Goals of Computational Biology

• Combine knowledge, data, and tools to …

• … conduct complex analyses.

• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.
 Goals of Computational Biology

• Combine knowledge, data, and tools to …

Analysis and
• … conduct complex analyses.
Prediction
• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.
 Goals of Computational Biology

• Combine knowledge, data, and tools to …

• … conduct complex analyses.

• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.

Model Development
 Experimental
Knowledge Data

BioLingua
Interactive
Guidance
from Biologists

Genomic
Tools
BioLingua: Computational Biology Workbench
• Integrates Genomic and Data Analysis Tools

• Integrates Organism-specific as well as General Knowledge

• Unifies Important Knowledge Bases

• Integrates Model Development and Refinement tools

• Offers a Flexible “Open Programming” Methodology

• Provides Convenient Universal Access (fully web-enabled)

 BioLingua Computational Biology Workbench

Unified Basic Structures provided for important biological

Concepts concepts: e.g., reactions, molecules, enzymes,
experiments, expression-levels, etc.
Layer
Integrated
K/DB Layer KEGG BioCyc GO Remote Access
Other K/DBs

Locally mirror important K/DBs SMD

 BioLingua Computational Biology Workbench

Computed An ever-expanding library of computations that

Concepts produce complex, virtual, biological concepts, such as
pathways, complexes, regulons, etc.
Layer
Unified Basic Structures provided for important biological
Concepts concepts: e.g., reactions, molecules, enzymes,
experiments, expression-levels, etc.
Layer
Integrated
K/DB Layer KEGG BioCyc GO Remote Access
Other K/DBs

Locally mirror important K/DBs SMD

 BioLingua Computational Biology Workbench

Standard
analytic tools

Computed An ever-expanding library of computations that

Concepts produce complex, virtual, biological concepts, such as
pathways, complexes, regulons, etc.
Layer
Unified Basic Structures provided for important biological
Concepts concepts: e.g., reactions, molecules, enzymes,
experiments, expression-levels, etc.
Layer
Integrated
K/DB Layer KEGG BioCyc GO Remote Access
Other K/DBs

Locally mirror important K/DBs SMD

 BioLingua Computational Biology Workbench

Standard
analytic tools,
plus discovery
Computed An ever-expanding library of computations that tools that
Concepts produce complex, virtual, biological concepts, such as
combine know-
pathways, complexes, regulons, etc.
Layer ledge and data
Unified Basic Structures provided for important biological under user
Concepts concepts: e.g., reactions, molecules, enzymes, control.
experiments, expression-levels, etc.
Layer
Integrated
K/DB Layer KEGG BioCyc GO Remote Access
Other K/DBs

Locally mirror important K/DBs SMD

 BioLingua Computational Biology Workbench

BioLisp A simple programming language to be used by Standard

Scripting biologists to answer specific questions regarding
the integration of their data with the concepts below. analytic tools,
Layer
plus discovery
Computed An ever-expanding library of computations that tools that
Concepts produce complex, virtual, biological concepts, such as
combine know-
pathways, complexes, regulons, etc.
Layer ledge and data
Unified Basic Structures provided for important biological under user
Concepts concepts: e.g., reactions, molecules, enzymes, control.
experiments, expression-levels, etc.
Layer
Integrated
K/DB Layer KEGG BioCyc GO Remote Access
Other K/DBs

Locally mirror important K/DBs SMD

BioLisp (loop for pm4gene in (#^Genes ProcMed4)
as all-orthologous = (all-blast-orthologs pm4gene)
as 6803ortholog = (intersect (#^Genes Syny6803) all-orthologous)
when (and (not-any #’member-geneid
(#^Genes slotv Proc9313) all-orthologous))
(any #'member-geneID 6803ortholog)
(>= ma-ratio (ma-select 6803ortholog Hihara1) 2)))
collect light-specific-genes 6803ortholog)

• Biologically Specialized Programming Language

• Highly efficient (deeply compiled and optimized)
• Very Concise and Expressive (general purpose)
• Based upon Lisp
• The second oldest programming language
• The standard language of Artificial Intelligence
BioLisp (loop for pm4gene in (#^Genes ProcMed4)
as all-orthologous = (all-blast-orthologs pm4gene)
as 6803ortholog = (intersect (#^Genes Syny6803) all-orthologous)
when (and (not-any #’member-geneid
(#^Genes slotv Proc9313) all-orthologous))
(any #'member-geneID 6803ortholog)
(>= ma-ratio (ma-select 6803ortholog Hihara1) 2)))
collect light-specific-genes 6803ortholog)

