Background: In an era of precision health, researchers must prioritize among research directions addressing different sources of uncertainty and variation. Research may reduce parameter uncertainty (e.g., improve average treatment effect estimates) or explore unexplained individual-level heterogeneity (e.g., identify new biomarkers). Existing frameworks evaluate these directions separately, limiting direct comparisons. We develop a unified framework for jointly estimating the value of resolving parameter uncertainty and unexplained heterogeneity. Methods: Our framework comprises six uncertainty states combining available parameter and unexplained heterogeneity information, extending the Value of Unexplained Heterogeneity framework. We define the value of a research direction as the difference in value between two states. We formalize counterfactual outcomes across interventions to estimate value and suggest ways to reduce computational burden. We illustrate the framework using a three-option microsimulation model. Results: The framework enables direct comparison of research value across sources of uncertainty and variation. In the illustrative example, exploring unexplained heterogeneity had the greatest value. Comparing the value of resolving unexplained heterogeneity across individual-level outcome components (e.g., health states, costs, and side effects) indicated little value in personalizing interventions based on whether patients entered the sicker state. Conclusion: Our framework enables direct, quantitative comparisons of the value of different research priorities and identifies the one with the greatest potential to improve population-level cost-effectiveness. It serves as a practical tool for performing research prioritization in the era of precision health.

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