Nucleic Acids Research, 2003, Vol. 31, No. 16 e96
© 2003 Oxford University Press
A model-based analysis of microarray experimental error and normalisation
1 School of Biological Sciences, University of Manchester, Manchester M13 9PT, UK, 2 Department of Computer Science, University of Manchester, Manchester M13 9PL, UK and 3 Roslin Institute, Midlothian EH25 9PS, UK
*To whom correspondence should be addressed. Tel: +44 161 275 6187; Fax: +44 161 275 6204; Email: magnus{at}cs.man.ac.uk
A statistical model is proposed for the analysis of errors in microarray experiments and is employed in the analysis and development of a combined normalisation regime. Through analysis of the model and two-dye microarray data sets, this study found the following. The systematic error introduced by microarray experiments mainly involves spot intensity-dependent, feature-specific and spot position-dependent contributions. It is difficult to remove all these errors effectively without a suitable combined normalisation operation. Adaptive normalisation using a suitable regression technique is more effective in removing spot intensity-related dye bias than self-normalisation, while regional normalisation (block normalisation) is an effective way to correct spot position-dependent errors. However, dye-flip replicates are necessary to remove feature-specific errors, and also allow the analyst to identify the experimentally introduced dye bias contained in non-self-self data sets. In this case, the bias present in the data sets may include both experimentally introduced dye bias and the biological difference between two samples. Self-normalisation is capable of removing dye bias without identifying the nature of that bias. The performance of adaptive normalisation, on the other hand, depends on its ability to correctly identify the dye bias. If adaptive normalisation is combined with an effective dye bias identification method then there is no systematic difference between the outcomes of the two methods.
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