Adam Pah, Dissertation presentation at Northwestern University on the cartography of metabolic...

Cartography of metabolism and its uses in assessing data reliability and understanding

cellular network functionality

Adam Pah Thesis

June 1, 2013

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Where do we stand and how can we do better?

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Where do we stand and how can we do better?

We are generating biological data faster than ever

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Where do we stand and how can we do better?

We are generating biological data faster than ever

But generating is only one part, we still have to convert that to actual usable knowledge

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Knowledge

Where do we stand and how can we do better?

We are generating biological data faster than ever

But generating is only one part, we still have to convert that to actual usable knowledge

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KnowledgeData

Where do we stand and how can we do better?

We are generating biological data faster than ever

But generating is only one part, we still have to convert that to actual usable knowledge

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KnowledgeData

Know

ledge

Why metabolism?

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Why metabolism?

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Why metabolism?

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• My goal is to create a generalizable framework for understanding cellular networks

!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

Talk Outline

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!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

Talk Outline

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!

• Define the global framework

How do we construct a metabolic network

Metabolic networks are constructed from the Kyoto Encyclopedia of Genes and Genomes database for each organism where:

How do we construct a metabolic network

Metabolic networks are constructed from the Kyoto Encyclopedia of Genes and Genomes database for each organism where:

• Metabolites are connected if they are a part of the main reaction pair

How do we construct a metabolic network

Metabolic networks are constructed from the Kyoto Encyclopedia of Genes and Genomes database for each organism where:

• Metabolites are connected if they are a part of the main reaction pair

• Substrates are connected to Products only.

How do we construct a metabolic network

Metabolic networks are constructed from the Kyoto Encyclopedia of Genes and Genomes database for each organism where:

• Metabolites are connected if they are a part of the main reaction pair

• Substrates are connected to Products only.

How do we construct a metabolic network

UDP-Glucose + H2O + 2 NAD+ UDP-Glucuronate + 2 NADH + 2 H+

Metabolic networks are constructed from the Kyoto Encyclopedia of Genes and Genomes database for each organism where:

• Metabolites are connected if they are a part of the main reaction pair

• Substrates are connected to Products only.

How do we construct a metabolic network

UDP-Glucose + H2O + 2 NAD+ UDP-Glucuronate + 2 NADH + 2 H+UDP-Glucose + H2O + 2 NAD+ UDP-Glucuronate + 2 NADH + 2 H+

Metabolic networks are constructed from the Kyoto Encyclopedia of Genes and Genomes database for each organism where:

• Metabolites are connected if they are a part of the main reaction pair

• Substrates are connected to Products only.

How do we construct a metabolic network

UDP-Glucose + H2O + 2 NAD+ UDP-Glucuronate + 2 NADH + 2 H+UDP-Glucose + H2O + 2 NAD+ UDP-Glucuronate + 2 NADH + 2 H+

UDP-Glucose UDP-Glucuronate

2 NAD+ 2 NADH

Looking at one organism

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Methanococcus maripaludis

Looking at one organism

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Methanococcus maripaludis

How do we construct the framework

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Methanococcus maripaludis

How do we construct the framework

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Methanococcus maripaludis Escherichia coli Homo sapiensArabidopsis thaliana

How do we construct the framework

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Methanococcus maripaludis Escherichia coli Homo sapiensArabidopsis thaliana

It can identify new features

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It can identify new features

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Increased emphasison metabolite roles

It can identify new features

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Increased emphasison metabolite roles

It can identify new features

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Increased emphasison metabolite roles

Putative metabolic‘devices’

We can use this network to revise our knowledge

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Methanococcus maripaludis

We can use this network to revise our knowledge

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Methanococcus maripaludis

We can use this network to revise our knowledge

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Methanococcus maripaludis

Helping to sort out the bigger picture

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!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

Talk Outline

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!

• Curating organismal networks

How much of a need exists to correct databases?

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In the course of 1 year for 979 organisms in the Kyoto Encyclopedia of Genes and Genomes Database:

How much of a need exists to correct databases?

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In the course of 1 year for 979 organisms in the Kyoto Encyclopedia of Genes and Genomes Database:

• 88,000 metabolites have been added as annotations

How much of a need exists to correct databases?

