Methodological Concerns Regarding the Association Between Creatinine/Cystatin C Ratio and ADL Disability Trajectories

Dear Editor,

1.

We read with interest Wu et al.'s report on the inverse association between CCR and ADL disability trajectories. While their 10‐year longitudinal CHARLS cohort design provides valuable population‐based observational data, we raise four critical methodological concerns that limit the reliability and clinical translation of their core conclusions [1].

First, renal function adjustment is insufficient. As both creatinine and cystatin C are GFR‐dependent markers, CCR concentration ratio is intrinsically susceptible to disturbances in glomerular filtration. Adjusting for CKD only as a crude binary variable fails to capture the continuous modifying effect of eGFR. An identical CCR value may reflect sufficient skeletal muscle reserve among participants with normal renal function, yet merely represent impaired creatinine excretion in individuals with renal insufficiency [2]. Without stratified analyses across eGFR subgroups or formal testing of the CCR × eGFR interaction term, the genuine independent association between CCR and progressive disability is inevitably confounded.

Second, the authors failed to provide essential laboratory precision parameters, including intra‐ and inter‐assay coefficients of variation for creatinine and cystatin C determinations. Considering the relatively weak protective effect sizes observed (ORs: 0.84–0.94), it is plausible that analytical imprecision could have introduced non‐differential misclassification, potentially biasing the results toward the null and underestimating the true effect. Moreover, systematic differences across various biochemical testing platforms limit the external validity and reproducibility of the tertile‐specific CCR thresholds proposed in this study [3]. We suggest that future investigations routinely report assay performance characteristics and, if feasible, conduct cross‐platform calibration to enhance the robustness and clinical applicability of their findings.

Third, the marital status subgroup suffers from severe sample size imbalance. Married participants accounted for 89.04% of the total analytical sample, with merely 11% falling into the non‐married category. The statistically significant modifying effect observed within married subgroups is likely driven by overwhelming statistical power rather than a true biological interaction. Marital status also acts as a proxy for unmeasured socioeconomic status, household care support and physical activity, which were not fully disentangled in adjusted models [4]. No weighted sensitivity analysis was performed to mitigate selection bias caused by uneven subgroup distribution.

Fourth, the authors' inference that CCR enables “early identification” of individuals at high disability risk is methodologically premature. Standard diagnostic performance metrics—sensitivity, specificity and ROC curve analysis—were entirely absent from all analyses, yet these parameters are mandatory to verify any biomarker's utility for population‐level screening [5]. No validated, clinically actionable CCR cutoff value was established to support risk stratification. As such, CCR can only be considered a correlative research index, not a robust, ready‐to‐use clinical screening tool.

In consideration of the methodological concerns raised in this letter, additional rigorous methodological work remains necessary before CCR can be recommended for routine geriatric screening. Future investigations should adopt eGFR‐stratified analytical frameworks, fully report laboratory measurement characteristics, and conduct formal diagnostic performance assessments to strengthen the translational potential of CCR in predicting long‐term functional disability.

Funding

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Ethics Statement

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Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.