04.29.2015

Maria Shkrob, PhDSr. Bioinformatics Scientist

R&D Solutions, Elsevier

m.shkrob@elsevier.com

Cell-Centered Database for Immunology and Cancer Research

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Information avalanche

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2015200519951985197519651955

“Cancer Immunotherapy” in PubMed as of February 12, 2015

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Below the tip of the iceberg

Image source: Tumor-altered dendritic cell function: implications for antitumor immunity.

Hargadon KM. Front Immunol. 2013 Jul 11;4:192.

Drug Targets

Biomarkers

Cancer

immunotherapy

Too much information: how

to survive

Our approach

What Pathway Studio has

to offer

Too much information

about cells in particular

Examples of problems that

the database helps to

solve

Today:

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If only we knew what we know…

Amorphous information Structured information

Image Source: http://www.thesocialleader.com/wp-content/uploads/2011/03/paper-piles.jpg

Text mining: analyzing text to extract information that is useful for particular purposes

Text

mining

• Hard to deal with

• Hard to deal with algorithmically

• Not scalable

• Search

• Visualize

• Network analysis

• Scalable

• Compressed

20km

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From text to fact

Tregs contribute to the progression of HNSCC

Regulatory

T cell

Head and neck

squamous cell

carcinoma

text

fact

positive

regulation

sentence

5.6 M facts

24 M abstracts

3.5 M full texts

standard name

standard link

standard name

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Find cells involved in HNSCC

Pathway Studio: manipulate facts not text

96 publications

• type of connection

• sign

• intersect, combine and expand

Visualize

Summarize

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Pathway Studio Overview

Pathway Studio

ToolsKnowledgebase

Manually

curated

pathways

Ontologies

Biological

relations

extracted from

literature

Experiment analysis:Gene expression

Proteomics

Metabolomics

NGS (beta)

Search

Summarization

Navigation

Visualization

24M abstracts

3.5M full texts

4.8M relations

+836K new

relations

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Pathway Studio databases

standard name

standard link

standard name

Mammalprotein-centered

ChemEffectdrug-centered

DiseaseFXbiomarker-centered

+Biomarker

facts+Drugs

Proteins +

• diseases

• clinical parameters

• small molecules

• cell processes

• treatments

• genetic change

• state change

• quantitative change

Cells

+Cell facts

Cells

Finding cells and

facts about cells

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Have you seen this cell?

full name

nickname

aka

formerly known as

scars

and

marks

for short

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Epitope

From inconsistent names to standard names

Basic cell“Attribute”

CD4+ CD25 regulatory T cell

T-lymphocyte leukocyte

T-cell leucocytehemopoetic

hemopoietic

haemopoetic

haemopoietic

hematopoetic

hematopoietic

haematopoetic

haematopoietic

regulatory

immunoregulatoryCD4+CD25+

CD25+FOXP3+

CD4+ CD25+ FOXP3+

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From inconsistent names to standard names

Epitopes

“Attribute”

Basic cell

Standard

cell name

Image source: http://www.biooncology.com/images/therapeutic-targets/b-cell.png

Combination Frequency Standard name

Ep1+ Ep2- BC3 1000 BC4

Ep5+ BC6 2 BC6

Combination Frequency Standard name

Ep1+ Ep2- BC3 1000 BC4

Ep5+ BC6 100 EP5+ BC6

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Adding cell processes to the mixture

proliferation of

death of

migration of human polarization

cytotoxicity

quantity

It allows to • Have more cell processes in the database

• Assign cell processes to rare cells

• Quickly introduce changes if needed

Standard

cell

name

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Recognizing cell processes in text

• Information about more specific cell types

• Doubles the number of cell processes compared to Gene Ontology + EmTree

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Cell-centered database

standard name

standard link

standard name

BETA

Proteins

Clinical

ParametersDiseases

Small

molecules

Cells

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• What cells are involved in the

disease of interest, and how?

• What proteins/small

molecules affect those cells,

and how?

• What proteins are exposed

on the surface of the cell?

• What proteins are secreted

from the cell?

What questions do we want to be answered?