• Biologically Specialized Programming Language

• Highly efficient (deeply compiled and optimized)
• Very Concise and Expressive (general purpose)
• Based upon Lisp
• The second oldest programming language
• The standard language of Artificial Intelligence
• And 8th-graders can learn it!
 Goals of Computational Biology

Enable biologists to…

• Combine knowledge, data, and tools to …
Analysis and
• … conduct complex analyses.
Prediction
• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.

Model Development
 Goals of Computational Biology

Enable biologists to…

• Combine knowledge, data, and tools to …
Analysis and
• … conduct complex analyses.
Prediction
• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.
 How do cells control response to light?
I.e., What genes are related to the adaptation to high light?

Prochlorococcus MED4

Prochlorococcus MIT9313
 How do cells control response to light?
I.e., What genes are related to the adaptation to high light?

Outline Protocol

Look for:
• Gene present in Prochlorococcus MED4
MED4 is naturally adapted to grow in high light.
• Ortholog absent in Prochlorococcus MIT9313
MIT9313 is naturally adapted to grow in low light
• Ortholog present in Synechocystis PCC 6803
In order to make contact with annotation and microarray data

• Synechocystis PCC 6803 ortholog responds to high light

Gene turns on by factor > 2 in response to high light
 “English” Protocol

For each gene in ProMed4,

Find all the gene’s Blast orthologs,
Find those from Syny6803,
When there are not any Pro9313 genes in the Blast orthologs,
and there are any the 6803 orthologs
and the expression ratio for the 6803 orthologs
in the Hihara microarray data is >= 2,
collect the 6803 orthologs in a list, called light-specific-genes.
 BioLingua Computational Biology Workbench

BioLisp A simple programming language to be used by Standard

Scripting biologists to answer specific questions regarding
the integration of their data with the concepts below. analytic tools,
Layer
plus discovery
Computed An ever-expanding library of computations that tools that
Concepts produce complex, virtual, biological concepts, such as
combine know-
pathways, complexes, regulons, etc.
Layer ledge and data
Unified Basic Structures provided for important biological under user
Concepts concepts: e.g., reactions, molecules, enzymes, control.
experiments, expression-levels, etc.
Layer
Integrated
K/DB Layer KEGG BioCyc GO Remote Access
Other K/DBs

Locally mirror important K/DBs SMD

 BioLisp Program

(loop for pm4gene in (#^Genes ProcMed4)

as all-orthologous = (all-blast-orthologs pm4gene)
as 6803ortholog = (intersect (#^Genes Syny6803) all-
orthologous)
when (and (not-any #’member-geneid
(#^Genes slotv Proc9313) all-orthologous))
(any #'member-geneID 6803ortholog)
(>= ma-ratio (ma-select 6803ortholog Hihara1) 2)))
collect light-specific-genes 6803ortholog)
By Jeff Elhai
 For each gene in ProMed4,
Find all the gene’s Blast orthologs,
Find those from Syny6803,
When there are not any Pro9313 genes in the Blast orthologs,
and there are any the 6803 orthologs
and the expression ratio for the 6803 orthologs
in the Hihara microarray data is >= 2,
collect the 6803 orthologs in a list, called light-specific-genes.

(loop for pm4gene in (#^Genes ProcMed4)

as all-orthologous = (all-blast-orthologs pm4gene)
as 6803ortholog = (intersect (#^Genes Syny6803) all-
orthologous)
when (and (not-any #’member-geneid
(#^Genes slotv Proc9313) all-orthologous))
(any #'member-geneID 6803ortholog)
(>= ma-ratio (ma-select 6803ortholog Hihara1) 2)))
collect light-specific-genes 6803ortholog)
 BioLingua
Alpha Platform