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In the course of 1 year for 979 organisms in the Kyoto Encyclopedia of Genes and Genomes Database:

• 88,000 metabolites have been added as annotations

• 31,000 metabolites that were annotated have been removed

How much of a need exists to correct databases?

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In the course of 1 year for 979 organisms in the Kyoto Encyclopedia of Genes and Genomes Database:

• 88,000 metabolites have been added as annotations

• 31,000 metabolites that were annotated have been removed

• Resulting in an average of over 100 changes per organism

How much of a need exists to correct databases?

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How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Reaction1(Annotated)

Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Reaction1(Annotated)

Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

Enzyme1Organism1

Enzyme1Organism2

Enzyme1Organism3

Enzyme1Organism4

Reaction1enzymes

How can we make predictions?

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Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

Enzyme1Organism1

Enzyme1Organism2

Enzyme1Organism3

Enzyme1Organism4

Reaction1enzymes

How can we make predictions?

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Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

Enzyme1Organism1

Enzyme1Organism2

Enzyme1Organism3

Enzyme1Organism4

Reaction1enzymes

How can we make predictions?

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Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

Enzyme1Organism1

Enzyme1Organism2

Enzyme1Organism3

Enzyme1Organism4

Reaction1enzymes

Protein BLASTfor Enzyme Sequences

How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Reaction1(Annotated)

Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

Enzyme1Organism1

Enzyme1Organism2

Enzyme1Organism3

Enzyme1Organism4

Reaction1enzymes

0.0

MatchE-values

10-3

10-45.0

10-2

How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Protein1Organism1

Protein2Organism1

Protein3Organism1

Protein4Organism1

Organism1proteins

Enzyme1Organism1

Enzyme1Organism2

Enzyme1Organism3

Enzyme1Organism4

Reaction1enzymes

0.0

MatchE-values

10-3

10-45.0

10-2

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1.0

ExcellentMatches

Frac

tion

of M

atch

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PoorMatches

How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Reaction1(Annotated)

Reaction2(Unannotated)

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tion

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PoorMatches

How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Reaction1(Annotated)

Reaction2(Unannotated)

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How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

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How can we make predictions?

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For every reaction there is a set of enzyme sequences that we can compare to each organismal set of proteins

to see how well that reaction ‘fits’

Repeat this for all 3328 reactions using 5.94 million enzyme sequences in 873 organisms

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Are there real differences?

10-3

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Are there real differences?

Unannotated

10-3

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Picking an optimal threshold

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Frac

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Picking an optimal threshold

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Frac

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Picking an optimal threshold

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Picking an optimal threshold

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How do we validate our results?

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• We have one starting dataset, metabolic networks from KEGG 2009

How do we validate our results?

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• We have one starting dataset, metabolic networks from KEGG 2009

• We have our predicted networks and its changes to this dataset (Predicted Changes)

How do we validate our results?

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• We have one starting dataset, metabolic networks from KEGG 2009

• We have our predicted networks and its changes to this dataset (Predicted Changes)

• I also have the entire KEGG dataset for 2 years following that date (KEGG Changes)

How do we validate our results?

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• We have one starting dataset, metabolic networks from KEGG 2009

• We have our predicted networks and its changes to this dataset (Predicted Changes)

• I also have the entire KEGG dataset for 2 years following that date (KEGG Changes)

• I also have other databases to use (FBA Reconstructions, Ma Zeng, Zeng)

How do we validate our results?

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• We have one starting dataset, metabolic networks from KEGG 2009

• We have our predicted networks and its changes to this dataset (Predicted Changes)

• I also have the entire KEGG dataset for 2 years following that date (KEGG Changes)

• I also have other databases to use (FBA Reconstructions, Ma Zeng, Zeng)

• So where’s my accuracy number?

How do we validate our results?

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Well, our test source isn’t perfect over time

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Well, our test source isn’t perfect over time

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And if we look across databases....

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And if we look across databases....

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So really, it’s more like “accuracy”

And if we look across databases....

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So really, it’s more like “accuracy”

But as an approximation we can use a consensus network

How to build a consensus network

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KEGG 2009 Zeng 2011 FBA

How to build a consensus network

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KEGG 2009 Zeng 2011 FBA

Consensus Network We use majority rule to make the

consensus network

How do the databases compare

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Global Network

How do the databases compare

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Global Network

What are we mispredicting?

