We present the extention and application of a new unsupervised statistical
learning technique--the Partition Decoupling Method--to gene expression data.
Because it has the ability to reveal non-linear and non-convex geometries
present in the data, the PDM is an improvement over typical gene expression
analysis algorithms, permitting a multi-gene analysis that can reveal
phenotypic differences even when the individual genes do not exhibit
differential expression. Here, we apply the PDM to publicly-available gene
expression data sets, and demonstrate that we are able to identify cell types
and treatments with higher accuracy than is obtained through other approaches.
By applying it in a pathway-by-pathway fashion, we demonstrate how the PDM may
be used to find sets of mechanistically-related genes that discriminate
phenotypes.Comment: Revise

Braun, Rosemary

Leibon, Gregory

Pauls, Scott

Rockmore, Daniel

English

arXiv

Rosemary Braun

Gregory Leibon

Scott Pauls

Daniel Rockmore

Springer - Publisher Connector

Partition decoupling for multi-gene analysis of gene expression profiling data

Abstract Background Multi-gene interactions likely play an important role in the development of complex phenotypes, and relationships between interacting genes pose a challenging statistical problem in microarray analysis, since the genes involved in these interactions may not exhibit marginal differential expression. As a result, it is necessary to develop tools that can identify sets of interacting genes that discriminate phenotypes without requiring that the classification boundary between phenotypes be convex. Results We describe an extension and application of a new unsupervised statistical learning technique, known as the Partition Decoupling Method (PDM), to gene expression microarray data. This method may be used to classify samples based on multi-gene expression patterns and to identify pathways associated with phenotype, without relying upon the differential expression of individual genes. The PDM uses iterated spectral clustering and scrubbing steps, revealing at each iteration progressively finer structure in the geometry of the data. Because spectral clustering has the ability to discern clusters that are not linearly separable, it is able to articulate relationships between samples that would be missed by distance- and tree-based classifiers. After projecting the data onto the cluster centroids and computing the residuals ("scrubbing"), one can repeat the spectral clustering, revealing clusters that were not discernible in the first layer. These iterations, each of which provide a partition of the data that is decoupled from the others, are carried forward until the structure in the residuals is indistinguishable from noise, preventing over-fitting. We describe the PDM in detail and apply it to three publicly available cancer gene expression data sets. By applying the PDM on a pathway-by-pathway basis and identifying those pathways that permit unsupervised clustering of samples that match known sample characteristics, we show how the PDM may be used to find sets of mechanistically-related genes that may play a role in disease. An R package to carry out the PDM is available for download. Conclusions We show that the PDM is a useful tool for the analysis of gene expression data from complex diseases, where phenotypes are not linearly separable and multi-gene effects are likely to play a role. Our results demonstrate that the PDM is able to distinguish cell types and treatments with higher accuracy than is obtained through other approaches, and that the Pathway-PDM application is a valuable technique for identifying disease-associated pathways.</p

Braun Rosemary

Leibon Gregory

Pauls Scott

Rockmore Daniel

Directory of Open Access Journals

BMC Bioinformatics

Background:
Multi-gene interactions likely play an important role in the development of complex phenotypes, and relationships between interacting genes pose a challenging statistical problem in microarray analysis, since the genes involved in these interactions may not exhibit marginal differential expression. As a result, it is necessary to develop tools that can identify sets of interacting genes that discriminate phenotypes without requiring that the classification boundary between phenotypes be convex.    Results:
We describe an extension and application of a new unsupervised statistical learning technique, known as the Partition Decoupling Method (PDM), to gene expression microarray data. This method may be used to classify samples based on multi-gene expression patterns and to identify pathways associated with phenotype, without relying upon the differential expression of individual genes. The PDM uses iterated spectral clustering and scrubbing steps, revealing at each iteration progressively finer structure in the geometry of the data. Because spectral clustering has the ability to discern clusters that are not linearly separable, it is able to articulate relationships between samples that would be missed by distance- and tree-based classifiers. After projecting the data onto the cluster centroids and computing the residuals ( scrubbing ), one can repeat the spectral clustering, revealing clusters that were not discernible in the first layer. These iterations, each of which provide a partition of the data that is decoupled from the others, are carried forward until the structure in the residuals is indistinguishable from noise, preventing over-fitting. We describe the PDM in detail and apply it to three publicly available cancer gene expression data sets. By applying the PDM on a pathway-by-pathway basis and identifying those pathways that permit unsupervised clustering of samples that match known sample characteristics, we show how the PDM may be used to find sets of mechanistically-related genes that may play a role in disease. An R package to carry out the PDM is available for download.    Conclusions:
We show that the PDM is a useful tool for the analysis of gene expression data from complex diseases, where phenotypes are not linearly separable and multi-gene effects are likely to play a role. Our results demonstrate that the PDM is able to distinguish cell types and treatments with higher accuracy than is obtained through other approaches, and that the Pathway-PDM application is a valuable technique for identifying disease-associated pathways

Dartmouth Digital Commons (Dartmouth College)

Partition Decoupling for Multi-Gene Analysis of Gene Expression Profiling Data

file:///data/core-remote/dit/data/Springer-OA/pdf/fff/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMTQ3MS0yMTA1LTEyLTQ5Ny5wZGY=.pdf

Partition Decoupling for Multi-gene Analysis of Gene Expression
  Profiling Data

Partition Decoupling for Multi-gene Analysis of Gene Expression Profiling Data

Abstract

Similar works

Full text

Available Versions

Springer - Publisher Connector

Springer - Publisher Connector

Directory of Open Access Journals

Dartmouth Digital Commons (Dartmouth College)