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Artifacts and Effects in Gene Expression Data

Artifacts and Effects in Gene Expression Data. Carlo Colantuoni. April 12, 2006. Experimental Artifacts. NIA cDNA microarray Core Facility. Nylon. P 33. 9600 MGC elements. ~200 microarrays ~100 samples. Uncorrected Intensities: MDS Colored by Batch. Much Like Red : Green Analysis.

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Artifacts and Effects in Gene Expression Data

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  1. Artifacts and Effects in Gene Expression Data Carlo Colantuoni April 12, 2006

  2. Experimental Artifacts

  3. NIA cDNA microarray Core Facility Nylon P33 9600 MGC elements ~200 microarrays ~100 samples

  4. Uncorrected Intensities: MDS Colored by Batch

  5. Much Like Red:Green Analysis Removing The Batch Effect We Will Use These Dimensions for Additional Corrective Transformations

  6. Uncorrected Intensities: MDS Colored by Batch

  7. Batch Subtracted Measures: MDS Colored by Batch

  8. MDS of All Array Experiments: Subject Replicates

  9. Hybridization Artifacts

  10. A “Simple” Pilot: 2 subjects in rep. = 4 arrays Differing amounts of dye 2-color (reference) ~48,000 probes

  11. 4 arrays: Raw Log Intensities

  12. 4 arrays: Raw Linear Intensities

  13. 1 array: Ratio v. Intensity

  14. 1 array: Ratio v. Intensity

  15. Biological Effects … or are they?

  16. Big Effects: Tissue Types and Growth Factor Treatments

  17. Illumina 24K

  18. Smaller Effects: Correlation of Gene Expression with Biological Indices

  19. pH

  20. PMI

  21. age

  22. Nylon P33 10K

  23. Illumina custom 700

  24. More Subtle Effects: Differential Gene Expression by Genotype

  25. VV VM MM COMT Val158Met SNP Affects Cognition and Risk for Schizophrenia Cognition & Disease Genetics • COMT enzyme activity • Risk for Schizophrenia • Working Memory Performance • Patterns of Cortical Activation • Amphetamine & Tolcapone Response

  26. Over-Expression of HSP70 in VV Homozygotes p<0.00002

  27. Effect of COMT V158M on Gene Expression Nylon P33 10K VV-VM

  28. Effect of COMT V158M on Gene Expression Nylon P33 10K MM-VM

  29. Effect of COMT V158M on Gene Expression Nylon P33 10K VV-MM

  30. MM-VM T-stat VV-VM T-stat

  31. Looking Across Multiple Effects: Age and Genotype

  32. N=15 genes across 80 subjects p<7.34e-13

  33. Alternative Approaches

  34. COMT Activity as a Function of COMT Genotype

  35. Correlation of COMT Activity with Expression N=64 Permuted Observed Correlation (r)

  36. r=0.45 p<0.000089

  37. Acknowledgements Clinical Brain Disorders Branch, NIMH, NIH Daniel Weinberger Section on Neuropathology Joel Kleinman Thomas Hyde Tissue Resources Mary Herman Amy Deep-Soboslay Colleen Lynch Genotyping Richard Straub Bhaskar Kolachana COMT Activity Jingshan Chen Samer Helem RNA Resources Johanna Creswell Claudia Aguirre Robert Fatula Jeet Bahra Isha Khan Debora Rothmond Barbara Lipska Nick Be Mariam Khan National Institute on Drug Abuse, NIH, DHHS William Freed Elin Lehrmann National Institute on Aging , NIH, DHHS Kevin Becker William Wood Diane Teichberg Johns Hopkins School of Public Health Department of Biostatistics Scott Zeger Zhianqan Tan Rafael Irizarry Giovanni Parmigiani Elizabeth Johnson NHGRI Microarray Facility Abdel Elkahloun Iddil Berkov CBDB

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