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Analysis of the relationship between longitudinal gene expressions and ordered categorical event data

by Natasa Rajicic, Dianne M. Finkelstein, David A. Schoenfeld and the Inflammation and Host Response to Injury Research Program Investigators

The NIH project ‘Inflammatory and Host Response to Injury’ (Glue) is being conducted to study the changes in the body over time in response to trauma and burn. Patients are monitored for changes in their clinical status, such as the onset of and recovery from organ failure. Blood samples are drawn over the first days and weeks after the injury to obtain gene expression levels over time. Our goal was to develop a method of selecting genes that differentially expressed in patients who either improved or experienced organ failure. For this, we needed a test for the association between longitudinal gene expressions and the time to the occurrence of ordered categorical outcomes indicating recovery, stable disease, and organ failure. We propose a test for which the relationship between the gene expression and the events is modeled using the cumulative proportional odds model that is a generalization of the pooling repeated observation method. Given the high-dimensionality of the microarray data, it was necessary to control for the multiplicity of the testing. To control for the false discovery rate (FDR), we applied both a permutational approach as well as Efron’s empirical estimation method. We explore our method through simulations and provide the analysis of the multi-center, longitudinal study of immune response to inflammation and trauma (http://www.gluegrant.org). This paper was publish in Statistics in Medicine, 2009; 28:2817–2832, Published online 17 July 2009 in Wiley InterScience, (www.interscience.wiley.com) DOI: 10.1002/sim.3665