Introduction to Microarrays Contents of the Dissertation Dose-response Modelling Concluding Remarks and Future Research Classification, Dose-response Modelling, and the Evaluation of Biomarker in a Microarray Setting Dan Lin Promoter: Prof. dr. T. Burzykowski Co-promoter: Prof. dr. Z. Shkedy Diepenbeek March 28, 2008 Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Dose-response Modelling Concluding Remarks and Future Research Outline Introduction to microarrays 1 Contents of the dissertation 2 Focus: dose-response modelling + applications 3 Test for trend Classification of dose-response curve shapes Ratio test Conclusion & future research 4 Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Dose-response Modelling Concluding Remarks and Future Research 1. Introduction Dan Lin Analysis of Microarray Data
Introduction to Microarrays What are microarrays all about Contents of the Dissertation Microarray technology Dose-response Modelling Analysis of microarray data Concluding Remarks and Future Research Study of Functional Genomics Genome research Study of genetic sequences Tools of gene-expression analysis cDNA microarrays oligonucleotide microarrays SAGE Dan Lin Analysis of Microarray Data
Introduction to Microarrays What are microarrays all about Contents of the Dissertation Microarray technology Dose-response Modelling Analysis of microarray data Concluding Remarks and Future Research Central Dogma of Molecular Biology Dan Lin Analysis of Microarray Data
Introduction to Microarrays What are microarrays all about Contents of the Dissertation Microarray technology Dose-response Modelling Analysis of microarray data Concluding Remarks and Future Research Microarray Basics labeled mRNA sample mRNA quantitation apply to Chip process scan Dan Lin Analysis of Microarray Data
Introduction to Microarrays What are microarrays all about Contents of the Dissertation Microarray technology Dose-response Modelling Analysis of microarray data Concluding Remarks and Future Research Process of Microarray Data Analysis Dan Lin Analysis of Microarray Data
Introduction to Microarrays What are microarrays all about Contents of the Dissertation Microarray technology Dose-response Modelling Analysis of microarray data Concluding Remarks and Future Research 2. Contents of the Dissertation Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part I: Gene selection and class prediction Part II: Significance tests Part III: Dose-response modelling Part IV: Evaluation of biomarkers Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part I: Gene selection and class prediction Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part I: Gene selection and class prediction Control group Treatment group Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part II: Significance test Case study: human epidermal squamous carcinoma cell lines Table: Number of arrays in the case study. EGF (ng/ml) Setting 0 1 10 100 Control 3 3 3 3 Treatment A 3 3 3 3 Treatment B 3 3 3 3 Treatment C 3 3 3 3 16,998 genes on each array used for analysis Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part II: Significance test (inference and multiplicity) Multiplicity: comparisons of several treatments with one control Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part II: Significance test (inference and multiplicity) Multiplicity: comparisons of several treatments with one control Case Study EGF (ng/ml) Setting 0 1 10 100 Control 3 Treatment A 3 Treatment B 3 Treatment C 3 Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part II: Significance test (inference and multiplicity) Multiplicity: comparisons of several treatments with one control Inference: Dunnett t -test and resampling-based procedure Several methods used for adjusting for multiple testing Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part III: Dose-response modelling Dose-response relationship Minimum-effective-dose (MED) Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part III: Dose-response modelling Dose-response relationship Minimum-effective-dose (MED) Case Study 4 EGF (ng/ml) + * Setting 0 1 10 100 gene expression + 3 * Control 3 3 3 3 Treatment A Treatment B 2 + * Treatment C + 1 * 0 1 10 100 dose Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Contents of the Dissertation Part IV: Evaluation of biomarkers Biomarkers: X i Gene Expressions Treatment Z Clinical Outcome Y Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Too Few or Too Many Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Issues in Analyzing Microarray Data Multiplicity Testing thousands of genes simultaneously Control of the Type I error Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Issues in Analyzing Microarray Data Test Results Accept H 0 Reject H 0 Hypotheses Total H 0 True U V m 0 H 0 False T S m 1 W R m Total Control of the Type I error Family-Wise Error Rate: FWER = p( V > 0) False Discovery Rate: FDR = E( Q ) (Benjamini and Hochberg 1995) � V / R R > 0 Q = R = 0 0 Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Mixed Directional FDR For one-sided test statistics MD-FDR = E ( Q ′ ) (Yekutieli and Benjamini 2005) Q ′ = 0, for R = 0 Q ′ = V ′ / R , for R > 0, where V ′ is the sum of results that are false positives results that are true positives but declared with a wrong direction Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Adjusting for Multiplicity Control of the FWER Bonferroni procedure Holm’s procedure (1979) maxT (Westfall and Young 1993) Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Adjusting for Multiplicity Control of the FWER Bonferroni procedure Holm’s procedure (1979) maxT (Westfall and Young 1993) Control of the FDR Benjamini and Hochberg procedure (BH-FDR 1999) Benjamini and Yekutieli procedure (BY-FDR 2001) Significance analysis of microarrays (SAM 2001) Dan Lin Analysis of Microarray Data
Introduction to Microarrays Contents of the Dissertation Contents Dose-response Modelling Issues in Analysis of Microarray Data Concluding Remarks and Future Research Issues in Analyzing Microarray Data Multiplicity Testing thousands of genes simultaneously Control the Type I error Small sample size Distribution of test statistics can be unknown or asymptotics can not be assumed Resampling-based inference Dan Lin Analysis of Microarray Data
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