Association between incidence of hypomagnesemia and better prognosis of NSCLC: A case on the immortal time bias
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PUBLIC SUMMARY
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Immortal time bias (ITB) was pervasive and detrimental in clinical follow-up studies.
Due to ITB risk, spurious negative associations between hypomagnesemia and cancer prognosis were reported.
Greater attention should be given to ITB in study design and analysis, with emphasis on time zero.
To address ITB, appropriate approaches should align with study population, research objective, and estimand.
The development and adoption of guidelines for controlling ITB are strongly advocated.
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ABSTRACT
Background Previous studies predominantly reported that the occurrence of hypomagnesemia was associated with improved cancer prognoses. However, utilizing publicly available data, we demonstrated the presence of bias in this association, attributable to the failure to account for immortal time bias (ITB) when grouping patients based on post-therapeutic characteristics/variates.Methods This research included 4,172 individuals from four clinical trials of Atezolizumab (NCT02366143, NCT02367794, NCT02367781, NCT02008227) in non-small cell lung cancer (NSCLC). Joint modelling, landmark, and clone-RMST (restricted mean survival time) methods were performed to remove ITB. Previous studies about hypomagnesemia and prognosis in cancers were pooled.Results Under the risk of ITB, spurious benefits in progression-free survival (PFS) and overall survival (OS) were observed in patients with at least one episode of hypomagnesemia, based on our research and previous studies. When controlling for ITB, the initially observed false beneficial effect disappeared, revealing a significant association between hypomagnesemia and worse OS [HR: 1.01 (1.00, 1.02), P=0.0330 ] in joint modelling. A similar trend was observed in PFS [HR: 1.01 (1.00, 1.02), P=0.0564 ]. Consistent results were obtained from landmark and clone-RMST analysis. The estimands and application scenarios of the three methods were compared and discussed.Conclusions Three methods were utilized and recommended to control ITB. Time zero definition should be emphasized to avoid ITB with advocacy of guidelines. In NSCLC, serum magnesium levels could serve as a potential prognostic biomarker in first-line therapy, but not in non-first-line therapy. -
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Zhou J., You D., Chen M., et al. (2025). Association between incidence of hypomagnesemia and better prognosis of NSCLC: A case on the immortal time bias. The Innovation Medicine 3:100124. https://doi.org/10.59717/j.xinn-med.2025.100124
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Zhou J., You D., Chen M., et al. (2025). Association between incidence of hypomagnesemia and better prognosis of NSCLC: A case on the immortal time bias. The Innovation Medicine 3:100124. https://doi.org/10.59717/j.xinn-med.2025.100124
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Figure 1.
Data profile and analysis steps
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Figure 2.
Under the risk of immortal time bias, Kaplan-Meier curves for overall survival (OS) among patients whether hypomagnesemia occurred in any laboratory test
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Figure 3.
Kaplan-Meier curves with 21-day landmark analysis for overall survival (OS) in patients with or without hypomagnesemia
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Figure 4.
Associations between hypomagnesemia, serum magnesium (mg), and change from baseline serum magnesium, and progression-free survival (PFS) and overall survival (OS) from pooled results using joint modelling of four clinical trials.
