Statistical Bioinformatics: For Biomedical and Life Science Researchers

CONTRIBUTORS xiii

1 ROAD TO STATISTICAL BIOINFORMATICS 1

Challenge 1: Multiple-Comparisons Issue 1

Challenge 2: High-Dimensional Biological Data 2

Challenge 3: Small-n and Large-p Problem 3

Challenge 4: Noisy High-Throughput Biological Data 3

Challenge 5: Integration of Multiple, Heterogeneous Biological Data Information 3

References 5

2 PROBABILITY CONCEPTS AND DISTRIBUTIONS FOR ANALYZING LARGE BIOLOGICAL DATA 7

2.1 Introduction 7

2.2 Basic Concepts 8

2.3 Conditional Probability and Independence 10

2.4 Random Variables 13

2.5 Expected Value and Variance 15

2.6 Distributions of Random Variables 19

2.7 Joint and Marginal Distribution 39

2.8 Multivariate Distribution 42

2.9 Sampling Distribution 46

2.10 Summary 54

3 QUALITY CONTROL OF HIGH-THROUGHPUT BIOLOGICAL DATA 57

3.1 Sources of Error in High-Throughput Biological Experiments 57

3.2 Statistical Techniques for Quality Control 59

3.3 Issues Specific to Microarray Gene Expression Experiments 66

3.4 Conclusion 69

References 69

4 STATISTICAL TESTING AND SIGNIFICANCE FOR LARGE BIOLOGICAL DATA ANALYSIS 71

4.1 Introduction 71

4.2 Statistical Testing 72

4.3 Error Controlling 78

4.4 Real Data Analysis 81

4.5 Concluding Remarks 87

Acknowledgments 87

References 88

5 CLUSTERING: UNSUPERVISED LEARNING IN LARGE BIOLOGICAL DATA 89

5.1 Measures of Similarity 90

5.2 Clustering 99

5.3 Assessment of Cluster Quality 115

5.4 Conclusion 123

References 123

6 CLASSIFICATION: SUPERVISED LEARNING WITH HIGH-DIMENSIONAL BIOLOGICAL DATA 129

6.1 Introduction 129

6.2 Classification and Prediction Methods 132

6.3 Feature Selection and Ranking 140

6.4 Cross-Validation 144

6.5 Enhancement of Class Prediction by Ensemble Voting Methods 145

6.6 Comparison of Classification Methods Using High-Dimensional Data 147

6.7 Software Examples for Classification Methods 150

References 154

7 MULTIDIMENSIONAL ANALYSIS AND VISUALIZATION ON LARGE BIOMEDICAL DATA 157

7.1 Introduction 157

7.2 Classical Multidimensional Visualization Techniques 158

7.3 Two-Dimensional Projections 161

7.4 Issues and Challenges 165

7.5 Systematic Exploration of Low-Dimensional Projections 166

7.6 One-Dimensional Histogram Ordering 170

7.7 Two-Dimensional Scatterplot Ordering 174

7.8 Conclusion 181

References 182

8 STATISTICAL MODELS, INFERENCE, AND ALGORITHMS FOR LARGE BIOLOGICAL DATA ANALYSIS 185

8.1 Introduction 185

8.2 Statistical/Probabilistic Models 187

8.3 Estimation Methods 189

8.4 Numerical Algorithms 191

8.5 Examples 192

8.6 Conclusion 198

References 199

9 EXPERIMENTAL DESIGNS ON HIGH-THROUGHPUT BIOLOGICAL EXPERIMENTS 201

9.1 Randomization 201

9.2 Replication 202

9.3 Pooling 209

9.4 Blocking 210

9.5 Design for Classifications 214

9.6 Design for Time Course Experiments 215

9.7 Design for eQTL Studies 215

References 216

10 STATISTICAL RESAMPLING TECHNIQUES FOR LARGE BIOLOGICAL DATA ANALYSIS 219

10.1 Introduction 219

10.2 Resampling Methods for Prediction Error Assessment and Model Selection 221

10.3 Feature Selection 225

10.4 Resampling-Based Classification Algorithms 226

10.5 Practical Example: Lymphoma 226

10.6 Resampling Methods 227

10.7 Bootstrap Methods 232

10.8 Sample Size Issues 233

10.9 Loss Functions 235

10.10 Bootstrap Resampling for Quantifying Uncertainty 236

10.11 Markov Chain Monte Carlo Methods 238

10.12 Conclusions 240

References 247

11 STATISTICAL NETWORK ANALYSIS FOR BIOLOGICAL SYSTEMS AND PATHWAYS 249

11.1 Introduction 249

11.2 Boolean Network Modeling 250

11.3 Bayesian Belief Network 259

11.4 Modeling of Metabolic Networks 273

References 279

12 TRENDS AND STATISTICAL CHALLENGES IN GENOMEWIDE ASSOCIATION STUDIES 283

12.1 Introduction 283

12.2 Alleles, Linkage Disequilibrium, and Haplotype 283

12.3 International HapMap Project 285

12.4 Genotyping Platforms 286

12.5 Overview of Current GWAS Results 287

12.6 Statistical Issues in GWAS 290

12.7 Haplotype Analysis 296

12.8 Homozygosity and Admixture Mapping 298

12.9 Gene Gene and Gene Environment Interactions 298

12.10 Gene and Pathway-Based Analysis 299

12.11 Disease Risk Estimates 301

12.12 Meta-Analysis 301

12.13 Rare Variants and Sequence-Based Analysis 302

12.14 Conclusions 302

Acknowledgments 303

References 303

13 R AND BIOCONDUCTOR PACKAGES IN BIOINFORMATICS: TOWARDS SYSTEMS BIOLOGY 309

13.1 Introduction 309

13.2 Brief overview of the Bioconductor Project 310

13.3 Experimental Data 311

13.4 Annotation 318

13.5 Models of Biological Systems 328

13.6 Conclusion 335

13.7 Acknowledgments 336

References 336

INDEX 339