Multiplex meta-analysis of RNA expression to identify genes with variants associated with immune dysfunction.
OBJECTIVE
We demonstrate a genome-wide method for the integration of many studies of gene expression of phenotypically similar disease processes, a method of multiplex meta-analysis. We use immune dysfunction as an example disease process.


METHODS
We use a heterogeneous collection of datasets across human and mice samples from a range of tissues and different forms of immunodeficiency. We developed a method integrating Tibshirani's modified t-test (SAM) is used to interrogate differential expression within a study and Fisher's method for omnibus meta-analysis to identify differentially expressed genes across studies. The ability of this overall gene expression profile to prioritize disease associated genes is evaluated by comparing against the results of a recent genome wide association study for common variable immunodeficiency (CVID).


RESULTS
Our approach is able to prioritize genes associated with immunodeficiency in general (area under the ROC curve = 0.713) and CVID in particular (area under the ROC curve = 0.643).


CONCLUSIONS
This approach may be used to investigate a larger range of failures of the immune system. Our method may be extended to other disease processes, using RNA levels to prioritize genes likely to contain disease associated DNA variants.
Biomedical Informatics Graduate Training Program and Division of Systems Medicine, Department of Pediatrics, Stanford University, Stanford, California 94305-5415, USA.
Alexander A
AA
Morgan
Vasilios J
VJ
Pyrgos
Kari C
KC
Nadeau
Peter R
PR
Williamson
Atul Janardhan
AJ
Butte
D000818:Animals; D019540:Area Under Curve; D019295:Computational Biology; D016208:Databases, Factual; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D051379:Mice; D012313:RNA / Q000378:metabolism*; D012372:ROC Curve
D012313:RNA