cross-study projections of genomic biomarkers an evaluation in cancer genomicscross-study预测基因的生物标志物评估癌症基因组学.pdfVIP

Cross-Study Projections of Genomic Biomarkers: An Evaluation in Cancer Genomics 1 2 1 1 3 Joseph E. Lucas *, Carlos M. Carvalho , Julia Ling-Yu Chen , Jen-Tsan Chi , Mike West 1 Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina, United States of America, 2 Graduate School of Business, The University of Chicago, Chicago, Illinois, United States of America, 3 Department of Statistical Science, Duke University, Durham, North Carolina, United States of America Abstract Human disease studies using DNA microarrays in both clinical/observational and experimental/controlled studies are having increasing impact on our understanding of the complexity of human diseases. A fundamental concept is the use of gene expression as a ‘‘common currency’’ that links the results of in vitro controlled experiments to in vivo observational human studies. Many studies – in cancer and other diseases – have shown promise in using in vitro cell manipulations to improve understanding of in vivo biology, but experiments often simply fail to reflect the enormous phenotypic variation seen in human diseases. We address this with a framework and methods to dissect, enhance and extend the in vivo utility of in vitro derived gene expression signatures. From an experimentally defined gene expression signature we use statistical factor analysis to generate multiple quantitative factors in human cancer gene expression data. These factors retain their relationship to the original, one-dimensional in vitro signature but better describe the diversity of in vivo biology. In a breast cancer analysis, we show that factors can reflect fundamentally different biological processes linked to molecular and cl