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Cell type–specific gene expression differences in complex tissues

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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Figure 1: Overview of csSAM.
Figure 2: Statistical deconvolution of complex tissues yields accurate estimates of pure tissue-subset expression.
Figure 3: csSAM reveals cell type–specific differential expression undetectable at heterogeneous tissue level.

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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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Contributions

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.

Corresponding authors

Correspondence to Mark M Davis or Atul J Butte.

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Competing interests

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.

Supplementary information

Supplementary Text and Figures

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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