IsoGeneGUI: a graphical user interface for analyzing dose-response - - PowerPoint PPT Presentation

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IsoGeneGUI: a graphical user interface for analyzing dose-response - - PowerPoint PPT Presentation

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Background Test for Monotone Trend Software IsoGeneGUI Package IsoGeneGUI: a graphical user interface for analyzing dose-response studies in microarray experiments Research team: Setia Pramana 1 , Dan Lin 1 , Ziv Shkedy 1 , Tobias Verbeke 2 ,

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SLIDE 1

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: a graphical user interface for analyzing dose-response studies in microarray experiments

Research team: Setia Pramana 1, Dan Lin 1, Ziv Shkedy 1, Tobias Verbeke 2, Philippe Haldermans 1,Willem Talloen 3.

  • 1. IBioStat, Universiteit Hasselt, Belgium
  • 2. OpenAnalytics, Belgium
  • 3. Johnson & Johnson Pharmaceutical R&D, Belgium

useR! 2010 Conference, 21 July 2010, Gaithersburg, Maryland, USA

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SLIDE 2

Background Test for Monotone Trend Software IsoGeneGUI Package

Overview

Background: Dose-response Studies Test for Monotone Trend The Software Analysis using IsoGeneGUI Package

Data exploration Likelihood Ratio Test E2 analysis Resampling-based analysis Significance Analysis of Microarrays (SAM) User defined graphical display

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SLIDE 3

Background Test for Monotone Trend Software IsoGeneGUI Package

Dose-response studies

The fundamental objective of drug development is to find a dose or a range of dose that efficacious and safe. Dose-response study investigates the dependence of the response on doses. Within a microarray setting the response of interest is gene expression.

dose gene expression 0.01 0.04 0.16 0.63 2.5 6 7 8 9 10

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SLIDE 4

Background Test for Monotone Trend Software IsoGeneGUI Package

Dose-response studies in Microarray Experiments

The aim is to identify a subset of genes with a monotone trend. In general, increasing the dose will result in a proportional increase in the response. Estimation: Isotonic regression with Pool-Adjacent-Violator-Algorithm (PAVA).

0.5 1.0 1.5 2.0 2.5 3.0 3.5 doses gene expression 1 2 3 4

PAVA

* * * * * *

+ + + +

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SLIDE 5

Background Test for Monotone Trend Software IsoGeneGUI Package

Testing for Monotonic Trend

Hypotheses: For gene i (i = 1, · · · , m) with K + 1 doses (j = 0, · · · , K) H0 : µ(d0) = µ(d1) = · · · = µ(dK) (No Dose Effect) HUp

1

: µ(d0) ≤ µ(d1) ≤ · · · ≤ µ(dK) (Ordered alternative) The likelihood ratio test (¯ E2

01).

The t-type tests: Williams, Marcus, M and M′ Lin et.al 2007

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SLIDE 6

Background Test for Monotone Trend Software IsoGeneGUI Package

Testing for Monotonic Trend: Inference

Inference Exact Distribution Resampling-based Inference Permutations

LRT (

2 01

E ) Williams Marcus Significance Analysis

  • f Microarrays (SAM)

LRT (

2 01

E ) Williams Marcus M Modified M LRT (

SAM 2 01

E ) WilliamsSAM MarcusSAM MSAM Modified M (

SAM

M ' ) Both approaches will be discussed in the next slides

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SLIDE 7

Background Test for Monotone Trend Software IsoGeneGUI Package

Resampling-based Inference: Permutations

Observed test statistics E2: ¯ E2

1, ¯

E2

2, . . . , ¯

E2

m

Resampling-based Inference, the permutation matrix T: T =      ¯ E2

11

¯ E2

11

. . . ¯ E2

1B

¯ E2

21

¯ E2

22

. . . ¯ E2

2B

. . . . . . ¯ E2

m1

¯ E2

m2

. . . ¯ E2

mB,

     B is the number of permutations. Raw p-values: Pi = #(b:¯

E2

ib≥E2 i )

B

.

