Physiological imaging-defined subvolumes of tissues/disease are identified to yield spatially-defined prognostic and/or predictive indicators and/or focal therapy targets within such tissues, in particular tumors, for evaluation over time, for example, prior to and after a therapy treatment. Medical image data is analyzed to delineate subvolumes of tissue based upon multiple physiological, metabolic, and biological imaging properties, where those subvolumes are extracted and analyzed in a probabilistic manner to associate with one or more abnormal or disease phenotype conditions.