Advancements in information technology have facilitated information exchange practices within the Military Health System (MHS), enabling "systems of systems" approaches that broaden and coordinate the set of capabilities available to enhance patient outcomes. This is applicable for MHS modeling and simulation (M&S) applications as well. Learning from successful approaches applied in current interoperability solutions used in the military helps to ensure interoperability practices yield trusted compositions of simulations. The use of formal methods provides the rigor necessary to unambiguously communicate these approaches across the MHS community. Here, 3 formal methods are proposed to ensure the harmonization of models and alignment of M&S data needed for simulation interoperability for MHS applications. To clarify considerations relevant for establishing simulation interoperability, the proposed formal methods are examined within a notional example of an injury sustained because of blast exposure. The first method applies the principles of semiotics, addressing the coding of information via syntax and semantics, to understand how to align and transform data across simulations within a composition. The second method applies the concepts of well-specified co-simulations, and the use of different techniques, tools, and algorithms to address the composition and synchronization of M&S components. The third method applies the mathematical branch of model theory to codify expert knowledge about concepts, assumptions, and constraints to ensure conceptual alignment within the simulation composition. Biomedical research must contend with complexity inherent to computational human body modeling, enlisting expert knowledge from multiple domains supporting the development of cross-disciplinary research tools that resolve research foci and associated differences in underlying theories, methods, and applied tools. This is closely related to the broader context of digital engineering for military systems engineering.
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