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What are we mispredicting?

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What are we mispredicting?

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Reactions that we predict to exist but

are not in other databases are

primarily composed of reactions that are poorly understood, if

at all

But can we validate in another way?

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• Traditional validation is hamstrung by what we “know”

But can we validate in another way?

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• Traditional validation is hamstrung by what we “know”

• We can instead try to validate by assessing how well connected a metabolic network is, namely:

But can we validate in another way?

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• Traditional validation is hamstrung by what we “know”

• We can instead try to validate by assessing how well connected a metabolic network is, namely:

• Do we leave gaps between reactions when the organismal network is overlaid on the Res Potentia?

But can we validate in another way?

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• Traditional validation is hamstrung by what we “know”

• We can instead try to validate by assessing how well connected a metabolic network is, namely:

• Do we leave gaps between reactions when the organismal network is overlaid on the Res Potentia?

• When we remove reactions do we make more components than necessary, increasing the reliance on nutrient import?

But can we validate in another way?

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Validate by promoting connectedness

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We can test and see how the actual changes in the database do at completing and filling in gaps

in the networks

Validate by promoting connectedness

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We can test and see how the actual changes in the database do at completing and filling in gaps

in the networks

Validate by promoting connectedness

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Gap Size0.00

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Frac

tion

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aps

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d KEGG ChangesRandom

1 2 3 4 5

Predicted Changes

We can test and see how the actual changes in the database do at completing and filling in gaps

in the networks

Validate by promoting connectedness

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Gap Size0.00

0.02

0.04

0.06

0.08

0.10

0.12

Frac

tion

of G

aps

Fille

d KEGG ChangesRandom

1 2 3 4 5

Predicted Changes

We can test and see how the actual changes in the database do at completing and filling in gaps

in the networks

Validate by promoting connectedness

���28

Gap Size0.00

0.02

0.04

0.06

0.08

0.10

0.12

Frac

tion

of G

aps

Fille

d KEGG ChangesRandom

1 2 3 4 5

Predicted Changes

We can test and see how the actual changes in the database do at completing and filling in gaps

in the networks

Validate by promoting connectedness

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Gap Size0.00

0.02

0.04

0.06

0.08

0.10

0.12

Frac

tion

of G

aps

Fille

d KEGG ChangesRandom

1 2 3 4 5

Predicted Changes

We can test and see how the actual changes in the database do at completing and filling in gaps

in the networks

Validate by promoting connectedness

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We can test and see how the actual changes in the database create gaps

Validate by promoting connectedness

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We can test and see how the actual changes in the database create gaps

Validate by promoting connectedness

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We can test and see how the actual changes in the database create gaps

Validate by promoting connectedness

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We can test and see how the actual changes in the database create gaps

-0.1 -0.06 -0.02 0.02 0.06 0.1

RPF PredictedDeletions

KEGG 2011Deletions

Relative fraction of removed reactionsthat create additional components

Validate by promoting connectedness

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We can test and see how the actual changes in the database create gaps

-0.1 -0.06 -0.02 0.02 0.06 0.1

RPF PredictedDeletions

KEGG 2011Deletions

Relative fraction of removed reactionsthat create additional components

We can also ‘type’ the current curation efforts

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0

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AdditionsRemovals

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More changesin KEGG

Fewer changesin KEGG

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0

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10-2 10-1 100 101 102Predictions

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!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

Talk Outline

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!

• Finding intermediate structures

We typically examine local structure in two ways!

Using known pathways and reaction conversions

We typically examine local structure in two ways!

Using known pathways and reaction conversions

!

Using a priori defined structures

We typically examine local structure in two ways!

Using known pathways and reaction conversions

!

Using a priori defined structures

!

Both are predetermined functionally

We establish a profile for each reaction

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Reaction1(Annotated)

We establish a profile for each reaction

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Reaction1(Annotated)

!

For each reaction tested in an organism we know the

percentage of BLAST alignments that returned a ‘good’ result

We establish a profile for each reaction

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Reaction1(Annotated)

H. sapiens

fhits = 0.84

!

For each reaction tested in an organism we know the

percentage of BLAST alignments that returned a ‘good’ result

We establish a profile for each reaction

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Reaction1(Annotated)

H. sapiens

fhits = 0.84

!

