We propose a comprehensive information processing, knowledge discovery and simulation platform for Big Data Healthcare. In addition, we present a related, well-defined workflow that promotes model-guided personalized medicine. We start by identifying disease signatures and homogeneous patient groups, whilst modeling case-based patient similarity. Then we analyze correlations between variables and patient groups to deliver accurate and reusable predictive statistical simulation models. Such a framework provides significant advantages on both the clinician's daily routine and targeted biomedical research.