Computer Methods Part B

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CONTENTS

Contributors xiii
Preface xix
Volumes in Series xxi

1. Correlation Analysis: A Tool for Comparing Relaxation-Type

Models to Experimental Data 1
Maurizio Tomaiuolo, Joel Tabak, and Richard Bertram
1. Introduction 2
2. Scatter Plots and Correlation Analysis 3
3. Example 1: Relaxation Oscillations 4
4. Example 2: Square Wave Bursting 13
5. Example 3: Elliptic Bursting 15
6. Example 4: Using Correlation Analysis on Experimental Data 18
7. Summary 19
Acknowledgment 20
References 20

2. Trait Variability of Cancer Cells Quantified by High-Content

Automated Microscopy of Single Cells 23
Vito Quaranta, Darren R. Tyson, Shawn P. Garbett, Brandy Weidow,
Mark P. Harris, and Walter Georgescu
1. Introduction 24
2. Background 25
3. Experimental and Computational Workflow 26
4. Application to Traits Relevant to Cancer Progression 34
5. Conclusions 54
Acknowledgments 54
References 54

3. Matrix Factorization for Recovery of Biological Processes

from Microarray Data 59
Andrew V. Kossenkov and Michael F. Ochs
1. Introduction 59
2. Overview of Methods 63

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vi Contents

3. Application to the Rosetta Compendium 68

4. Results of Analyses 70
5. Discussion 74
References 75

4. Modeling and Simulation of the Immune System

as a Self-Regulating Network 79
Peter S. Kim, Doron Levy, and Peter P. Lee
1. Introduction 80
2. Mathematical Modeling of the Immune Network 84
3. Two Examples of Models to Understand T Cell Regulation 92
4. How to Implement Mathematical Models in
Computer Simulations 100
5. Concluding Remarks 105
Acknowledgments 106
References 107

5. Entropy Demystified: The ‘‘Thermo’’-dynamics

of Stochastically Fluctuating Systems 111
Hong Qian

1. Introduction 112
2. Energy 113
3. Entropy and ‘‘Thermo’’-dynamics of
Markov Processes 117
4. A Three-State Two-Cycle Motor Protein 122
5. Phosphorylation–Dephosphorylation Cycle Kinetics 125
6. Summary and Challenges 131
References 132

6. Effect of Kinetics on Sedimentation Velocity Profiles

and the Role of Intermediates 135
John J. Correia, P. Holland Alday, Peter Sherwood, and Walter F. Stafford
1. Introduction 136
2. Methods 138
3. ABCD Systems 141
4. Monomer–Tetramer Model 151
5. Summary 158
Acknowledgments 159
References 159
Contents vii

7. Algebraic Models of Biochemical Networks 163

Reinhard Laubenbacher and Abdul Salam Jarrah
1. Introduction 164
2. Computational Systems Biology 165
3. Network Inference 176
4. Reverse-Engineering of Discrete Models: An Example 181
5. Discussion 190
References 193

8. High-Throughput Computing in the Sciences 197

Mark Morgan and Andrew Grimshaw
1. What is an HTC Application? 199
2. HTC Technologies 200
3. High-Throughput Computing Examples 204
4. Advanced Topics 218
5. Summary 226
References 226

9. Large Scale Transcriptome Data Integration Across

Multiple Tissues to Decipher Stem Cell Signatures 229
Ghislain Bidaut and Christian J. Stoeckert
1. Introduction 230
2. Systems and Data Sources 231
3. Data Integration 236
4. Artificial Neural Network Training and Validation 238
5. Future Development and Enhancement Plans 243
Acknowledgments 244
References 244

10. DynaFit—A Software Package for Enzymology 247

Petr Kuzmič

1. Introduction 248
2. Equilibrium Binding Studies 250
3. Initial Rates of Enzyme Reactions 255
4. Time Course of Enzyme Reactions 260
5. General Methods and Algorithms 262
6. Concluding Remarks 275
Acknowledgments 276
References 276
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11. Discrete Dynamic Modeling of Cellular

Signaling Networks 281
Réka Albert and Rui-Sheng Wang

1. Introduction 282
2. Cellular Signaling Networks 284
3. Boolean Dynamic Modeling 286
4. Variants of Boolean Network Models 297
5. Application Examples 301
6. Conclusion and Discussion 303
Acknowledgments 303
References 303