For each reaction tested in an organism we know the

percentage of BLAST alignments that returned a ‘good’ result

E. colifhits = 0.6

S. pombefhits = 0.7 . . .

We establish a profile for each reaction

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Reaction1(Annotated)

H. sapiens

fhits = 0.84

!

For each reaction tested in an organism we know the

percentage of BLAST alignments that returned a ‘good’ result

E. colifhits = 0.6

S. pombefhits = 0.7 . . .

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CDF

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We pick every edge and try to “grow” a device

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Reaction1(Annotated)

We pick every edge and try to “grow” a device

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Reaction1(Annotated)

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Reaction1(Annotated)

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Reaction1(Annotated)

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Reaction1(Annotated)

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Reaction1(Annotated)

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We pick every edge and try to “grow” a device

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Reaction1(Annotated)

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We pick every edge and try to “grow” a device

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Reaction1(Annotated)

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Reaction1(Annotated)

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Reaction1(Annotated)

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device

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Accept growth

What are general characteristics of what we found?

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We find 230 devices using this methodology, spanning in size from 3 to 6 compounds

Some are small linear chains

What are general characteristics of what we found?

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We find 230 devices using this methodology, spanning in size from 3 to 6 compounds

Some are small linear chains

m32-C03785

m32-C00111

m18-C06893

m43-C00062

m48-C01201

m48-C00301

m43-C03296

Some are small linear chains

What are general characteristics of what we found?

���35

We find 230 devices using this methodology, spanning in size from 3 to 6 compounds

Some are small linear chains

m32-C03785

m32-C00111

m18-C06893

m43-C00062

m48-C01201

m48-C00301

m43-C03296

Others branch

Some are small linear chains

m22-C05956

m22-C00696

m22-C00584

m22-C00427

m32-C06140

m32-C06141

m32-C04927

m32-C06134

m32-C06139

m32-C06138

Is there any significance to these devices?

���36

Some are small linear chains

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Is there any significance to these devices?

���36

Some are small linear chains

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Is there any significance to these devices?

���37

Some are small linear chains

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Is there any significance to these devices?

���37

Some are small linear chains

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!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

Talk Outline

���38

!

• Identify community structure

Community detection is a heuristic solution

���39

Community detection is a heuristic solution

• Modularity Landscape Surveying (MLS) 64 communities

3030

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Community detection is a heuristic solution

• Modularity Landscape Surveying (MLS) 64 communities

• MLS with simulated annealing (SA) for structure extraction13 communities

0

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Community detection is a heuristic solution

• Modularity Landscape Surveying (MLS) 64 communities

• MLS with simulated annealing (SA) for structure extraction13 communities

• SA Modularity Maximization (100 runs)Min: 16 communitiesMax: 24 communities

���39

Why not just start over entirely?

���40

Why not just start over entirely?

• Time

���40

Why not just start over entirely?

• Time

• Modularity Landscape Run-time for the Res Potentia network is 40 days

���40

Why not just start over entirely?

• Time

• Modularity Landscape Run-time for the Res Potentia network is 40 days

• Changing the structure extraction to simulated annealing increases the time dramatically (>60 days)

���40

Why not just start over entirely?

• Time

• Modularity Landscape Run-time for the Res Potentia network is 40 days

• Changing the structure extraction to simulated annealing increases the time dramatically (>60 days)

• Final evaluations and comparisons of structure

���40

What can we make final determinations on?

���41

What can we make final determinations on?

• Qualitative

���41

What can we make final determinations on?

• Qualitative

• Distribution of conservation values

���41

What can we make final determinations on?

• Qualitative

• Distribution of conservation values

• Pathway/functional conservation

���41

What can we make final determinations on?

• Qualitative

• Distribution of conservation values

• Pathway/functional conservation

• Quantitative

���41

What can we make final determinations on?

• Qualitative

• Distribution of conservation values

• Pathway/functional conservation

• Quantitative

• Modularity

���41

What can we make final determinations on?

• Qualitative

• Distribution of conservation values

• Pathway/functional conservation

• Quantitative

• Modularity

• Matrix cost

���41

How can we make improvements?

���42

How can we make improvements?

• Work on moving the communities themselves instead of the nodes

���42

How can we make improvements?

