Objective:

Respond to concerns that candidemia phenotypes identified by unsupervised clustering were tautological or driven by inclusion of SAPS II, and report a sensitivity analysis excluding that score.

Approach:

• Sensitivity analysis: Repeated the complete clustering procedure after removing SAPS II from the baseline feature set.
• Contextualization: Discussed the use of composite severity scores in other critical-care clustering studies and proposed directions for future research.

Key Findings:

• Phenotype 1, characterized by hematological malignancy, neutropenia, high fever, and low leukocyte counts, remained identifiable without SAPS II; mortality was 70.1%, compared with 72.9% in the original model.
• Without SAPS II, separation between Phenotypes 2 and 3 was less distinct, with patients redistributed between groups.
• Microbiological associations persisted in the sensitivity analysis, including C. glabrata enrichment in the cirrhotic/digestive cluster (31.5% versus 24.2% in the original analysis).
• In the original analysis, Phenotypes 1 and 2 had comparably high mortality despite distinct underlying characteristics associated with immunosuppression and cirrhosis.

Interpretation:

The authors argue that the sensitivity analysis supports patient heterogeneity not attributable solely to SAPS II. They consider severity scores appropriate when the aim is to characterize the complete clinical syndrome, while agreeing that future studies should also investigate clustering without composite severity scores.

Limitations:

• The study is retrospective.
• The phenotypes lack external validation.
• The sensitivity analysis was post hoc.

Conclusion:

The authors propose a two-layer approach for future work: first define biology- and microbiology-based groups without composite severity scores, then stratify by severity. They also suggest incorporating transcriptomic, proteomic, or metabolomic biomarkers.