What can allow a few isolated cases of an infectious disease to blossom into an outbreak and further expand into a true pandemic? This is the driving question for the Center for Analysis and Prediction of Pandemic Expansion (APPEX). Biomedical and physical, ecological, socio-behavioral, economic, built and natural environmental, and information access factors are all likely to contribute to these perfect storm scenarios. In isolation, the contribution of each aspect may seem minor, or even overlooked, only leading to serious impacts when acting in synergy. This vastly complicates how to study, understand, and prepare to address pandemic risks. The APPEX Center is predicated on the idea that the greatest barriers to multidisciplinary insights in pandemic science exist when disciplinary researchers fail to appreciate, or even be aware of, the value of other fields in addressing complex research questions. The APPEX Center focuses on enabling multidisciplinary collaborations specifically focused on combinatorial risk scenarios that need simultaneous consideration by multiple domains and disciplines. In this way, APPEX provides for the development of a rigorous hierarchy of evidence for pandemic risk, leading to improved methodologies for scenario-to-scenario comparison, and creates and meets audacious challenges in multidisciplinary hypothesis generation, model/tool building, and information infrastructure. <br/><br/>The APPEX Center assembles a core team of researchers and practitioners spanning many areas of expertise to foster participation from the entire science community. Bringing together and materially supporting diverse teams of experts and decision makers in pandemic science, APPEX seeks to tackle questions about pandemic expansion that can only be answered at the interface among disciplines and domains. Operationally, APPEX research groups employ a previously piloted Guided Self-Organizing Teaming Process (GSOTP) in which targeted research questions are inspired by proposals from individuals, but tackled by a multidisciplinary team that coalesces around the idea and collaboratively refines it into a clear, compelling challenge, motivating the engagement of all team members and their domains. APPEX goes beyond existing research on disciplinarily targeted factors affecting pandemic risks and instead provides an enabling framework for synergy, complementing domain-driven research efforts. As such, APPEX ensures that the vision of pandemic science is proactive, focusing on framing how to meet complex challenges, improving both our ability to respond to existing disease threats and to be flexible, nimble, and adaptable to the next emerging pathogen we cannot yet anticipate to increase health security regionally, nationally, and globally.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.