• Work on moving the communities themselves instead of the nodes

• With only one type of move proposed: Merge two communities

���42

How can we make improvements?

• Work on moving the communities themselves instead of the nodes

• With only one type of move proposed: Merge two communities

• Start with communities that have only one link

���42

How can we make improvements?

• Work on moving the communities themselves instead of the nodes

• With only one type of move proposed: Merge two communities

• Start with communities that have only one link

• Proceed to attempt merges of smaller communities

���42

How can we make improvements?

• Work on moving the communities themselves instead of the nodes

• With only one type of move proposed: Merge two communities

• Start with communities that have only one link

• Proceed to attempt merges of smaller communities

• Evaluate each merge with modularity and matrix costs

���42

How can we make improvements?

• Work on moving the communities themselves instead of the nodes

• With only one type of move proposed: Merge two communities

• Start with communities that have only one link

• Proceed to attempt merges of smaller communities

• Evaluate each merge with modularity and matrix costs

• Make sure that one community continually maps to one network component

���42

Iteration 1, What do we select?

3030

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-0.003 -0.0025 -0.002 -0.0015 -0.001 -0.0005 0 0.0005Normalized Additional Modularity Cost

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���44

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Accept Changes

���44

What does one iteration of merging do?

3030

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51515151515151

3636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636

53535353535353535353535353535353

52525252

333333333333333333333333333333333333333333

55555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555

3737373737

47

5757575757575757575757

5050505050505050

���45

What does one iteration of merging do?

3030

28282828292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929

606060606060606060

626262626262626262626262

64646464646464

35353535353535

343434

242424242424242424242424242424242424242424242424

2525252525252525252525252626262626262626

272727272727

2020

212121

4848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848

494949494949

4646464646

47

444444444444

454545454545 424242424242424242424242424242424242424242424242

434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434040

4141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141 111111

0000000

33335555555

4444444

7777777777777777777777777777777777

1414141414141414141414

9999999999999999999999999999888888888888888

13

1212121212

15151515

323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232

585858

1111111111

101010

393939393939

38383838

595959595959595959595959

2222222222222222222222222222222222222222222222222222222222222222222222

16161616161616161616161616161616161616161616161616161616161616161616161616161616

19191919191919191919191919191919

54

31

2323232323232323232323232323232323232323232323232323232323

51515151515151

36363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636

53535353535353535353535353535353

52525252

333333333333333333333333333333333333333333

555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555

3737373737

181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818185757575757575757575757

5050505050505050

3030

282828282929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929

606060

616161616161

626262626262

636363636363

64646464646464

35353535353535

343434

242424242424242424242424242424242424242424242424

2525252525252525252525252626262626262626

27272727

2020

212121

4848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848

494949494949

4646464646

2323232323232323232323232323232323232323232323232323232323

44444444444444

454545454545 424242424242424242424242424242424242424242424242

43434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343404040

41414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141 111

0000000

3333222

5555555

44

7777777777777777777777777777777777

66666

9999999999999999999999999999888888888888888

181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818

13

1212121212

1717171717171717171717171717171717171717171717171717171717171717171717

15151515

3232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232

5858585858

1111111111

101010

393939393939

38383838

595959595959595959595959

2222222222222222222222222222222222222222222222222222222222222222222222

1414141414141414141414

1616161616

19191919191919191919191919191919

54

31

5656

51515151515151

3636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636

53535353535353535353535353535353

52525252

333333333333333333333333333333333333333333

55555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555

3737373737

47

5757575757575757575757

5050505050505050

���45

How do we pick more complicated targets?

���46

Modules with a small degree

How do we pick more complicated targets?

���46

Are complicated moves worthwhile?

