Abstract
We describe cell type–specific significance analysis of microarrays (csSAM) for analyzing differential gene expression for each cell type in a biological sample from microarray data and relative cell-type frequencies. First, we validated csSAM with predesigned mixtures and then applied it to whole-blood gene expression datasets from stable post-transplant kidney transplant recipients and those experiencing acute transplant rejection, which revealed hundreds of differentially expressed genes that were otherwise undetectable.
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Acknowledgements
We thank N. Hartmann, M. Letzkus and E.J. Oakeley for support with mixing experiments; A. Morgan, B. Narasimhan, R. Olshen, E. Eden, members of Stanford Molecular Profiling Colloquium and Biostats forum for enlightening discussions; O. Goldberger, M. Drukker, G. Nestorova, X. Ji and D. Hirschberg for generating mixture datasets; A. Skrenchuk and B. Oskotsky for computer support; and the Lucile Packard Foundation for Children's Health and the Hewlett Packard Foundation for support and computational resources. S.S.S.-O., M.M.D. and A.J.B. are supported by the US National Institutes of Health (NIH) (U19 AI057229). S.S.S.-O. was also supported by the Brennan family. R.T. is supported by the National Science Foundation (DMS-9971405) and NIH (contract N01-HV-28183). P.K. and M.M.S. are supported by NIH (U01 AI077821 and R21 AI075256). T.H. is supported by the National Science Foundation (DMS-0505676) and NIH (2R01 CA 72028-07).
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S.S.S.-O., R.T., D.L.B., F.S., M.M.D. and A.J.B. designed the experiments. S.S.S.-O., R.T., T.H. and P.K. developed the algorithms. M.M.S., F.S. and D.L.B. generated the data. S.S.S.-O., R.T., P.K., N.M.P. and D.L.B. analyzed the data. S.S.S.-O., R.T., P.K., M.M.D. and A.J.B. wrote the manuscript.
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D.L.B. and F.S. are employees of Novartis. M.M.D. is a paid consultant to Novartis. A.J.B. is or has served as a scientific advisor and/or consultant to NuMedii, Genstruct, Prevendia, Tercica, Eli Lilly and Company, and Johnson and Johnson.
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Supplementary Figures 1–8, Supplementary Tables 1–3, Supplementary Notes 1–2 (PDF 5148 kb)
Supplementary Data
Source code for csSAM (ZIP 1040 kb)
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Shen-Orr, S., Tibshirani, R., Khatri, P. et al. Cell type–specific gene expression differences in complex tissues. Nat Methods 7, 287–289 (2010). https://doi.org/10.1038/nmeth.1439
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DOI: https://doi.org/10.1038/nmeth.1439
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