Representing, Reasoning and Answering Questions about Biological Pathways Various ...

401 Pages·2014·1.69 MB·English

Representing, Reasoning and Answering Questions about Biological Pathways
Various Applications
by
Saadat Anwar
A Dissertation Presented in Partial Fulfillment
of the Requirement for the Degree
Doctor of Philosophy
Approved November 2013 by the
Graduate Supervisory Committee:
Chitta Baral, Chair
Katsumi Inoue
Yi Chen
Hasan Davulcu
Joohyung Lee
ARIZONA STATE UNIVERSITY
May 2014
ABSTRACT
Biological organisms are made up of cells containing numerous interconnected bio-
chemical processes. Diseases occur when normal functionality of these processes is
disrupted, manifesting as disease symptoms. Thus, understanding these biochem-
ical processes and their interrelationships is a primary task in biomedical research
and a prerequisite for activities including diagnosing diseases and drug development.
Scientists studying these interconnected processes have identified various pathways
involved in drug metabolism, diseases, and signal transduction, etc.
High-throughput technologies, new algorithms and speed improvements over the
last decade have resulted in deeper knowledge about biological systems, leading to
more refined pathways. Such pathways tend to be large and complex, making it
difficult for an individual to remember all aspects. Thus, computer models are needed
to represent and analyze them. The refinement activity itself requires reasoning with
a pathway model by posing queries against it and comparing the results against the
real biological system.
Many existing models focus on structural and/or factoid questions, relying on
surface-level information. These are generally not the kind of questions that a biolo-
gist may ask someone to test their understanding of biological processes. Examples
of questions requiring understanding of biological processes are available in introduc-
tory college level biology text books. Such questions serve as a model for the question
answering system developed in this thesis.
Thus, the main goal of this thesis is to develop a system that allows the encoding
of knowledge about biological pathways to answer questions demonstrating under-
standing of the pathways. To that end, a language is developed to specify a pathway
and pose questions against it. Some existing tools are modified and used to accom-
i
plish this goal. The utility of the framework developed in this thesis is illustrated
with applications in the biological domain.
Finally, the question answering system is used in real world applications by ex-
tracting pathway knowledge from text and answering questions related to drug de-
velopment.
ii
This dissertation is dedicated to my parents, my family, and especially my grand
mother.
iii
ACKNOWLEDGEMENTS
I would like to express my gratitude to my thesis adviser Dr. Chitta Baral for
his support, guidance and patience throughout my degree. Dr. Baral’s ability to
find creative research dimensions and application areas is an inspiration for me. I
would also like to thank my committee members for their time in supervising this
dissertation. In particular, I want to thank Dr. Katsumi Inoue, Dr. Luis Tari, and
Dr. J¨org Hakenberg for their collaboration in the research.
I would also like to thank my colleagues from Dr. Baral’s lab, who were always
ready to lend me an ear to bounce ideas, review presentations, and give valuable
feedback. In this regard, I specifically thank Vo Ha Nguyen for his efforts.
None of this would have been possible without the support of my boss at work,
Dr. Phil Christensen, who persuaded me to finish my degree and wholeheartedly
supported my efforts. I thank my colleagues at my work place for taking over tasks
and responsibilities in order to lighten my load.
Lastly, my words are not enough for my family for their support, understanding
and patience in this long journey.
iv
TABLE OF CONTENTS
Page
LIST OF TABLES......................................................... xi
LIST OF FIGURES........................................................ xii
CHAPTER
1 Introduction......................................................... 1
1.1 Choosing the right questions..................................... 2
1.2 Choosing the right tools......................................... 2
1.3 Need for a pathway a specification and a query language........... 3
1.4 Text extraction ................................................. 3
1.5 Overview....................................................... 4
1.6 Specific contributions ........................................... 6
1.6.1 General ASP encoding of Petri Net for simulation .......... 6
1.6.2 Answering simulation based reasoning questions............ 7
1.6.3 BioPathQA: a system and a language to represent pathways
and query them.......................................... 8
1.6.4 TextExtractiontoAnswerQuestionsaboutRealWorldAp-
plications................................................ 9
1.7 Summary ...................................................... 10
2 Petri Net Encoding in ASP for Biological Domain...................... 12
2.1 Introduction.................................................... 12
2.2 Background .................................................... 13
2.2.1 Answer Set Programming................................. 13
2.2.2 Multiset................................................. 18
2.2.3 Petri Net................................................ 19
2.3 Translating Basic Petri Net Into ASP ............................ 22
v
Page
2.3.1 An example execution .................................... 26
2.4 Changing Firing Semantics ...................................... 26
2.5 Extension - Reset Arcs .......................................... 28
2.6 Extension - Inhibitor Arcs....................................... 32
2.7 Extension - Read Arcs .......................................... 33
2.8 Extension - Colored Tokens...................................... 35
2.9 Translating Petri Nets with Colored Tokens to ASP ............... 38
2.10 Extension - Priority Transitions.................................. 43
