C-reactive protein-albumin-lymphocyte (CALLY) index and all-cause and cardiovascular mortality in the general population: a national health and nutrition examination survey analysis

BACKGROUND: The C-reactive protein-albumin-lymphocyte (CALLY) index is a composite biomarker integrating systemic inflammation (elevated C-reactive protein), nutritional status (decreased albumin), and immune function (reduced lymphocyte count). Its prognostic significance for mortality in the general population remains insufficiently characterized. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES, 1999-2010), comprising 11,797 adults (5,671 men [weighted 48.4%] and 6,126 women [weighted 51.6%]; median age, 45 years). The CALLY index was calculated for each participant. Associations between the CALLY index and all-cause and cardiovascular mortality were evaluated using Kaplan-Meier analysis (for descriptive visualization), weighted multivariable Cox proportional hazards regression, Fine-Gray competing risk models, and restricted cubic spline (RCS) regression. Predictive performance was assessed using time-dependent receiver operating characteristic (ROC) analysis. The incremental predictive value beyond established risk factors was quantified using the integrated discrimination improvement (IDI) and category-free net reclassification improvement (NRI). RESULTS: Compared with the lowest quartile, the highest CALLY quartile was associated with lower risks of all-cause mortality (multivariable-adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.74; P < 0.001) and cardiovascular mortality (HR, 0.51; 95% CI, 0.39-0.68; P < 0.001). In Fine-Gray competing risk models, the subdistribution hazard ratio for cardiovascular mortality was 0.55 (95% CI, 0.39-0.76; P < 0.001), with a lower cumulative incidence of cardiovascular death in quartile 4 versus quartile 1 (Gray's test, P < 0.001). RCS analyses revealed significant non-linear associations: an approximately L-shaped relationship for all-cause mortality and a monotonically decreasing non-linear pattern for cardiovascular mortality (both P for non-linearity < 0.001). The CALLY index provided modest incremental predictive value beyond established risk factors for all-cause mortality (IDI, 0.4%; P = 0.007), but individual-level risk reclassification was limited (continuous NRI, 2.7%; P = 0.272). Significant effect modification for all-cause mortality was observed only for alcohol use (P for interaction = 0.005). CONCLUSION: Higher CALLY index values were significantly associated with lower mortality risk. The CALLY index demonstrated a significant, independent, and non-linear inverse association with all-cause and cardiovascular mortality in US adults. Its standalone predictive discrimination was modest (time-dependent AUC < 0.70), but its integration into multivariable risk models provided modest yet statistically significant incremental prognostic information (IDI, 0.4%; P = 0.007). Individual-level risk reclassification was limited (continuous NRI, 2.7%; P = 0.272). These findings suggest that CALLY may serve as a complementary biomarker for risk stratification when integrated with conventional risk factors rather than as a standalone prediction tool.