(http://nostoc.stanford.edu:8002/biologin)
 Set: Light-specific genes
Syny6803:sll0990 Formaldehyde dehydrogenase (glutathione dependent)
Syny6803:srl7009 trnR tRNA Arg (UCU)
Syny6803:slr1331 Processing protease
Syny6803:slr1332 fabF beta ketoacyl acyl carrier protein synthase
Syny6803:sll0337 Sensor histidine kinase
Syny6803:sll0335 Hypothetical
Syny6803:sll0789 Response regulator (OmpR)
Syny6803:sll0788 Hypothetical protein
Syny6803:sll0576 Putative epimerase/hydratase
 Goals of Computational Biology

Enable biologists to…

• Combine knowledge, data, and tools to …
Analysis and
• … conduct complex analyses.
Prediction
• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.
 Cyclodyn Experimental Design
Continuous Culture Turbidostat
Light Levels

Sampling mRNA/cDNA

Time
Light
 20030303 Cyclodyn (Cy5) Light Correlated

P700 apoprotein subunit Ia (psaA)

SLL1577 275.18512 phycocyanin b
subunit (cpcB)

SLL1578 207.43861 phycocyanin a

subunit (cpcA )
2
ATP synthase subunit a (atpI)
SLR2067 393.91397 allophycocyanin
a chain (apcA )
SLR1311 204.0282 photosystem II D1

photosystem I subunit III (psaF)

protein (psbA2)
SLL1579 60.437798 phycocyanin
associated linker protein (cpcC)
0
0 5 10 15 20
photosystem II D2 protein (psbD2)
SLL1330 201.90501 OmpR subf amily

SLL1321 102.15744 hypothetical

sensory transduction histidine kinasephycocyanin b

protein (atp1)
Log2(Measure/Ref)

SLL0851 74.04078 photosystem II

CP43 protein (psbC)

-2 subunit (cpcB)
SLL1867 50.749165 photosystem II
D1 protein (psbA 3)
SLL1745 105.46256 50S ribosomal

phycocyanin a subunit (cpcA)

protein L10 (rpl10)
SLR1834 396.65952 P700 apoprotein
subunit Ia (psaA )

-4 allophycocyanin a chain (apcA)

SLL1322 63.89238 ATP synthase
subunit a (atpI)
SLL0819 83.48433 photosystem I

photosystem II D1 protein (psbA2)

subunit III (psaF)
SLR0927 52.74279 photosystem II D2
protein (psbD2)

-6 phycocyanin associated linker protein (cpcC)

SLR0533 130.25998 sensory
transduction histidine kinase

OmpR subfamily
-8
phycocyanin b subunit (cpcB) hypothetical protein (atp1)
phycocyanin a subunitHours
(cpcA)
after midnight
photosystem II CP43 protein (psbC)
allophycocyanin a chain (apcA) photosystem II D1 protein (psbA3)
photosystem II D1 protein (psbA2) 50S ribosomal protein L10 (rpl10)
phycocyanin associated linker protein (cpcC) P700 apoprotein subunit Ia (psaA)
OmpR subfamily ATP synthase subunit a (atpI)
hypothetical protein (atp1) photosystem I subunit III (psaF)
photosystem II CP43 protein (psbC) photosystem II D2 protein (psbD2)
photosystem II D1 protein (psbA3) sensory transduction histidine kinase
50S ribosomal protein L10 (rpl10)
Verbal Model:
When "awake" (day) the cell regulates its photosystem (PS) genes so as to match
photosynthetic output to energy demands. When the available light exceeds its needs, the PS
is down-regulated, leading to an "M" pattern of expression. At night, the cell sleeps, leading
to another drop in expression patterns at night.

