Analyses of longitudinal, hospital clinical laboratory data with application to blood glucose concentrations

Electronic medical record (EMR) systems afford researchers with opportunities to investigate a broad range of scientific questions. In contrast to purposeful study designs, however, EMR data acquisition procedures typically do not align with any specific hypothesis. Subsequent investigations therefore require detailed characterization of clinical procedures and protocols that underlie EMR data, as well as careful consideration of model choice. For example, many intensive care units currently implement insulin infusion protocols to better control patients' blood glucose levels. The protocols use prior glucose levels to determine, in part, how to adjust the infusion rate. Such feedback loops introduce time-dependent confounding into longitudinal analyses even though they may not always be evident to the analyst. In this paper, we review commonly used longitudinal model specifications and interpretations and show how these are particularly important in the presence of hospital-based clinical protocols. We show that parameter relationships among various models can be used to identify and characterize the impact of time-dependent confounding and therefore help explain seemingly incongruous conclusions. We also review important estimation challenges in the presence of time-dependent confounding and show how certain model specifications may be more or less susceptible to bias. To illustrate these points, we present a detailed analysis of the relationship between blood glucose levels and insulin doses on the basis of data from an intensive care unit.