Limited incremental value of three complete-blood-count inflammatory indices for cardiovascular mortality: a development and external validation study in 30,533 US adults
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Routine blood tests can be used to calculate several inflammation-related ratios, including the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR). These indices are widely reported as markers of cardiovascular risk, but it is unclear whether they provide comparable information or whether SII, which is derived from platelet count and NLR, adds anything beyond NLR. We analyzed two independent samples from the National Health and Nutrition Examination Survey (NHANES): 15,141 adults from 2005-2010 (development cohort) and 15,392 adults from 2011-2016 (validation cohort), each with complete blood count data and linked mortality follow-up. Survey-weighted Cox models, restricted cubic splines, multiple imputation, and model comparison were used, and the development model was applied to the validation cohort. During a median follow-up of 11.4 years, 795 cardiovascular deaths occurred in the development cohort; the validation cohort recorded 364 cardiovascular deaths over 5.75 years. In the development cohort, hazard ratios per 1-SD increase were 1.32 (95% CI 1.21-1.44) for NLR, 1.21 (1.12-1.32) for SII, and 1.13 (1.04-1.22) for PLR. When NLR and SII were entered together, only NLR remained associated (HR 1.49, 1.23-1.81). The validation cohort showed the same pattern: NLR was strongest (HR 1.35, 1.22-1.49), and neither SII nor PLR remained significant after mutual adjustment. The frozen model showed good discrimination (C-index 0.8991 to 0.9023) and calibration (slope 0.96). Adding NLR produced only a small improvement in discrimination, and reclassification results were inconsistent between cohorts.
Author Summary
Blood tests are commonly used to estimate inflammation, and several ratios calculated from a complete blood count, such as the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR), have been proposed as markers of cardiovascular risk. Because SII is calculated from platelet count and NLR, it is important to know whether SII provides information beyond NLR. We studied this question in more than 30,000 US adults from two independent national surveys, with mortality follow-up through 2019. NLR was the strongest and most consistent marker in both samples. SII and PLR were associated with cardiovascular death when examined alone, but neither remained associated after NLR was taken into account. A model developed in the earlier survey also performed well in the later survey, with good discrimination and calibration. However, adding NLR to a model that already included established risk factors produced only a small improvement in prediction. These results suggest that SII should not be automatically preferred over NLR.