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- Protein/gene

- receptor

- ligand

- kinase

- phosphatase

- Complex

- Functional class

- miRNA

protein regulates cell

cell expresses protein:

• surface

• secretion

Cells and proteins

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• chemicals naturally occurring

in human body

• pharmaceuticals

• biologically active peptides

• antibody drugs

• environmental chemicals,

• products of metabolism

Small molecules affect

cells

Cell produces small

molecule

Cells and small molecules

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State is changedCells are related to

disease

Quantity is changed

Cells play active role in diseases

Cells and diseases

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• General disease

properties

• Measurable

parameters

• Scores

Cells and clinical parameters

Cells affect clinical parameters

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(beta)

Database statistics

Objects

Cells 617

Cell Processes 7 K

Diseases 7.3 K

Clinical Parameters 1.5 K

Proteins and

protein classes

17.7 K

Small molecules 13.5 K

Relations

Regulation 540 K

Cell expression 250 K

Quantitative Change 10 K

State change 7.7 K

Functional Association 31.5 K

Over 830 K new relations

On top of 4.8 million previously extracted relations

Example 1:

Browse the literature

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How proteins secreted from breast carcinoma

affect cells involved in its mechanism?

Step 1

What proteins are secreted from

breast carcinoma cells?

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How proteins secreted from breast carcinoma

affect cells involved in its mechanism?

Step 1

What proteins are secreted from

breast carcinoma cells?

Disease Secretion Protein

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Disease Secretion Protein

Step 2

What cells are involved

in breast carcinoma?

Cell Regulation Disease

How proteins secreted from breast carcinoma

affect cells involved in its mechanism?

Step 1

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Step 3

Find proteins that stimulate

pro-disease cells and inhibit

anti-disease cells

Protein Regulation Cell

How proteins secreted from breast carcinoma

affect cells involved in its mechanism?

Step 2

Step 1

Disease Secretion Protein

Cell Regulation Disease

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How proteins secreted from breast carcinoma

affect cells involved in its mechanism?

Example 2

Analyze experiments:• Gene expression

• Metabolomics

• Proteomics

• NGS

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High grade astrocytoma survival

Background: 3-5% of glioblastoma patients survive longer than 3 years

What are the predictors of long survival?

High grade astrocytoma patient survival: brain tumor (GSE33331)

Comparison of surgical brain tumors of the long survival vs average survival

Increased Immune Gene Expression and Immune Cell Infiltration in High Grade Astrocytoma Distinguish Long from

Short-Term Survivors

Donson AM, Birks DK, Schittone SA, Kleinschmidt-DeMasters BK, Sun DY, Hemenway MF, Handler MH, Waziri AE, Wang M, Foreman NK.

J Immunol. 2012 Aug 15; 189(4): 1920–1927.

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What is needed for long survival?

Survival

over 70

months

vs Functionally

annotate

genes

What processes

are they

involved in?

What pathways

are they

involved in?

Standard

survival

Results depend

on the quality

and granularity

of the database

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Experiment analysis in Pathway Studio

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Analysis of genes positively correlating with prognosis

Genes positively

correlated with

survival

Gene Set

Enrichment

Analysis using

Gene Ontology

Immune system

is involved, but

can we be more

specific?

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Dig deeper into immune component

Gene Ontology

Mammal

ChemEffect

DIseaseFX

Mammal

ChemEffect

DIseaseFX+cells

28 55 63

T cells

B cells

Leukocytes

Lymphocytes

Neutrofils

+

Macrophages

Dendritic cells

Monocytes

T helpers

+

Th1 cells

Th2 cells

Th17 cells

Tregs

CD8+ T cells

immune

processes

in top 100

immune

cells

in top 100

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Additional cell processes – additional results

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Does this new information make sense?

Known connections

between immune cells

identified in analysis

and brain tumors

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• New database is focused on cell-centered

facts

• It adds over 800K new relations and 4.4K

entities to the knowledgebase

• New data can be used to answer complex

biological questions and analyze

experiments

• Flexible recognition of cells and cell

processes allows customization

Summary

Thank you