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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: a graphical user interface foranalyzing 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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Background Test for Monotone Trend Software IsoGeneGUI Package
Overview
Background: Dose-response Studies
Test for Monotone Trend
The Software
Analysis using IsoGeneGUI PackageData exploration
Likelihood Ratio Test E2 analysis
Resampling-based analysis
Significance Analysis of Microarrays (SAM)
User defined graphical display
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Background Test for Monotone Trend Software IsoGeneGUI Package
Dose-response studies
The fundamental objective ofdrug development is to find adose or a range of dose thatefficacious and safe.
Dose-response studyinvestigates the dependence ofthe response on doses.
Within a microarray setting theresponse of interest is geneexpression.
dose
gene
exp
ress
ion
0 0.01 0.04 0.16 0.63 2.5
67
89
10
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Background Test for Monotone Trend Software IsoGeneGUI Package
Dose-response studies in Microarray Experiments
The aim is to identify a subset ofgenes with a monotone trend.
In general, increasing the dosewill result in a proportionalincrease in the response.
Estimation: Isotonic regressionwithPool-Adjacent-Violator-Algorithm(PAVA). 0.
51.
01.
52.
02.
53.
03.
5
doses
gene
exp
ress
ion
1 2 3 4
PAVA
*
*
*
*
* *+
+ +
+
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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)
HUp1 : µ(d0) ≤ µ(d1) ≤ · · · ≤ µ(dK ) (Ordered alternative)
The likelihood ratio test (E201).
The t-type tests: Williams, Marcus, M and M ′
Lin et.al 2007
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Background Test for Monotone Trend Software IsoGeneGUI Package
Testing for Monotonic Trend: Inference
Inference
Exact Distribution Resampling-based Inference
PermutationsLRT ( 2
01E )
Williams
Marcus
Significance Analysis
of Microarrays (SAM)
LRT ( 2
01E )
Williams
Marcus
M
Modified M
LRT ( SAM2
01E )
WilliamsSAM
MarcusSAM
MSAM
Modified M ( SAMM ' )
Both approaches will be discussed in the
next slides
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Background Test for Monotone Trend Software IsoGeneGUI Package
Resampling-based Inference: Permutations
Observed test statistics E2:
E21 , E2
2 , . . . , E2m
Resampling-based Inference, the permutation matrix T :
T =
E211 E2
11 . . . E21B
E221 E2
22 . . . E22B
......
E2m1 E2
m2 . . . E2mB,
B is the number of permutations.
Raw p-values: Pi =#(b:E2
ib≥E2i )
B .
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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 ′=
µ⋆
K−µ⋆
0s′
Modified:
M ′SAM=
µ⋆
K−µ⋆
0s′+s0
s0 is the fudge factor added to protect against inflatedstatistic due to small standard errors.
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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 theBioconductor project:http://bioconductor.org/packages/2.7/bioc/html/IsoGeneGUI.html
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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: Main Window
Load Data
Data ExplorationAnalysis:
E201 exact distribution.
Resampling-basedInferenceMultiplicity adjustment(FWER and FDR)Significant Analysis ofMicroarrays (SAM)
Output & GraphicalDisplays
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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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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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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: The E201 Analysis
Antipsychotic study.6 dose levels4-5 samples at each doselevel.11,565 genes.The dataset is availableinside the package.
dose
gene
exp
ress
ion
0 0.01 0.04 0.16 0.63 2.5
67
89
10
The E201 test and BH-FDR (0.05)
are specified:
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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: E201 Result
E201 with BH-FDR (0.05).
298 genes with significantmonotone trend
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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: List of Significant Genes
List significantgenes.
The list be saved asan R object or/andan excel file
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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: Volcano Plot
E201 vs. Fold change
The graph can be copiedinto clipboard and besaved into different imagetypes.
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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: Resampling-based Inference
Required specification:number of permutations,test statistic and multiplicityadjustment.
The permutation result canbe saved and used later.
List of significant genesusing the selectedstatistic(s).
Graphical displays.
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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: SAM (specification)
Required : Number ofpermutations and thefudge factor.
SAM regularized teststatistic, e.g.,:
M ′SAM =µ
⋆
K −µ⋆
0s′+s0
Delta (∆) is chosen withestimation of the FDR.
SAM permutation dialog box
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Background Test for Monotone Trend Software IsoGeneGUI Package
IsoGeneGUI: SAM (Results)
Threshold/Delta: 0.68FDR: 0.0436Number of significant genes: 164Delta table:
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Background Test for Monotone Trend Software IsoGeneGUI Package
User Defined Graphical Display
User can define their own figures:
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Background Test for Monotone Trend Software IsoGeneGUI Package
Help
Html help with screen shots
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Background Test for Monotone Trend Software IsoGeneGUI Package
More detail...
Book of Lin, D., Shkedy, Z., Yekutieli, D., Amaratunga, D., andBijnens., L., editors. Modeling Dose-response MicroarrayData 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...