12. The Basic Concepts of Molecular Modeling 307

Akansha Saxena, Diana Wong, Karthikeyan Diraviyam, and David Sept

1. Introduction 308
2. Homology Modeling 308
3. Molecular Dynamics 317
4. Molecular Docking 324
References 330

13. Deterministic and Stochastic Models of

Genetic Regulatory Networks 335
Ilya Shmulevich and John D. Aitchison

1. Introduction 336
2. Boolean Networks 337
3. Differential Equation Models 343
4. Probabilistic Boolean Networks 347
5. Stochastic Differential Equation Models 351
References 353

14. Bayesian Probability Approach to ADHD Appraisal 357

Raina Robeva and Jennifer Kim Penberthy

1. Introduction 358
2. Bayesian Probability Algorithm 362
3. The Value of Bayesian Probability Approach as a
Meta-Analysis Tool 369
4. Discussion and Future Directions 373
Acknowledgment 377
References 378
Contents ix

15. Simple Stochastic Simulation 381

Maria J. Schilstra and Stephen R. Martin
1. Introduction 382
2. Understanding Reaction Dynamics 385
3. Graphical Notation 386
4. Reactions 389
5. Reaction Kinetics 389
6. Transition Firing Rules 393
7. Summary 406
8. Notes 407
References 409

16. Monte Carlo Simulation in Establishing Analytical Quality

Requirements for Clinical Laboratory Tests: Meeting
Clinical Needs 411
James C. Boyd and David E. Bruns
1. Introduction 412
2. Modeling Approach 414
3. Methods for Simulation Study 416
4. Results 417
5. Discussion 429
References 431

17. Nonlinear Dynamical Analysis and Optimization for

Biological/Biomedical Systems 435
Amos Ben-Zvi and Jong Min Lee
1. Introduction 436
2. Hypothalamic–Pituitary–Adrenal Axis System 437
3. Development of a Clinically Relevant
Performance-Assessment Tools 441
4. Dynamic Programming 452
5. Computation of Optimal Treatments for
HPA Axis System 455
6. Conclusions 458
Acknowledgments 458
References 458
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18. Modeling of Growth Factor-Receptor Systems: From

Molecular-Level Protein Interaction Networks to
Whole-Body Compartment Models 461
Florence T. H. Wu, Marianne O. Stefanini, Feilim Mac Gabhann,
and Aleksander S. Popel

1. Background 462
2. Molecular-Level Kinetics Models: Simulation of In Vitro Experiments 466
3. Mesoscale Single-Tissue 3D Models: Simulation of In Vivo
Tissue Regions 474
4. Single-Tissue Compartmental Models: Simulation of In Vivo Tissue 482
5. Multitissue Compartmental Models: Simulation of Whole Body 485
6. Conclusions 493
Acknowledgments 494
References 494

19. The Least-Squares Analysis of Data from Binding and Enzyme

Kinetics Studies: Weights, Bias, and Confidence Intervals in
Usual and Unusual Situations 499
Joel Tellinghuisen
1. Introduction 500
2. Least Squares Review 503
3. Statistics of Reciprocals 506
4. Weights When y is a True Dependent Variable 511
5. Unusual Weighting: When x is the Dependent Variable 521
6. Assessing Data Uncertainty: Variance Function Estimation 524
7. Conclusion 526
References 527

20. Nonparametric Entropy Estimation Using Kernel Densities 531

Douglas E. Lake

1. Introduction 532
2. Motivating Application: Classifying Cardiac Rhythms 533
3. Renyi Entropy and the Friedman–Tukey Index 535
4. Kernel Density Estimation 536
5. Mean-Integrated Square Error 538
6. Estimating the FT Index 540
7. Connection Between Template Matches and Kernel Densities 544
8. Summary and Future Work 545
Acknowledgments 545
References 546
Contents xi

21. Pancreatic Network Control of Glucagon Secretion and

Counterregulation 547
Leon S. Farhy and Anthony L. McCall

1. Introduction 548
2. Mechanisms of Glucagon Counterregulation (GCR)
Dysregulation in Diabetes 550
3. Interdisciplinary Approach to Investigating the Defects in the GCR 551
4. Initial Qualitative Analysis of the GCR Control Axis 553
5. Mathematical Models of the GCR Control Mechanisms
in STZ-Treated Rats 556
6. Approximation of the Normal Endocrine Pancreas by a Minimal
Control Network (MCN) and Analysis of the GCR Abnormalities
in the Insulin Deficient Pancreas 560
7. Advantages and Limitations of the Interdisciplinary Approach 571
8. Conclusions 575
Acknowledgment 575
References 575