2.11 Extension - Timed Transitions ................................... 44
2.12 Other Extensions ............................................... 47
2.13 Related Work .................................................. 47
2.14 Conclusion ..................................................... 48
3 Answering Questions using Petri Nets and ASP........................ 49
3.1 Introduction.................................................... 49
3.2 Comparing Altered Trajectories due to Reset Intervention ......... 49
3.3 Determining Conditions Leading to an Observation ............... 54
3.4 Comparing Altered Trajectories due to Accumulation Intervention . 57
3.5 Comparing Altered Trajectories due to Initial Value Intervention ... 60
3.6 Comparing Altered Trajectories due to Inhibition Intervention ..... 64
3.7 Comparing Altered Trajectories due to Gradient Equilization In-
tervention ...................................................... 68
3.8 Comparing Altered Trajectories due to Delay Intervention ......... 71
3.9 Comparing Altered Trajectories due to Priority and Read Interven-
tions........................................................... 74
vi
Page
3.10 Comparing Altered Trajectories due to Automatic Conversion In-
tervention ...................................................... 78
3.11 Comparing Altered Trajectories due to Initial Value Intervention ... 81
3.12 Conclusion ..................................................... 86
4 The BioPathQA System.............................................. 87
4.1 Introduction.................................................... 87
4.2 Description of BioPathQA....................................... 87
4.3 Syntax of Pathway Specification Language (BioPathQA-PL) ....... 88
4.4 Semantics of Pathway Specification Language (BioPathQA-PL) .... 97
4.4.1 Guarded-Arc Petri Net ................................... 99
4.4.2 Construction of Guarded-Arc Petri Net from a Pathway
Specification.............................................103
4.4.3 Guarded-Arc Petri Net with Colored Tokens ...............106
4.4.4 ConstructionofGuarded-ArcPetriNetwithColoredTokens
from a Pathway Specification with Locational Fluents ......111
4.5 Syntax of Query Language (BioPathQA-QL) .....................114
4.6 Semantics of the Query Language (BioPathQA-QL) ...............128
4.6.1 An Illustrative Example ..................................129
4.6.2 DomainTransformationduetoInterventionsandInitialCon-
ditions ..................................................131
4.6.3 Formula Semantics.......................................135
4.6.4 Trajectory Filtering due to Internal Observations...........151
4.6.5 Query Description Satisfaction ............................156
4.6.6 Query Statement Satisfaction .............................169
vii
Page
4.6.7 Example Encodings ......................................170
4.6.8 Example Encoding with Conditional Actions...............184
4.6.9 ASP Program ...........................................186
4.6.10 Implementation..........................................187
4.6.11 Evaluation Methodolgy...................................211
4.7 Related Work ..................................................211
4.7.1 Comparison with π-Calculus ..............................211
4.7.2 Comparison with Action Language A......................212
4.7.3 Comparison with Action Language B ......................213
4.7.4 Comparison with Action Language C ......................214
4.7.5 Comparison with Action Language C+ ....................214
4.7.6 Comparison with BC .....................................217
4.7.7 Comparison with ASPMT ................................218
4.7.8 Comparison with BioSigNet-RR...........................219
4.8 Conclusion .....................................................220
5 Text Extraction for Real World Applications ..........................222
5.1 Introduction....................................................222
5.2 Extracting Relationships about Drug Interactions .................224
5.2.1 Methods ................................................226
5.2.2 Results..................................................230
5.3 Extracting Knowledge About Genetic Variants....................230
5.3.1 Methods ................................................231
5.3.2 Results..................................................236
5.4 Applying BioPathQA to Drug-Drug Interaction Discovery .........236
viii
Page
5.4.1 Drug Administration .....................................238
5.4.2 Drug Development .......................................239
5.4.3 Drug Administration in Presence of Genetic Variation ......240
5.5 Conclusion .....................................................241
6 Conclusion and Future Work .........................................243
6.1 Pathway Extraction.............................................246
6.2 Pathway Selection ..............................................246
6.3 Pathway Modeling ..............................................247
6.4 Pathway Simulation.............................................248
6.5 Extend High Level Language ....................................248
6.6 Result Formatting and Visualization .............................249
6.7 Summary ......................................................250
REFERENCES ............................................................251
APPENDIX
A Proofs of Various Propositions........................................257
A.1 Proof of Proposition 1...........................................265
A.2 Proof of Proposition 2...........................................274
A.3 Proof of Proposition 3...........................................284
A.4 Poof of Proposition 4 ...........................................295
A.5 Proof of Proposition 5...........................................307
A.6 Proof of Proposition 6...........................................319
A.7 Proof of Proposition 7...........................................330
A.8 Proof of Proposition 8...........................................346
B Drug-Drug Interaction Queries .......................................363
ix