1. Functional Characterisation of
Metabolic Networks
Carlos Manuel Estévez-Bretón MSc
Doctorate in Systems Engineering and Computer Sciences
Advisors: Luis Fernando Niño PhD
Liliana Lopez Kleine PhD
Intelligent Systems Research Laboratory - LISI
Bioinformatics and Computational Biology research line “BioLisi”
Examining Committee:
Dr. Jason Papin, -U. ofVirginia, Bioengineering.
Dr.Andres Gonzalez, - U. de los Andes, Chemical Engineering.
Dr. Fabio Gonzalez, U. Nacional, Systems Engineering.
4. Metabolism are the
complete set of
metabolic
networks and
physical processes
that determine the
physiological and
biochemical properties
of a cell.
With the sequencing of complete
genomes, it is now possible to
reconstruct the network of biochemical
reactions in many organisms, from
bacteria to humans...
5. PMC 2011 August 17.
Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug; 2(4): 438–459.
doi: 10.1002/wsbm.75
Ecological Scale
Lucas B. Edelman, James A. Eddy, and Nathan D. Price
Systems BiologyIntroduction
6. PMC 2011 August 17.
Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug; 2(4): 438–459.
doi: 10.1002/wsbm.75
Ecological Scale
Lucas B. Edelman, James A. Eddy, and Nathan D. Price
Systems BiologyIntroduction
7. PMC 2011 August 17.
Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug; 2(4): 438–459.
doi: 10.1002/wsbm.75
Ecological Scale
Lucas B. Edelman, James A. Eddy, and Nathan D. Price
Systems BiologyIntroduction
8. PMC 2011 August 17.
Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug; 2(4): 438–459.
doi: 10.1002/wsbm.75
Ecological Scale
Lucas B. Edelman, James A. Eddy, and Nathan D. Price
Systems BiologyIntroduction
9. PMC 2011 August 17.
Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug; 2(4): 438–459.
doi: 10.1002/wsbm.75
Ecological Scale
Lucas B. Edelman, James A. Eddy, and Nathan D. Price
Multilevelfield
Systems BiologyIntroduction
10. PMC 2011 August 17.
Wiley Interdiscip Rev Syst Biol Med. 2010 Jul-Aug; 2(4): 438–459.
doi: 10.1002/wsbm.75
Ecological Scale
Lucas B. Edelman, James A. Eddy, and Nathan D. Price
Multilevelfield
Studied
Interdisciplinary
Systems BiologyIntroduction
15. “Techniques such as high-trougput (HT)
sequencing and gene/protein profiling have
transformed biological Research” (Khatri et al,2012)
“In this way,the advent of HT profiling technologies
presents a new challenge,that of extracting meaning from
a long list of differentially expressed genes and proteins”.
(Khatri et al,2012)
16. “Techniques such as high-trougput (HT)
sequencing and gene/protein profiling have
transformed biological Research” (Khatri et al,2012)
“In this way,the advent of HT profiling technologies
presents a new challenge,that of extracting meaning from
a long list of differentially expressed genes and proteins”.
(Khatri et al,2012)
These biological techniques changes the way we study
biological science.
Interdisciplinary effort to extract meaning, analyze, and
obtain information with high levels of confidence and
quality.
18. “In particular,supervised machine learning has been
used to great effect in numerous bioinformatics
prediction methods”.
(Jensen & Bateman,2011)
Machine learning is of immense importance in
bioinformatics and more generally for biomedical
sciences (Larrañaga et al.,2006;Tarca et al.,2007).
Because in metabolic systems analysis,is not common,
I think that is important to emphasise that:
19. There are no references in the literature for
analysis of metabolic pathways from a
functional approach,or using proposed
machine learning methods.
IntelligentSystems
20. Larrañaga et al. bib.oxfordjournals.org at The Reference Shelf on May 30, 2011
achineLearning
21. Larrañaga et al. bib.oxfordjournals.org at The Reference Shelf on May 30, 2011
Bayesian classifiers, Feature subset
selection
SVM,ANN, classification trees,
Evolutionary algorithms
tabu search
nearest neighbour, SVM, Bayesian
classifier, fuzzy k-NN
Bayesiangeneralizationofthe
SVM,ANN,lineardiscriminant
analysis,classificationtrees,ANN
SVMandHMM,
linear discriminant analysis,
quadratic discriminant
analysis, k-NN classifier,
bagging and boosting
classification trees, SVM and
random forest
achineLearning
22. Larrañaga et al. bib.oxfordjournals.org at The Reference Shelf on May 30, 2011
Bayesian classifiers, Feature subset
selection
SVM,ANN, classification trees,
Evolutionary algorithms
tabu search
nearest neighbour, SVM, Bayesian
classifier, fuzzy k-NN
Bayesiangeneralizationofthe
SVM,ANN,lineardiscriminant
analysis,classificationtrees,ANN
probabilistic graphical
models, classification
trees, boosting with
classification trees
SVMandHMM,
linear discriminant analysis,
quadratic discriminant
analysis, k-NN classifier,
bagging and boosting
classification trees, SVM and
random forest
achineLearning
25. ... or Methods are
not applied to
Metabolic Pathways...
