26F

26F

30Y

30L

37Y

37F

86V

86G

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

TCR Binding

CD8 Binding

ImmPort HLA SFVT Workflow
hla typing platforms and ambiguity
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
allelic ambiguity reduction
Allelic Ambiguity Reduction

Elimination of less-probable alleles by CWD status

Reduction of multiple alleles to G- or P-codes

Are any of the alleles reg-CWD?

Are any of the alleles CWD?

Are any of the alleles reg-Rare?

no

no

yes

yes

yes

Eliminate others

Eliminate others

Eliminate others

Do any alleles belong to a common G-code?

Do any alleles or G-codes belong to a common P-code?

Do the alleles contain any G- or P-codes?

no

no

yes

yes

yes

Combine to G-code

Combine to P-code

Eliminate rare alleles

outcome of hla ambiguity reduction
Outcome of HLA Ambiguity Reduction

Allelic Ambiguity Reduction

Genotypic Ambiguity Reduction

collaborative immport development projects1
Collaborative ImmPort Development Projects
  • HLA Region Genetics Consortium
    • HLA typing ambiguity reduction pipeline
    • HLA sequence feature definition and variant type analysis and visualization
    • PyPop-based genetic analysis
  • Population Genetics Program
    • Haploview implementation
    • Ped file generation
    • LD Select implementation
  • Special Populations Program
    • Novel methods and infrastructure for flow cytometry analysis – FLOCK
collaborative immport development projects2
Collaborative ImmPort Development Projects
  • HLA Region Genetics Consortium
    • HLA typing ambiguity reduction pipeline
    • HLA sequence feature definition and variant type analysis and visualization
    • PyPop-based genetic analysis
  • Population Genetics Program
    • Haploview implementation
    • Ped file generation
    • LD Select implementation
  • Special Populations Program
    • Novel methods and infrastructure for flow cytometry analysis – FLOCK
traditional flow cytometry analysis

Traditional Flow Cytometry Analysis

Goal - group together cells with similar characteristics

Traditional approach - manual gating 2D at a time

  • Subjective
  • Time-consuming
  • Doesn’t handle overlapping distributions well
  • Sensitive to slight difference in fluorescence intensity distributions between samples
  • Requires at least one 2D plot that clearly segregates populations in question
flock
FLOCK

FLOCK is an algorithmic application for the identification of unique cell populations in multi-dimensional flow cytometry data

A

PB

GSM

GNSM

UM3-4

UM1-2

CD27

N1-3

DNM

IgD

flowcap i results
FlowCAP-I Results

Automatically Predict Cluster Membership of Each Event (Cell)

popgen1
PopGen

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Population Genetics Analysis Program: Immunity to Vaccines/Infections Program

Grants/Contracts/Projects:

popgen2
PopGen

Browse Data/ ImmPort Research Data/ ImmPort Supported Programs

ImmPort Research Data | My Work Bench

Population Genetics Analysis Program: Immunity to Vaccines/Infections Program

Grants/Contracts/Projects:

user support
User Support

BISC Contacts for PopGen

richard.scheuermann@utsouthwestern.edu; 214-648-4115

data submission
Data Submission
  • Mechanistic assays (online or hard drive)
    • Metadata (.xls or .xml) – experiment, experiment sample, biological sample, subject, reagent, protocol
    • Results (native results formats) – FCM, HLA typing, microarray or RT-PCR for expression, ELISA for serum antibody or cytokine, ELISPOT, SNP genotyping
  • Clinical data
    • Study design timeline and clinical phenotypes from CRFs collected separately
    • No PHI
slide78

ImmPort Data Submission Fields and Relations

Suggested Flow of Filling Templates

blueprints
Blueprints
  • We have started to use “study blueprints” to help coordinate data submission.
  • Summarizes overall structural relationships among data components.
  • Helps projects teams keep track of data for submission.
  • Helps BISC team ensure that the correct links between data components are in place.
  • Helps DAIT program officers keep track of submission status.
blueprints1
Blueprints
  • Initial drafts prepared by BISC team based on project documentation – proposals, SOWs, study protocols
  • Need to be reviewed, revised and returned by project personnel.
  • Blueprints should be considered to be living documents subject to revision.
summary
Summary
  • ImmPort is starting to accumulate a lot of interesting immunology research data
  • First completed project dataset (ITN Casale) made available in semi-public workspace in Oct 2010
  • All of this data is now readily accessible by both the immunology research community and the study team itself
  • BISC team available to provide submission support
  • Request
    • For previous projects, allow BISC team access to PPW to validate accuracy and consistency data and representations before migration to semi-public workspace
    • For new/renewed projects, provide proposals, protocols, SOW and/or other documentation for blueprint drafting
    • Review blueprints when provided
    • Suggestion for future ImmPort enhancements
acknowledgments
Acknowledgments

UT Southwestern

David Karp

Megan Kong

Diane Xiang

Yu (Max) Qian

Jie Huang

Nishanth Marthandan

Young Bun Kim

Paula Guidry

David Dougall

Northrop Grumman

Carl Dahlke

Vincent Desborough

John Campbell

Yue Liu

Patrick Dunn

Liz Thompson

Tom Smith

Jeff Wiser

Mike Attasi

Collaborators

Karen 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

Dedicated to Carl Dahlke In Memorium

Supported by NIH N01AI40076