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xiii | |
Foreword |
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xvii | |
Preface |
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xix | |
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1 Variation, Variability, Batches and Bias in Microarray Experiments: An Introduction |
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1 | (4) |
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2 Microarray Platforms and Aspects of Experimental Variation |
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5 | (14) |
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5 | (1) |
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6 | (3) |
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6 | (1) |
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7 | (1) |
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7 | (1) |
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8 | (1) |
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2.2.5 Spotted Microarrays |
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8 | (1) |
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2.3 Experimental Considerations |
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9 | (8) |
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2.3.1 Experimental Design |
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9 | (1) |
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2.3.2 Sample and RNA Extraction |
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9 | (3) |
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12 | (1) |
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13 | (1) |
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13 | (1) |
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14 | (1) |
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15 | (1) |
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2.3.8 Image Analysis and Data Extraction |
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16 | (1) |
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17 | (1) |
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2.3.10 Interpretation of the Data |
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17 | (1) |
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17 | (2) |
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19 | (14) |
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19 | (1) |
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3.2 Principles of Experimental Design |
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20 | (4) |
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20 | (1) |
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3.2.2 Technical Variation |
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21 | (1) |
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3.2.3 Biological Variation |
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21 | (1) |
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3.2.4 Systematic Variation |
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22 | (1) |
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3.2.5 Population, Random Sample, Experimental and Observational Units |
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22 | (1) |
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3.2.6 Experimental Factors |
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22 | (1) |
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23 | (1) |
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3.3 Measures to Increase Precision and Accuracy |
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24 | (4) |
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25 | (1) |
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25 | (1) |
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25 | (1) |
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3.3.4 Further Measures to Optimize Study Design |
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26 | (2) |
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3.4 Systematic Errors in Microarray Studies |
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28 | (2) |
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28 | (1) |
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28 | (1) |
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3.4.3 Bias at Specimen/Tissue Collection |
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29 | (1) |
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3.4.4 Bias at mRNA Extraction and Hybridization |
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30 | (1) |
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30 | (3) |
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4 Batches and Blocks, Sample Pools and Subsamples in the Design and Analysis of Gene Expression Studies |
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33 | (18) |
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33 | (2) |
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35 | (1) |
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4.2 A Statistical Linear Mixed Effects Model for Microarray Experiments |
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35 | (4) |
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4.2.1 Using the Linear Model for Design |
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37 | (1) |
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4.2.2 Examples of Design Guided by the Linear Model |
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37 | (2) |
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39 | (2) |
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4.3.1 Complete Block Designs |
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39 | (1) |
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4.3.2 Incomplete Block Designs |
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39 | (1) |
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4.3.3 Multiple Batch Effects |
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40 | (1) |
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4.4 Reducing Batch Effects by Normalization and Statistical Adjustment |
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41 | (6) |
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4.4.1 Between and Within Batch Normalization with Multi-array Methods |
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43 | (3) |
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4.4.2 Statistical Adjustment |
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46 | (1) |
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4.5 Sample Pooling and Sample Splitting |
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47 | (2) |
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47 | (1) |
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4.5.2 Sample Splitting: Technical Replicates |
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48 | (1) |
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49 | (1) |
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49 | (2) |
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50 | (1) |
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5 Aspects of Technical Bias |
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51 | (10) |
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51 | (1) |
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5.2 Observational Studies |
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52 | (8) |
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5.2.1 Same Protocol, Different Times of Processing |
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52 | (1) |
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5.2.2 Same Protocol, Different Sites (Study 1) |
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53 | (2) |
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5.2.3 Same Protocol, Different Sites (Study 2) |
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55 | (2) |
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5.2.4 Batch Effect Characteristics at the Probe Level |
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57 | (3) |
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60 | (1) |
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6 Bioinformatic Strategies for cDNA-Microarray Data Processing |
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61 | (14) |
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61 | (3) |
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6.1.1 Spike-in Experiments |
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62 | (1) |
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6.1.2 Key Measures - Sensitivity and Bias |
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63 | (1) |
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6.1.3 The IC Curve and MA Plot |
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63 | (1) |
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64 | (7) |
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6.2.1 Scanning Procedures |
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65 | (1) |
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6.2.2 Background Correction |
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65 | (2) |
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67 | (1) |
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68 | (2) |
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70 | (1) |
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71 | (2) |
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71 | (1) |
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71 | (2) |
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73 | (2) |
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7 Batch Effect Estimation of Microarray Platforms with Analysis of Variance |