Graphical Model:
Computable Model:
(photosynthesis isa process with
inputs (chloroplast-inside.water everywhere.light chloroplast-outside.nadph+
chloroplast-outside.adp chloroplast-outside.pi)
outputs (chloroplast-outside.atp chloroplast-outside.nadph everywhere.o2)
implemented-by photosystem)
(photosystem composition (psii antenna-array atpase pq-pool))
(light-absorption isa process with
inputs (everywhere.light)
outputs (chlorophyll.energy)
function absorption
implemented-by chlorophyll)
(light-energy-concentration isa process with
outputs psii.energy
driver chlorophyll.energy
function concentration
implemented-by antenna-array)
(psii-water-breakdown isa process with
inputs (chloroplast-inside.water)
driver psii.energy
outputs (psii.e- psii.e- chloroplast-inside.h+ chloroplast-inside.o2)
function molecular-splitting
implemented-by psii)
(psii-pq-reduction isa process with
inputs (psii.e- chloroplast-membrane.h+ chloroplast-membrane.plastoquinone)
outputs (chloroplast-membrane.plastoquinol)
function reduction
implemented-by psii
inhibited-by dcmu)
Explanation by Pathway Tracing:
(photosynthesis isa process with
inputs (chloroplast-inside.water everywhere.light chloroplast-outside.nadph+
chloroplast-outside.adp chloroplast-outside.pi)
outputs (chloroplast-outside.atp chloroplast-outside.nadph everywhere.o2)
implemented-by photosystem)
(photosystem composition (psii antenna-array atpase pq-pool))
(light-absorption isa process with
inputs (everywhere.light)
outputs (chlorophyll.energy)
function absorption
implemented-by chlorophyll)
(light-energy-concentration isa process with
outputs psii.energy
driver chlorophyll.energy
function concentration
implemented-by antenna-array)
(psii-water-breakdown isa process with
inputs (chloroplast-inside.water)
driver psii.energy
outputs (psii.e- psii.e- chloroplast-inside.h+ chloroplast-inside.o2)
function molecular-splitting
implemented-by psii)
(psii-pq-reduction isa process with
inputs (psii.e- chloroplast-membrane.h+ chloroplast-membrane.plastoquinone)
outputs (chloroplast-membrane.plastoquinol)
function reduction
implemented-by psii
inhibited-by dcmu)
Explanation by Pathway Tracing:

(track-object 'chloroplast-inside.water)
Tracking CHLOROPLAST-INSIDE.WATER
-> PHOTOSYNTHESIS:
Tracking CHLOROPLAST-OUTSIDE.ATP
Tracking CHLOROPLAST-OUTSIDE.NADPH
Tracking EVERYWHERE.O2
-> PSII-WATER-BREAKDOWN:
Tracking PSII.E-
-> PSII-PQ-REDUCTION:
Tracking CHLOROPLAST-MEMBRANE.PLASTOQUINOL
-> E-FUNNLING-PSII-TO-PSI:
Tracking PSI.E-
-> PSI-NADPH-FORMATION:
Tracking CHLOROPLAST-INSIDE.H+
-> ATP-FORMATION:
Tracking CHLOROPLAST-INSIDE.O2
-> O2-DIFFUSSION:
Explanation by Pathway Tracing:

(track-object 'chloroplast-inside.water)
Tracking CHLOROPLAST-INSIDE.WATER
-> PHOTOSYNTHESIS:
Tracking CHLOROPLAST-OUTSIDE.ATP
Tracking CHLOROPLAST-OUTSIDE.NADPH
Tracking EVERYWHERE.O2
-> PSII-WATER-BREAKDOWN:
Tracking PSII.E-
-> PSII-PQ-REDUCTION:
Tracking CHLOROPLAST-MEMBRANE.PLASTOQUINOL
-> E-FUNNLING-PSII-TO-PSI:
Tracking PSI.E-
-> PSI-NADPH-FORMATION:
Tracking CHLOROPLAST-INSIDE.H+
-> ATP-FORMATION:
Tracking CHLOROPLAST-INSIDE.O2
-> O2-DIFFUSSION:
Current representational practice:

From GenNav, the NIH Gene Ontology Browser

Goal: Replace the Gene Ontology with Process Models
(photosynthesis isa process with
inputs (chloroplast-inside.water everywhere.light chloroplast-outside.nadph+
chloroplast-outside.adp chloroplast-outside.pi)
outputs (chloroplast-outside.atp chloroplast-outside.nadph everywhere.o2)
implemented-by photosystem)
(photosystem composition (psii antenna-array atpase pq-pool))
(light-absorption isa process with
inputs (everywhere.light)
outputs (chlorophyll.energy)
function absorption
implemented-by chlorophyll)
(light-energy-concentration isa process with
outputs psii.energy
driver chlorophyll.energy
function concentration
implemented-by antenna-array)
(psii-water-breakdown isa process with
inputs (chloroplast-inside.water)
driver psii.energy
outputs (psii.e- psii.e- chloroplast-inside.h+ chloroplast-inside.o2)
function molecular-splitting
implemented-by psii)
(psii-pq-reduction isa process with
inputs (psii.e- chloroplast-membrane.h+ chloroplast-membrane.plastoquinone)
outputs (chloroplast-membrane.plastoquinol)
function reduction
implemented-by psii
inhibited-by dcmu)
From GenNav, the NIH Gene Ontology Browser
 BioLingua Computational Biology Workbench

