Objective: Chronic diseases often have long durations with slow, nonlinear progression and complex, and multifaceted manifestation. Modeling the progression of chronic diseases based on observational studies is challenging. We developed a framework to address these challenges by building probabilistic disease progression models to enable better understanding of chronic diseases and provide insights that could lead to better disease management. Materials and Methods: We developed a framework to build probabilistic disease progression models using observational medical data. The framework consists of two steps. The first step determines the number of disease states. The second step builds a probabilistic disease progression model with the determined number of states. The model discovers typical states along the trajectory of the target disease, learns the characteristics of these states, and transition probabilities between the states. We applied the framework to an integrated observational HD dataset curated from four recent observational HD studies. Results: The resulting HD progression model identified nine disease states. Compared to state-of-art HD staging system, the model 1) covers wider range of HD progression; 2) is able to quantitatively describe complex changes around the time of clinical diagnosis; 3) discovers multiple potential HD progression pathways; and 4) reveals expected time durations of the identified states. Discussion and Conclusion: The proposed framework addresses practical challenges in observational data and can help enhance the understanding of progression of chronic diseases. The framework could be applied to other chronic diseases with the help of clinical knowledge.