...or are based onTopological (Graph Based)
network representations
26. • It should be possible to make some
advances in understanding the
underlying functional conformation
of metabolic pathways.
Statem
ent
http://www.scriptmag.com/wp-content/uploads/BrainStorm-NewColor-12-22_32-1280x980at86.jpg
29. • Information Retrieval algebraic models, like
vector space based ones, should “reveal” topics
that occurs in document collections.
• Is it possible to generate new - “really new” pathways?
• ...I’m talking about synthetic biology.
http://diversity-mining-lab.wikispaces.com/
Statem
ent
30. Research Question
Is it possible to
classify metabolic
networks only
using functional
features?
32. Goals
• To Classify functionally, (without considering the
topological structure) metabolic pathways
based on machine learning methods.
33. Goals
• To Classify functionally, (without considering the
topological structure) metabolic pathways
based on machine learning methods.
• To Build or adapt a system of functional representation
for metabolic networks.
34. Goals
• To Classify functionally, (without considering the
topological structure) metabolic pathways
based on machine learning methods.
• To Build or adapt a system of functional representation
for metabolic networks.
• To Classify metabolic networks using machine learning
methods.
35. Goals
• To Classify functionally, (without considering the
topological structure) metabolic pathways
based on machine learning methods.
• To Build or adapt a system of functional representation
for metabolic networks.
• To Classify metabolic networks using machine learning
methods.
• To Apply (in new ways) machine learning methods in
the study of systems biology.
36. Methodology
S1 + S2 + … Sn P1 + P2 + … Pn
Enzime
CoFactor CoEnzime
General Metabolic Reaction Model - GMRM
Vectorization of GMRM
S1 S2 S3 Enzime CoF CoE P1 P2 P3
MetaCyc
KEGG1
2
RepresentationClassification
CarlosManuelEstévez-BretónR.2012
DataSourceEvaluation
Method 2Method 1
ROC
Confusion
matrix
Entropy
purity
adjusted
Rand Index
Accuracy
Pipeline
paper paper
paper
46. PreliminaryResults
S1 + S2 + … Sn P1 + P2 + … Pn
Enzime
CoFactor CoEnzime
General Metabolic Reaction Model - GMRM
Vectorization of GMRM
S1 S2 S3 Enzime CoF CoE P1 P2 P3
MetaCyc
KEGG1
2
RepresentationClassification
CarlosManuelEstévez-BretónR.2012
DataSourceEvaluation
Method 2Method 1
ROC
Confusion
matrix
Entropy
purity
adjusted
Rand Index
Accuracy
Pipeline
paper paper
paper
47. Complexity
Metabolic Pathway
Reaction
Metabolites/ome
Metabolic Switch
Glucose
Glucose 6P ATP
Hidrolase
Pyrophosphate
Vocabulary
Words Molecules
the
Murder for a jar of red rum
frog
soap
Document
Phrase
Paragraph
rum Murder for
jar
a
ofred
rum Murder for
jar
a
ofred
Glucose Glucose 6PATP
Hidrolase
ADP+ +
ADP
LinguisticAnalogy
S1 + S2 + … Sn P1 + P2 + … Pn
Enzime
CoFactor CoEnzime
General Metabolic Reaction Model - GMRM
Vectorization of GMRM
S1 S2 S3 Enzime CoF CoE P1 P2 P3
48. Representation
S1 + S2 + … Sn P1 + P2 + … Pn
Enzime
CoFactor CoEnzime
General Metabolic Reaction Model - GMRM
Vectorization of GMRM
S1 S2 S3 Enzime CoF CoE P1 P2 P3
51. Review
- Proposing a vector representation of biochemical
reactions, based in a linguistic analogy.
I´m going to classify metabolic networks
only using functional features...
To find patterns that suggests constitution
rules on metabolic pathways.
- Searching patterns by clustering.