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75 | (12) |
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75 | (3) |
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7.1.1 Microarray Gene Expression Data |
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76 | (1) |
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7.1.2 Analysis of Variance in Gene Expression Data |
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77 | (1) |
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7.2 Variance Component Analysis across Microarray Platforms |
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78 | (1) |
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78 | (3) |
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78 | (1) |
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79 | (2) |
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7.3.3 Gene-Specific ANOVA Model |
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81 | (1) |
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7.4 Application: The MAQC Project |
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81 | (4) |
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7.5 Discussion and Conclusion |
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85 | (2) |
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85 | (2) |
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8 Variance due to Smooth Bias in Rat Liver and Kidney Baseline Gene Expression in a Large Multi-laboratory Data Set |
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87 | (14) |
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87 | (2) |
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89 | (1) |
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89 | (8) |
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8.3.1 Assessment of Smooth Bias in Baseline Expression Data Sets |
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89 | (2) |
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8.3.2 Relationship between Smooth Bias and Signal Detection |
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91 | (1) |
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8.3.3 Effect of Smooth Bias Correction on Principal Components Analysis |
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92 | (2) |
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8.3.4 Effect of Smooth Bias Correction on Estimates of Attributable Variability |
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94 | (1) |
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8.3.5 Effect of Smooth Bias Correction on Detection of Genes Differentially Expressed by Fasting |
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95 | (1) |
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8.3.6 Effect of Smooth Bias Correction on the Detection of Strain-Selective Gene Expression |
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96 | (1) |
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97 | (4) |
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99 | (2) |
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9 Microarray Gene Expression: The Effects of Varying Certain Measurement Conditions |
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101 | (12) |
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101 | (2) |
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9.2 Input Mass Effect on the Amount of Normalization Applied |
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103 | (1) |
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9.3 Probe-by-Probe Modeling of the Input Mass Effect |
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103 | (5) |
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9.4 Further Evidence of Batch Effects |
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108 | (2) |
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110 | (3) |
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10 Adjusting Batch Effects in Microarray Experiments with Small Sample Size Using Empirical Bayes Methods |
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113 | (18) |
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113 | (2) |
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10.1.1 Bayesian and Empirical Bayes Applications in Microarrays |
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114 | (1) |
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10.2 Existing Methods for Adjusting Batch Effect |
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115 | (2) |
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10.2.1 Microarray Data Normalization |
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115 | (1) |
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10.2.2 Batch Effect Adjustment Methods for Large Sample Size |
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115 | (1) |
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10.2.3 Model-Based Location and Scale Adjustments |
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116 | (1) |
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10.3 Empirical Bayes Method for Adjusting Batch Effect |
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117 | (4) |
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10.3.1 Parametric Shrinkage Adjustment |
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117 | (3) |
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10.3.2 Empirical Bayes Batch Effect Parameter Estimates using Nonparametric Empirical Priors |
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120 | (1) |
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10.4 Data Examples, Results and Robustness of the Empirical Bayes Method |
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121 | (7) |
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10.4.1 Microarray Data with Batch Effects |
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121 | (3) |
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10.4.2 Results for Data Set 1 |
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124 | (1) |
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10.4.3 Results for Data Set 2 |
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124 | (2) |
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10.4.4 Robustness of the Empirical Bayes Method |
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126 | (1) |
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10.4.5 Software Implementation |
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127 | (1) |
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128 | (3) |
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11 Identical Reference Samples and Empirical Bayes Method for Cross-Batch Gene Expression Analysis |
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131 | (10) |
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131 | (2) |
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133 | (2) |
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133 | (1) |
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11.2.2 Empirical Bayes Method for Batch Adjustment |
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134 | (1) |
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11.2.3 Naive t-test Batch Adjustment |
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135 | (1) |
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11.3 Application: Expression Profiling of Blood from Muscular Dystrophy Patients |
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135 | (3) |
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11.3.1 Removal of Cross-Experimental Batch Effects |
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135 | (1) |
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11.3.2 Removal of Within-Experimental Batch Effects |
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136 | (1) |
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11.3.3 Removal of Batch Effects: Empirical Bayes Method versus t-Test Filter |
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137 | (1) |
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11.4 Discussion and Conclusion |
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138 | (3) |
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11.4.1 Methods for Batch Adjustment Within and Across Experiments |
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138 | (1) |
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11.4.2 Bayesian Approach is Well Suited for Modeling Cross-Experimental Batch Effects |
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139 | (1) |
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11.4.3 Implications of Cross-Experimental Batch Corrections for Clinical Studies |
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139 | (2) |
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12 Principal Variance Components Analysis: Estimating Batch Effects in Microarray Gene Expression Data |
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141 | (14) |
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141 | (2) |
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143 | (3) |
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12.2.1 Principal Components Analysis |
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143 | (2) |
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12.2.2 Variance Components Analysis and Mixed Models |
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145 | (1) |
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12.2.3 Principal Variance Components Analysis |
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145 | (1) |
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146 | (2) |
