Weighted analysis of general microarray experiments.
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In a resampling-based simulation study, the p-values generated by WAME are found to be substantially more correct than the alternatives when a relatively small proportion of the genes is regulated.WAME is available as an R-package.The WAME procedure is generalized and the limitation to paired-design microarray datasets is removed.
Affiliation: Mathematical Statistics, Chalmers University of Technology, 412 96 Göteborg, Sweden. anders.sjogren@math.chalmers.se
ABSTRACT
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Background: In DNA microarray experiments, measurements from different biological samples are often assumed to be independent and to have identical variance. For many datasets these assumptions have been shown to be invalid and typically lead to too optimistic p-values. A method called WAME has been proposed where a variance is estimated for each sample and a covariance is estimated for each pair of samples. The current version of WAME is, however, limited to experiments with paired design, e.g. two-channel microarrays. Results: The WAME procedure is extended to general microarray experiments, making it capable of handling both one- and two-channel datasets. Two public one-channel datasets are analysed and WAME detects both unequal variances and correlations. WAME is compared to other common methods: fold-change ranking, ordinary linear model with t-tests, LIMMA and weighted LIMMA. The p-value distributions are shown to differ greatly between the examined methods. In a resampling-based simulation study, the p-values generated by WAME are found to be substantially more correct than the alternatives when a relatively small proportion of the genes is regulated. WAME is also shown to have higher power than the other methods. WAME is available as an R-package. Conclusion: The WAME procedure is generalized and the limitation to paired-design microarray datasets is removed. The examined other methods produce invalid p-values in many cases, while WAME is shown to produce essentially valid p-values when a relatively small proportion of genes is regulated. WAME is also shown to have higher power than the examined alternative methods. |
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Mentions: The analysis methods described in Background are applied to the data and p-values and ranks computed. The respective probability plots are shown in Figure 3, demonstrating that there are substantial differences in the distribution of p-values between the different statistics. Since correlations and unequal variances are observed, the model assumptions of the alternative standard methods do not seem to hold. The p-values could thereby have become optimistic. On the other hand, it cannot be ruled out that the temporary assumption in WAME of no regulated genes makes its p-values conservative, which could also partly explain the differences. These problems are studied below by use of resampled data. |
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Affiliation: Mathematical Statistics, Chalmers University of Technology, 412 96 Göteborg, Sweden. anders.sjogren@math.chalmers.se
Background: In DNA microarray experiments, measurements from different biological samples are often assumed to be independent and to have identical variance. For many datasets these assumptions have been shown to be invalid and typically lead to too optimistic p-values. A method called WAME has been proposed where a variance is estimated for each sample and a covariance is estimated for each pair of samples. The current version of WAME is, however, limited to experiments with paired design, e.g. two-channel microarrays.
Results: The WAME procedure is extended to general microarray experiments, making it capable of handling both one- and two-channel datasets. Two public one-channel datasets are analysed and WAME detects both unequal variances and correlations. WAME is compared to other common methods: fold-change ranking, ordinary linear model with t-tests, LIMMA and weighted LIMMA. The p-value distributions are shown to differ greatly between the examined methods. In a resampling-based simulation study, the p-values generated by WAME are found to be substantially more correct than the alternatives when a relatively small proportion of the genes is regulated. WAME is also shown to have higher power than the other methods. WAME is available as an R-package.
Conclusion: The WAME procedure is generalized and the limitation to paired-design microarray datasets is removed. The examined other methods produce invalid p-values in many cases, while WAME is shown to produce essentially valid p-values when a relatively small proportion of genes is regulated. WAME is also shown to have higher power than the examined alternative methods.