22. Enzyme Kinetics and Computational Modeling for

Systems Biology 583
Pedro Mendes, Hanan Messiha, Naglis Malys, and Stefan Hoops

1. Introduction 584
2. Computational Modeling and Enzyme Kinetics 586
3. Yeast Triosephosphate Isomerase (EC 5.3.1.1) 588
4. Initial Rate Analysis 590
5. Progress Curve Analysis 594
6. Concluding Remarks 598
Acknowledgments 598
References 598

23. Fitting Enzyme Kinetic Data with KinTek Global Kinetic Explorer 601
Kenneth A. Johnson
1. Background 602
2. Challenges of Fitting by Simulation 603
3. Methods 605
4. Progress Curve Kinetics 610
5. Fitting Full Progress Curves 613
6. Slow Onset Inhibition Kinetics 620
7. Summary 624
Acknowledgments 625
References 625

Author Index 627

Subject Index 637
CONTRIBUTORS

John D. Aitchison
Institute for Systems Biology, Seattle, Washington, USA
Réka Albert
Department of Physics, Pennsylvania State University, University Park,
Pennsylvania, USA
P. Holland Alday
Department of Biochemistry, University of Mississippi Medical Center, Jackson,
Mississippi, USA
Amos Ben-Zvi
Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta,
Canada
Richard Bertram
Department of Mathematics and Programs in Neuroscience and Molecular
Biophysics, Florida State University, Tallahassee, Florida, USA
Ghislain Bidaut
Inserm, UMR891, CRCM, Integrative Bioinformatics, and Institut Paoli-
Calmettes; Univ Méditerranée, Marseille, France
James C. Boyd
Department of Pathology, University of Virginia Health System,
Charlottesville, Virginia, USA
David E. Bruns
Department of Pathology, University of Virginia Health System,
Charlottesville, Virginia, USA
John J. Correia
Department of Biochemistry, University of Mississippi Medical Center, Jackson,
Mississippi, USA
Karthikeyan Diraviyam
Biomedical Engineering and Center for Computational Medicine and Bioinfor-
matics, University of Michigan, Ann Arbor, Michigan, USA
Leon S. Farhy
Department of Medicine, Center for Biomathematical Technology, University of
Virginia, Charlottesville, Virginia, USA

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xiv Contributors

Feilim Mac Gabhann

Department of Biomedical Engineering, Institute for Computational Medicine,
Johns Hopkins University, Baltimore, Maryland, USA
Shawn P. Garbett
Vanderbilt Integrative Cancer Biology Center, Vanderbilt University Medical
Center, Nashville, Tennessee, USA
Walter Georgescu
Vanderbilt Integrative Cancer Biology Center, and Department of Biomedical
Engineering, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Andrew Grimshaw
Department of Computer Science, University of Virginia, Charlottesville,
Virginia, USA
Mark P. Harris
Department of Cancer Biology, Vanderbilt University Medical Center, Nashville,
Tennessee, USA
Stefan Hoops
Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State
University, Blacksburg, Virginia, USA
Abdul Salam Jarrah
Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, Virginia, USA
Kenneth A. Johnson
Department of Chemistry and Biochemistry, Institute for Cell and Molecular
Biology, University of Texas, Austin, Texas, USA
Peter S. Kim
Department of Mathematics, University of Utah, Salt Lake City, Utah, USA
Andrew V. Kossenkov
The Wistar Institute, Philadelphia, Pennsylvania, USA
Petr Kuzmič
BioKin Ltd., Watertown, Massachusetts, USA
Douglas E. Lake
Departments of Internal Medicine (Cardiovascular Division) and Statistics,
University of Virginia, Charlottesville, Virginia, USA
Reinhard Laubenbacher
Virginia Bioinformatics Institute at Virginia Tech, Blacksburg, Virginia, USA
Jong Min Lee
Chemical and Materials Engineering, University of Alberta, Edmonton, Alberta,
Canada
Contributors xv