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12.3.1 A Transcription Inhibition Study |
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146 | (1) |
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12.3.2 A Lung Cancer Toxicity Study |
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147 | (1) |
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12.3.3 A Hepato-toxicant Toxicity Study |
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147 | (1) |
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12.4 Application of the PVCA Procedure to the Three Example Data Sets |
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148 | (5) |
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12.4.1 PVCA Provides Detailed Estimates of Batch Effects |
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148 | (1) |
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12.4.2 Visualizing the Sources of Batch Effects |
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149 | (1) |
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12.4.3 Selecting the Principal Components in the Modeling |
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150 | (3) |
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153 | (2) |
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13 Batch Profile Estimation, Correction, and Scoring |
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155 | (12) |
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155 | (2) |
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13.2 Mouse Lung Tumorigenicity Data Set with Batch Effects |
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157 | (7) |
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13.2.1 Batch Profile Estimation |
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159 | (1) |
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13.2.2 Batch Profile Correction |
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160 | (1) |
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13.2.3 Batch Profile Scoring |
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161 | (1) |
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13.2.4 Cross-Validation Results |
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162 | (2) |
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164 | (3) |
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165 | (2) |
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14 Visualization of Cross-Platform Microarray Normalization |
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167 | (16) |
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167 | (2) |
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14.2 Analysis of the NCI 60 Data |
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169 | (5) |
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14.3 Improved Statistical Power |
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174 | (4) |
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14.4 Gene-by-Gene versus Multivariate Views |
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178 | (3) |
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181 | (2) |
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15 Toward Integration of Biological Noise: Aggregation Effect in Microarray Data Analysis |
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183 | (8) |
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183 | (2) |
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15.2 Aggregated Expression Intensities |
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185 | (1) |
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15.3 Covariance between Log-Expressions |
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186 | (3) |
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189 | (2) |
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190 | (1) |
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16 Potential Sources of Spurious Associations and Batch Effects in Genome-Wide Association Studies |
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191 | (12) |
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191 | (1) |
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16.2 Potential Sources of Spurious Associations |
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192 | (4) |
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16.2.1 Spurious Associations Related to Study Design |
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194 | (1) |
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16.2.2 Spurious Associations Caused in Genotyping Experiments |
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195 | (1) |
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16.2.3 Spurious Associations Caused by Genotype Calling Errors |
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195 | (1) |
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196 | (5) |
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16.3.1 Batch Effect in Genotyping Experiment |
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196 | (1) |
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16.3.2 Batch Effect in Genotype Calling |
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197 | (4) |
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201 | (2) |
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201 | (2) |
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17 Standard Operating Procedures in Clinical Gene Expression Biomarker Panel Development |
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203 | (12) |
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203 | (1) |
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17.2 Theoretical Framework |
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204 | (1) |
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17.3 Systems-Biological Concepts in Medicine |
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204 | (1) |
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17.4 General Conceptual Challenges |
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205 | (1) |
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17.5 Strategies for Gene Expression Biomarker Development |
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205 | (8) |
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17.5.1 Phase 1: Clinical Phenotype Consensus Definition |
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206 | (1) |
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17.5.2 Phase 2: Gene Discovery |
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207 | (2) |
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17.5.3 Phase 3: Internal Differential Gene List Confirmation |
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209 | (1) |
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17.5.4 Phase 4: Diagnostic Classifier Development |
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209 | (1) |
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17.5.5 Phase 5: External Clinical Validation |
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210 | (1) |
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17.5.6 Phase 6: Clinical Implementation |
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211 | (1) |
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17.5.7 Phase 7: Post-Clinical Implementation Studies |
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212 | (1) |
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213 | (2) |
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18 Data, Analysis, and Standardization |
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215 | (16) |
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215 | (1) |
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216 | (3) |
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18.3 Computational Standards: From Microarray to Omic Sciences |
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219 | (7) |
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18.3.1 The Microarray Gene Expression Data Society |
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219 | (1) |
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18.3.2 The Proteomics Standards Initiative |
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220 | (1) |
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18.3.3 The Metabolomics Standards Initiative |
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220 | (1) |
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18.3.4 The Genomic Standards Consortium |
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220 | (1) |
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18.3.5 Systems Biology Initiatives |
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221 | (1) |
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18.3.6 Data Standards in Biopharmaceutical and Clinical Research |
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221 | (1) |
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18.3.7 Standards Integration Initiatives |
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222 | (1) |
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223 | (1) |
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223 | (1) |
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223 | (3) |
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18.4 Experimental Standards: Developing Quality Metrics and a Consensus on Data Analysis Methods |
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226 | (2) |
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18.5 Conclusions and Future Perspective |
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228 | (3) |
References |
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231 | (14) |
Index |
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245 | |