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Physiol. Genomics 4: 109-126, 2000;
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Received 20 December 1999; accepted in final form 4 September 2000.
Physiological Genomics 4:109-126 (2000)
1094-8341/00 $5.00 © 2000 American Physiological Society

Analysis of molecular profile data using generative and discriminative methods

E. J. Moler ,*, M. L. Chow ,* and I. S. Mian

Department of Cell and Molecular Biology, Radiation Biology and Environmental Toxicology Group, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

A modular framework is proposed for modeling and understanding the relationships between molecular profile data and other domain knowledge using a combination of generative (here, graphical models) and discriminative [Support Vector Machines (SVMs)] methods. As illustration, naive Bayes models, simple graphical models, and SVMs were applied to published transcription profile data for 1,988 genes in 62 colon adenocarcinoma tissue specimens labeled as tumor or nontumor. These unsupervised and supervised learning methods identified three classes or subtypes of specimens, assigned tumor or nontumor labels to new specimens and detected six potentially mislabeled specimens. The probability parameters of the three classes were utilized to develop a novel gene relevance, ranking, and selection method. SVMs trained to discriminate nontumor from tumor specimens using only the 50–200 top-ranked genes had the same or better generalization performance than the full repertoire of 1,988 genes. Approximately 90 marker genes were pinpointed for use in understanding the basic biology of colon adenocarcinoma, defining targets for therapeutic intervention and developing diagnostic tools. These potential markers highlight the importance of tissue biology in the etiology of cancer. Comparative analysis of molecular profile data is proposed as a mechanism for predicting the physiological function of genes in instances when comparative sequence analysis proves uninformative, such as with human and yeast translationally controlled tumour protein. Graphical models and SVMs hold promise as the foundations for developing decision support systems for diagnosis, prognosis, and monitoring as well as inferring biological networks.

microarrays; biological networks; graphical models; support vector machines; decision support systems; comparative molecular profile data analysis




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