Peter P. Lee
Division of Hematology, Department of Medicine, Stanford University, Stanford,
California, USA
Doron Levy
Department of Mathematics and Center for Scientific Computation and Mathe-
matical Modeling (CSCAMM), University of Maryland, College Park, Maryland,
USA
Naglis Malys
Manchester Centre for Integrative Systems Biology, and Faculty of Life Sciences,
The University of Manchester, Manchester, United Kingdom
Stephen R. Martin
Division of Physical Biochemistry, MRC National Institute for Medical Research,
London, United Kingdom
Anthony L. McCall
Department of Medicine, Center for Biomathematical Technology, University of
Virginia, Charlottesville, Virginia, USA
Pedro Mendes
Manchester Centre for Integrative Systems Biology, and School of Computer
Science, The University of Manchester, Manchester, United Kingdom; Virginia
Bioinformatics Institute, Virginia Polytechnic Institute and State University,
Blacksburg, Virginia, USA
Hanan Messiha
Manchester Centre for Integrative Systems Biology, and School of Chemistry,
The University of Manchester, Manchester, United Kingdom
Mark Morgan
Department of Computer Science, University of Virginia, Charlottesville,
Virginia, USA
Michael F. Ochs
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,
Baltimore, Maryland, USA
Jennifer Kim Penberthy
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia
Health System, Charlottesville, Virginia, USA
Aleksander S. Popel
Department of Biomedical Engineering, Johns Hopkins University School of
Medicine, Baltimore, Maryland, USA
Hong Qian
Department of Applied Mathematics, University of Washington, Seattle,
Washington, USA
xvi Contributors

Vito Quaranta
Department of Cancer Biology, and Vanderbilt Integrative Cancer Biology
Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Raina Robeva
Department of Mathematical Sciences, Sweet Briar College, Sweet Briar, Virginia,
USA
Akansha Saxena
Biomedical Engineering, Washington University, St Louis, Missouri, USA
Maria J. Schilstra
Biological and Neural Computation Group, Science and Technology Research
Institute, University of Hertfordshire, Hatfield, United Kingdom
David Sept
Biomedical Engineering and Center for Computational Medicine and
Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
Peter Sherwood
Boston Biomedical Research Institute, Watertown, Massachusetts, USA
Ilya Shmulevich
Institute for Systems Biology, Seattle, Washington, USA
Walter F. Stafford
Boston Biomedical Research Institute, Watertown, Massachusetts, USA
Marianne O. Stefanini
Department of Biomedical Engineering, Johns Hopkins University School of
Medicine, Baltimore, Maryland, USA
Christian J. Stoeckert
Center for Bioinformatics, Department of Genetics, University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania, USA
Joel Tabak
Department of Biological Science and Program in Neuroscience, Florida State
University, Tallahassee, Florida, USA
Joel Tellinghuisen
Department of Chemistry, Vanderbilt University, Nashville, Tennessee, USA
Maurizio Tomaiuolo
Department of Biological Science and Program in Neuroscience, Florida State
University, Tallahassee, Florida, USA
Darren R. Tyson
Department of Cancer Biology, and Vanderbilt Integrative Cancer Biology
Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Contributors xvii

Rui-Sheng Wang
Department of Physics, Pennsylvania State University, University Park,
Pennsylvania, USA
Brandy Weidow
Department of Cancer Biology, and Vanderbilt Integrative Cancer Biology
Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Diana Wong
Biomedical Engineering, Washington University, St Louis, Missouri, USA
Florence T.H. Wu
Department of Biomedical Engineering, Johns Hopkins University School of
Medicine, Baltimore, Maryland, USA
PREFACE

A general perception exists that the only applications of computers and

computer methods in biological and biomedical research are either basic
statistical analysis or the searching of DNA sequence databases. While these
are important applications they only scratch the surface of the current and
potential applications of computers and computer methods in biomedical
research. The various chapters within this volume include a wide variety of
applications that extend beyond this limited perception.
The use of computers and computational methods has become ubiquitous
in biological and biomedical research. This has been driven by numerous
factors, a few of which follow: One primary reason is the emphasis being
placed on computers and computational methods within the National Insti-
tutes of Health (NIH) Roadmap; another factor is the increased level
of mathematical and computational sophistication among researchers,
particularly amongst junior scientists, students, journal reviewers, and NIH
Study Section members; and another is the rapid advances in computer
hardware and software which make these methods far more accessible to
the rank and file research community.
The training of the majority of senior M.D.s and Ph.D.s in clinical or
basic disciplines at academic research and medical centers commonly does
not include advanced coursework in mathematics, numerical analysis,
statistics, or computer science. The chapters within this volume have been
written in order to be accessible to this target audience.

MICHAEL L. JOHNSON
LUDWIG BRAND

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