System‐wide analysis of hepatotoxicological responses: Tissomics is key

Background: Combining diverse data streams across different levels of biological observation, such as molecular, cellular, and clinical chemistry responses, support a system‐wide diagnostic approach. Recent progress in slide‐based cytometry contributes to the development of tissomics, a high‐throughput and high‐content phenotyping methodology that provides data‐rich profiles of cellular heterogeneity in tissues enabling correlative statistical treatments over multiple scales of biological hierarchies. Methods: Phenotypical data are covariants that can be used as biomarkers to identify relevant candidate genes by associating initiating molecular events with phenotypical changes and adverse outcomes. We introduce a procedure of combined statistical and analytical tools to identify and visualize such associations for nonpooled entities. The new utility is applied to a time‐controlled, low‐dose toxicological study including a control and two xenobiotic compounds. Results: An integrated analysis identified specific molecular and phenotypical biomarkers, which support the classification of animals in the absence of any visual indicators from pathology readings. Discussion: The introduction of controlled perturbations to tissues provides a prototypical setting to develop a sensitive, systems‐based analysis methodology suitable for a broader range of biomedical applications. © 2006 International Society for Analytical Cytology