BioLisp A simple programming language to be used by Standard

Scripting biologists to answer specific questions regarding
the integration of their data with the concepts below. analytic tools,
Layer
plus discovery
Computed An ever-expanding library of computations that tools that
Concepts produce complex, virtual, biological concepts, such as
combine know-
pathways, complexes, regulons, etc.
Layer ledge and data
Unified Basic Structures provided for important biological under user
Concepts concepts: e.g., reactions, molecules, enzymes, control.
experiments, expression-levels, etc.
Layer
Integrated
K/DB Layer KEGG BioCyc GO Remote Access
Other K/DBs

Locally mirror important K/DBs SMD

 BioLingua Frame Browser

NewGO (Computer-Usable Content)

NowGO (Human-Usable Content)

 Goals of Computational Biology

Enable biologists to…

• Combine knowledge, data, and tools to …

• … conduct complex analyses.

• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.

Model Development
Model Development
Model Development as Search in “Model Space”
Generic Biological Experimental
Biological Constraints Data
Processes

Model Space Search Model Fitting

Possible Best Model

Models and Parameterization
Some Generic Biological Processes
[Photo Protein] [Light]

- PhotoSynthesis
[Product] UnControlled
Degradation
[Redox [Reactive
- Potential] Oxygen
Species]
[Product] Controlled
[Control Degradation
Species] Rate
[Control
- Species] Type I
Regulation
[RNA] [Protein]
Translation
[Control Rate
Species] Type II
Rate [RNA]
Regulation -
Transcription
With no constraints, any genes could be co-
regulated:
How many regulatory models are there?

n=300
L=4
How many regulatory models are there?

2
1/2(n - n) 89700
L = ~4

Model
n=300 Identification
L=4 n
requires ~2
observations!
 Model Development Protocol
Generic Biological Experimental
Biological Constraints Data
Processes

Model Space Search Model Fitting

Possible Best Model

Models and Parameterization
Genomic Analysis

Regulon
Architecture
(simplified)

Some promoters have

high sequence
similarity, suggesting
correlated-regulation
Bacterial
Genome
Genomic analysis constrains co-regulation:
Data regularities further constrain probable
co-regulation:
Data regularities further constrain probable
co-regulation:
Regularities based upon predicted correlations:

+ -
DFR NBLR NBLA
 AntiCorrelated

+ -
DFR NBLR NBLA

Correlated AntiCorrelated
 Goals of Computational Biology

Enable biologists to…

• Combine knowledge, data, and tools to …

• … conduct complex analyses.

• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.

Model Development
 Model Development Protocol
Generic Biological Experimental
Biological Constraints Data
Processes

Model Space Search Model Fitting

Possible Best Model

Models and Parameterization
Model with
fitted parameters
 Goals of Computational Biology

Enable biologists to…

• Combine knowledge, data, and tools to …

• … conduct complex analyses.

• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.

Model Development
 Model of Photosynthetic Light Regualtion

+ -
NBLR NBLA PBS
+
-
DFR psbA1 Health
+
- -
+
- +
+ RR psbA2 Photosynthetic
activity
-
Light cpcB
 Model Development Protocol

Biological
Preliminary
Process
Hypotheses
Knowledge Experimental
Data

Model Neighborhood Search

Neighborhood search
limits the search to
subsystems thought to
be relevant.
 Model of Photosynthetic Light Regualtion

+ -
NBLR NBLA PBS
+
-
DFR psbA1 Health
+
- -
+
- +
+ RR psbA2 Photosynthetic
activity
-
Light cpcB
Adding Regulon Constraints

+ -
NBLR NBLA PBS
+
-
Regulon Constraints
DFR psbA1 Health
+
- -
+
- +
+ RR psbA2 Photosynthetic
activity
-
Light cpcB
Adding Biological Process Knowledge

energy
+ - +
NBLR NBLA PBS +
+
+ damage
Si
Regulon Constraints -
DFR Ca gna psbA1 Health
sc l +
ad - -
e
Detection
Signal

