L-Shaped Association of Serum Chloride Level With All-Cause and Cause-Specific Mortality in American Adults: Population-Based Prospective Cohort Study
Bibliographic record
Abstract
BACKGROUND: Chloride is the most abundant anion in the human extracellular fluid and plays a crucial role in maintaining homeostasis. Previous studies have demonstrated that hypochloremia can act as an independent risk factor for adverse outcomes in various clinical settings. However, the association of variances of serum chloride with long-term mortality risk in general populations has been rarely investigated. OBJECTIVE: This study aims to assess the association of serum chloride with all-cause and cause-specific mortality in the general American adult population. METHODS: Data were collected from 10 survey cycles (1999-2018) of the National Health and Nutrition Examination Survey. All-cause mortality, cardiovascular disease (CVD) mortality, cancer mortality, and respiratory disease mortality data were obtained by linkage to the National Death Index through December 31, 2019. After adjusting for demographic factors and relevant lifestyle, laboratory items, and comorbid factors, weighted Cox proportional risk models were constructed to estimate hazard ratios and 95% CIs for all-cause and cause-specific mortality. RESULTS: A total of 51,060 adult participants were included, and during a median follow-up of 111 months, 7582 deaths were documented, 2388 of CVD, 1639 of cancer, and 567 of respiratory disease. The weighted Kaplan-Meier survival analyses showed consistent highest mortality risk in individuals with the lowest quartiles of serum chloride. The multivariate-adjusted hazard ratios from lowest to highest quartiles of serum chloride (≤101.2, 101.3-103.2, 103.2-105.0, and ≥105.1 mmol/L) were 1.00 (95% CI reference), 0.77 (95% CI 0.67-0.89), 0.72 (95% CI 0.63-0.82), and 0.77 (95% CI 0.65-0.90), respectively, for all-cause mortality (P for linear trend<.001); 1.00 (95% CI reference), 0.63 (95% CI 0.51-0.79), 0.56 (95% CI 0.43-0.73), and 0.67 (95% CI 0.50-0.89) for CVD mortality (P for linear trend=.004); 1.00 (95% CI reference), 0.67 (95% CI 0.54-0.84), 0.65 (95% CI 0.50-0.85), and 0.65 (95% CI 0.48-0.87) for cancer mortality (P for linear trend=.004); and 1.00 (95% CI reference), 0.68 (95% CI 0.41-1.13), 0.59 (95% CI 0.40-0.88), and 0.51 (95% CI 0.31-0.84) for respiratory disease mortality (P for linear trend=.004). The restricted cubic spline analyses revealed the nonlinear and L-shaped associations of serum chloride with all-cause and cause-specific mortality (all P for nonlinearity<.05), in which lower serum chloride was prominently associated with higher mortality risk. The associations of serum chloride with mortality risk were robust, and no significant additional interaction effect was detected for all-cause mortality and CVD mortality (P for interaction>.05). CONCLUSIONS: In American adults, decreased serum chloride concentrations were independently associated with increased all-cause mortality, CVD mortality, cancer mortality, and respiratory disease mortality. Our findings suggested that serum chloride may serve as a promising cost-effective health indicator in the general adult population. Further studies are warranted to explore the potential pathophysiological mechanisms underlying the association between serum chloride and mortality.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".