Understanding patient heterogeneity is key to improving prognostic modeling in traumatic brain injury (TBI). Unsupervised clustering is widely used to explore patterns in patient characteristics that may define subgroups. However, it involves a multitude of decisions, including the choice of algorithm, the distance metric, and the method used to determine the "optimal" number of clusters. The aim of this study is to investigate how these choices influence the resulting clustering solution. We analyzed data from 4,509 patients enrolled in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study. K-medoids, agglomerative, and spectral clustering were applied in a complete 3 X 2 X 2 factorial design, in combination with Euclidean or Gower's distances, and silhouette score or gap statistic to choose the number of clusters. We investigated the agreement of clustering solutions with UpSet Plots and stability with the (adjusted) Rand index. Comparisons were made both across approaches using the original dataset and within approaches using bootstrap resampling. Clustering results varied substantially depending on the analysis choices. The number of suggested clusters varied widely, from one to twenty-five. Adjusted Rand indices confirmed low concordance between methods. Moreover, none of the clustering solutions demonstrated discriminatory performance comparable to a supervised logistic regression model in classifying patient recovery illustrating the limited usefulness of clustering for this purpose. The high instability in clustering results compromises interpretability and underscores that such solutions should not be blindly interpreted as underlying structure.

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