+
- +
+ RR psbA2 Photosynthetic
activity
-
Light cpcB
 Model Development Protocol

Biological
Preliminary
Process
Hypotheses
Knowledge Experimental
Data

Model Neighborhood Search

 Improved Regulatory Model
~3000 candidates tried

energy
+ - +
NBLR NBLA PBS +
+
+ damage
Si
Regulon Constraints -
DFR Ca gna psbA1 Health
sc l +
ad - -
e
Detection
Signal

-- - +
+ RR psbA2 Photosynthetic
activity
-
Light cpcB
 Goals of Computational Biology

Enable biologists to…

• Combine knowledge, data, and tools to …
Analysis and
• … conduct complex analyses.
Prediction
• … simulate complex phenomena.
• … propose abstract models.
• … refine specific models.

Model Development
BioLingua: Computational Biology Workbench
• Integrates Genomic and Data Analysis Tools
• Integrates Organism-specific as well as General Knowledge
• Unifies Important Knowledge Bases
• Integrates Model Development and Refinement tools
• Offers a Flexible “Open Programming” Methodology
• Provides Convenient Universal Access (fully web-enabled)
BioLingua: Computational Biology Workbench
• Integrates Genomic and Data Analysis Tools
• Integrates Organism-specific as well as General Knowledge
• Unifies Important Knowledge Bases
• Integrates Model Development and Refinement tools
• Offers a Flexible “Open Programming” Methodology
• Provides Convenient Universal Access (fully web-enabled)
• And 8th-graders can learn it!
 BioLingua:
• JP Massar
• Mike Travers
• Stephen Bay
• Devaki Bhaya
• Jeff Elhai
• Bob Haxo
• Sumudu Watagala
• Monica Jain
• Ashvin Kumar
• Pat Langley
• Andrew Pohorille
• Karl Schweighofer
• Colin Smith
• Serdar Uckun

With support from NASA, Franz Inc., and Xanalys

 Cyclodyn Experiments:
• Rochelle Labiosa
• Stephen Bay
• Devaki Bhaya
• CJ Tu
• Arthur Grossman
• Tasha Reddy
• Kevin Arrigo

With support from NASA, Stanford, and Arthur and Kevin’s Labs
Discovery Tools:
• Pat Langley
• Stephen Bay
• Andrew Pohorille
• Lonnie Chrisman
• Kazumi Saito
• Dileep George

With support from NASA and NTT

Available reports and papers:
JP Massar, M Travers, J Shrager (in prep.) BioLingua: A new paradigm in interactive computational biology.
(And online: http://aracyc.stanford.edu/~jshrager/jeff/mbcs/weblistener/index.html)
S Bay, J Shrager, A Pohorille, P Langley (to appear). Revising regulatory networks: From expression data
to linear causal models. J. Biomed. Informatics.
K Saito, D George, S Bay, J Shrager (2003). Inducing biological models from temporal gene expression
data. Proceedings of the 6th International Conference on Discovery Systems. Sapporo, Japan.
J Shrager (2003). The fiction of function. BioInformatics.
L Chrisman, et al. (2003). Incorporating biological knowledge into evaluation of causal
regulatory hypotheses. Proc. of the Pacific Symposium on Biocomputing (PSB2003). Hawaii.
R Labiosa, et al. (2003). Diurnal variations in pathways of photosynthetic carbon fixation in a
freshwater cyanobacterium. Presented at the Euro-American Geophysical Society meeting; Nice, France.
P Langley, J Shrager, & K Saito (2002). Computational discovery of communicable scientific knowledge.
In Magnani, Nersessian, & Pizzi (Eds), Logical and Computational Aspects of Model-Based Reasoning.
Dordrecht: Kluwer Academic.
J Shrager, P Langley, & A Pohorille (2002), Guiding revision of regulatory models with
expression data. Proc. of the Pacific Symposium on BioComputing. World Scientific Press.
J Shrager (2001). High throughput discovery: Search and interpretation on the path to new drugs.
In K. Crowley, et al. (Eds.) Design for Science. Hillsdale, NJ: Lawrence Erlbaum. pp 325-348.