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SLIDE 8

Background Test for Monotone Trend Software IsoGeneGUI Package

Significance Analysis of Microarrays (SAM, Tusher et al., 2001) for microarrays under order restriction A modified score is assigned to each gene. For the t-type test statistics (i.e., Williams, Marcus, the M, and the M′): Original:

M′ = ˆ

µ⋆

K−ˆ

µ⋆ ˆ s′

Modified:

M′SAM = ˆ

µ⋆

K−ˆ

µ⋆ ˆ s′+ˆ s0

ˆ s0 is the fudge factor added to protect against inflated statistic due to small standard errors.

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SLIDE 9

Background Test for Monotone Trend Software IsoGeneGUI Package

Software

Software for dose-response in microarrays analysis: R package: IsoGene, available in CRAN: http://cran.ii.uib.no/web/packages/IsoGene/ Pramana et.al 2010, The R Journal R GUI package: IsoGeneGUI, available in the Bioconductor project:

http://bioconductor.org/packages/2.7/bioc/html/IsoGeneGUI.html

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SLIDE 10

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: Main Window

Load Data Data Exploration Analysis:

¯ E2

01 exact distribution.

Resampling-based Inference Multiplicity adjustment (FWER and FDR) Significant Analysis of Microarrays (SAM)

Output & Graphical Displays

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SLIDE 11

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: Data Format

The package can read data in the following formats: R workspace (*.RData files) Excel file (*.xls files) text file (*.txt files)

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SLIDE 12

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: Data Exploration

Exploratory Data Analysis The Isotonic regression plots The summary statistic

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SLIDE 13

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: The ¯ E2

01 Analysis

Antipsychotic study. 6 dose levels 4-5 samples at each dose level. 11,565 genes. The dataset is available inside the package.

dose gene expression 0.01 0.04 0.16 0.63 2.5 6 7 8 9 10

The ¯ E2

01 test and BH-FDR (0.05)

are specified:

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SLIDE 14

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: ¯ E2

01 Result

¯ E2

01 with BH-FDR (0.05).

298 genes with significant monotone trend

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SLIDE 15

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: List of Significant Genes

List significant genes. The list be saved as an R object or/and an excel file

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SLIDE 16

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: Volcano Plot

¯ E2

01 vs. Fold change

The graph can be copied into clipboard and be saved into different image types.

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SLIDE 17

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: Resampling-based Inference

Required specification: number of permutations, test statistic and multiplicity adjustment. The permutation result can be saved and used later. List of significant genes using the selected statistic(s). Graphical displays.

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SLIDE 18

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: SAM (specification)

Required : Number of permutations and the fudge factor. SAM regularized test statistic, e.g.,: M′SAM = ˆ

µ⋆

K −ˆ

µ⋆ ˆ s′+ˆ s0

Delta (∆) is chosen with estimation of the FDR. SAM permutation dialog box

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SLIDE 19

Background Test for Monotone Trend Software IsoGeneGUI Package

IsoGeneGUI: SAM (Results)

Threshold/Delta: 0.68 FDR: 0.0436 Number of significant genes: 164 Delta table:

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SLIDE 20

Background Test for Monotone Trend Software IsoGeneGUI Package

User Defined Graphical Display

User can define their own figures:

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SLIDE 21

Background Test for Monotone Trend Software IsoGeneGUI Package

Help

Html help with screen shots

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SLIDE 22

Background Test for Monotone Trend Software IsoGeneGUI Package

More detail...

Book of Lin, D., Shkedy, Z., Yekutieli, D., Amaratunga, D., and Bijnens., L., editors. Modeling Dose-response Microarray Data in Early Drug Development Experiments Using R.

  • Springer. To be published in 2010.

IsoGene Project site: http://www.ibiostat.be/software/IsoGeneGUI/index.html

Thank you for your attention...