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Statistical Applications in Genetics and Molecular Biology

Editor-in-Chief: Stumpf, Michael P.H.

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Evaluation of Multiple Models to Distinguish Closely Related Forms of Disease Using DNA Microarray Data: an Application to Multiple Myeloma

Johanna Hardin1 / Michael Waddell2 / C. David Page3 / Fenghuang Zhan4 / Bart Barlogie5 / John Shaughnessy6 / John J Crowley7

1Pomona College

2University of Wisconsin, Madison

3University of Wisconsin

4University of Arkansas for Medical Sciences, Little Rock

5University of Arkansas

6University of Arkansas for Medical Sciences

7Cancer Research And Biostatistics

Citation Information: Statistical Applications in Genetics and Molecular Biology. Volume 3, Issue 1, Pages 1–21, ISSN (Online) 1544-6115, DOI: 10.2202/1544-6115.1018, June 2004

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Motivation: Standard laboratory classification of the plasma cell dyscrasia monoclonal gammopathy of undetermined significance (MGUS) and the overt plasma cell neoplasm multiple myeloma (MM) is quite accurate, yet, for the most part, biologically uninformative. Most, if not all, cancers are caused by inherited or acquired genetic mutations that manifest themselves in altered gene expression patterns in the clonally related cancer cells. Microarray technology allows for qualitative and quantitative measurements of the expression levels of thousands of genes simultaneously, and it has now been used both to classify cancers that are morphologically indistinguishable and to predict response to therapy. It is anticipated that this information can also be used to develop molecular diagnostic models and to provide insight into mechanisms of disease progression, e.g., transition from healthy to benign hyperplasia or conversion of a benign hyperplasia to overt malignancy. However, standard data analysis techniques are not trivial to employ on these large data sets. Methodology designed to handle large data sets (or modified to do so) is needed to access the vital information contained in the genetic samples, which in turn can be used to develop more robust and accurate methods of clinical diagnostics and prognostics.

Results: Here we report on the application of a panel of statistical and data mining methodologies to classify groups of samples based on expression of 12,000 genes derived from a high density oligonucleotide microarray analysis of highly purified plasma cells from newly diagnosed MM, MGUS, and normal healthy donors. The three groups of samples are each tested against each other. The methods are found to be similar in their ability to predict group membership; all do quite well at predicting MM vs. normal and MGUS vs. normal. However, no method appears to be able to distinguish explicitly the genetic mechanisms between MM and MGUS. We believe this might be due to the lack of genetic differences between these two conditions, and may not be due to the failure of the models. We report the prediction errors for each of the models and each of the methods. Additionally, we report ROC curves for the results on group prediction.

Availability: Logistic regression: standard software, available, for example in SAS. Decision trees and boosted trees: C5.0 from www.rulequest.com. SVM: SVM-light is publicly available from svmlight.joachims.org. Naïve Bayes and ensemble of voters are publicly available from www.biostat.wisc.edu/~mwaddell/eov.html. Nearest Shrunken Centroids is publicly available from http://www-stat.stanford.edu/~tibs/PAM.

Keywords: Microarray; Logistic Regression; Boosted Decision Trees; Ensemble of Voters; Support Vector Machines; Nearest Shrunken Centroid; Multiple Myeloma; MGUS

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