-0.006 -0.005 -0.004 -0.003 -0.002 -0.001 0 0.001Normalized Additional Modularity Cost

0

0.005

0.01

0.015

0.02

0.025

Nor

mal

ized

Add

ition

al M

atrix

Cos

t

���47

We can also improve at the node level

���48

We can also improve at the node level

The network is supposed to focus on the flow of mass through reactions

���48

We can also improve at the node level

The network is supposed to focus on the flow of mass through reactions

But association and disassociation reactions don’t follow this strictly

���48

We can also improve at the node level

The network is supposed to focus on the flow of mass through reactions

But association and disassociation reactions don’t follow this strictly

Metabolitea Metabolitea’ + Metabolitea’’

���48

We can also improve at the node level

The network is supposed to focus on the flow of mass through reactions

But association and disassociation reactions don’t follow this strictly

Metabolitea Metabolitea’ + Metabolitea’’

Main Reaction Pairs

���48

We can also improve at the node level

The network is supposed to focus on the flow of mass through reactions

But association and disassociation reactions don’t follow this strictly

Metabolitea Metabolitea’ + Metabolitea’’

Main Reaction Pairs

���48

We can also improve at the node level

The network is supposed to focus on the flow of mass through reactions

But association and disassociation reactions don’t follow this strictly

Metabolitea Metabolitea’ + Metabolitea’’

Main Reaction Pairs

MetaboliteaMetabolitea’ Metabolitea’’

���48

Is this really a problem?

���49

Is this really a problem?

Not that much, but it can interfere when these are the reactions that connect between modules.

���49

Is this really a problem?

Not that much, but it can interfere when these are the reactions that connect between modules.

���49

What is the end result of all these moves?

4242424242424242424242424242424242

2929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929

626262626262626262626262

24242424242424242424242424242424

25252525252525

212121

2222222222222222222222222222222222222222222222222222222222222222222222

2323232323232323232323232323232323232323232323232323232323

28282828

43434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343

414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141

11111111

000000

7777777777777777777777777777777777777777777777777777777777

888888888888888

1313131313131313131313131313131313131313131313131313131313

1414141414141414141414

393939393939393939393939393939393939393939393939393939393939393939393939

595959595959595959595959595959595959595959595959595959595959

484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848

16161616161616161616161616161616161616161616161616161616161616161616161616161616

19191919191919191919191919191919

181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818181818

5757575757575757575757

3737373737

3636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636363636

53535353535353535353535353535353

34343434343434343434

555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555555

323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232323232

���50

What is the end result of all these moves?

Reduction of modules from 64 to 30

4242424242424242424242424242424242

2929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929292929

626262626262626262626262

24242424242424242424242424242424

25252525252525

212121

2222222222222222222222222222222222222222222222222222222222222222222222

2323232323232323232323232323232323232323232323232323232323

28282828

43434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343434343

414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141414141

11111111

000000

7777777777777777777777777777777777777777777777777777777777

888888888888888

1313131313131313131313131313131313131313131313131313131313

1414141414141414141414

393939393939393939393939393939393939393939393939393939393939393939393939

595959595959595959595959595959595959595959595959595959595959

484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848484848

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Modularity: Matrix Cost: ���50

!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

!

• Define the global framework

• Curating organismal networks

• Finding intermediate structures

• Identify community structure

• Visualizing metabolism at depth

Talk Outline

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!

• Visualizing metabolism at depth

How do we currently look at metabolism?

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What are the other ways researchers try?

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What are the other ways researchers try?

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How do we interact with these graphs?

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How do we interact with these graphs?

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How do we interact with these graphs?

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What am I proposing?

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What am I proposing?

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• Let’s share more than our raw data

What am I proposing?

���56

• Let’s share more than our raw data

• Make a visualization that allows for interaction with our data and analyses

What am I proposing?

���56

• Let’s share more than our raw data

• Make a visualization that allows for interaction with our data and analyses

• Make it freely available

MetExplore Workflows within a level

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Splash Page

MetExplore Workflows within a level

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Splash Page hover

MetExplore Workflows: Exploring deeper

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MetExplore Workflows: Exploring deeper

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click

MetExplore Workflows: Exploring deeper

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click

click

MetExplore Workflows: Moving across

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click

MetExplore Workflows: Moving across

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click

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Wrapping up

• I have developed a framework to analyze cellular processes, we can:

• Predict organismal networks

• Assess curation efficacy

• Identify intermediate and global structure

• We also are able now to make visualizations that allow for graph traversal and exploration

Acknowledgements

• Luis Amaral

• Eric Weiss, Adilson Motter, Joshua Leonard

• Dan McClary, Erin Sawardecker, Pat McMullen, Laura Timmerman, Julia Poncela, Renee Robbins

With financial support from:

• Northwestern/NIH Biotechnology Training Grant

• Chicago Biomedical Consortium