Comparing the continuous representation of time-series expression profiles to identify differentially expressed genes

^*Laboratory for Computer Science and ^§Artificial Intelligence Laboratory, Massachusetts Institute of Technology, 200 Technology Square, Cambridge, MA 02139; ^¶Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142; and ^‡Hebrew University Medical School, Hadassah Ein Kerem, Jerusalem 91120, Israel

Edited by Michael S. Waterman, University of Southern California, Los Angeles, CA, and approved June 30, 2003 (received for review April 29, 2003)

Abstract

We present a general algorithm to detect genes differentially expressed between two nonhomogeneous time-series data sets. As increasing amounts of high-throughput biological data become available, a major challenge in genomic and computational biology is to develop methods for comparing data from different experimental sources. Time-series whole-genome expression data are a particularly valuable source of information because they can describe an unfolding biological process such as the cell cycle or immune response. However, comparisons of time-series expression data sets are hindered by biological and experimental inconsistencies such as differences in sampling rate, variations in the timing of biological processes, and the lack of repeats. Our algorithm overcomes these difficulties by using a continuous representation for time-series data and combining a noise model for individual samples with a global difference measure. We introduce a corresponding statistical method for computing the significance of this differential expression measure. We used our algorithm to compare cell-cycle-dependent gene expression in wild-type and knockout yeast strains. Our algorithm identified a set of 56 differentially expressed genes, and these results were validated by using independent protein-DNA-binding data. Unlike previous methods, our algorithm was also able to identify 22 non-cell-cycle-regulated genes as differentially expressed. This set of genes is significantly correlated in a set of independent expression experiments, suggesting additional roles for the transcription factors Fkh1 and Fkh2 in controlling cellular activity in yeast.