Phase-independent rhythmic analysis of genome-wide expression patterns

We introduce a model-based analysis technique for extracting and characterizing rhythmic expression pro � les from genome-wide DNA microarray hybridization data. These patterns are clues to discovering rhythmic genes implicated in cell-cycle, circadian, or other biological processes. The algorithm, implemented in a program called RAGE (Rhythmic Analysis of Gene Expression), decouples the problems of estimating a pattern’s wavelength and phase. Our algorithm is linear-time in frequency and phase resolution, an improvement over previous quadratic-time approaches. Unlike previous approaches, RAGE uses a true distance metric for measuring expression pro � le similarity, based on the Hausdorff distance. This results in better clustering of expression pro � les for rhythmic analysis. The con � dence of each frequency estimate is computed using Z-scores. We demonstrate that RAGE is superior to other techniques on synthetic and actual DNA microarray hybridization data. We also show how to replace the discretized phase search in our method with an exact (combinatorially precise) phase search, resulting in a faster algorithm with no complexity dependence on phase resolution. Key words: functional genomics, DNA microarray analysis, mRNA expression time-series, rhythmic genes, circadian genes, Hausdorff distance, autocorrelation, cell-cycle, expression pro � le similarity, computational genomics