Seasonally Normalized Vitamin D Status and Long-Term Mortality and Multisystem Disease Risk in the UK Biobank
- 1Leumit Health Services
Abstract
BackgroundVitamin D deficiency has been associated with mortality and chronic disease. In a recent study of Israeli Leumit Health Services (LHS) and US TriNetX populations, severe deficiency was reproducibly associated with mortality and multisystem morbidity, while longitudinal supplementation reconstructed from pharmacy dispensing was associated with lower risk.
MethodsWe sought to reproduce these associations and address a wide range of potential confounders in the deeply phenotyped UK Biobank. Baseline circulating 25-hydroxyvitamin D [25(OH)D] was standardized to a common late-winter nadir using an eight-harmonic model, and participants were categorized according to nadir-equivalent 25(OH)D as <5, 5-10, 10-15, 15-20, or [≥]20 ng/mL. Primary survival analyses used one-year delayed entry and complete-case multivariable adjustment.
ResultsAnalyses included 412,020 participants and 31,197 deaths. Mortality hazard ratios were 2.03 (95% CI 1.90-2.18), 1.34 (1.29-1.39), 1.08 (1.04-1.11), respectively, for <5, 5-10 and 10-15, versus [≥]20 ng/mL. Associations previously observed in LHS and TriNetX were reproduced, notably for diabetes, myocardial infarction, cerebrovascular disease, dementia, diabetic retinopathy, and end-stage renal disease, whereas skin malignancies showed the opposite gradient, consistent with greater ultraviolet exposure. DAG-informed causal analyses using generalized overlap weighting achieved acceptable balance across measured covariates; weighted 10-year mortality was 9.7% with very severe deficiency versus 4.8% with [≥]20 ng/mL, supporting a causal interpretation. Estimates remained stable with landmark lags extending to 5 years after measurement.
ConclusionsSeasonally normalized 25(OH)D identifies a reproducible state of systemic vulnerability while reducing exposure misclassification caused by calendar timing of measurement. An interactive implementation of the normalization model is available: https://vitamind.medil.ai.
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BibTeX
@misc{israel2026seasonally,
title = {{Seasonally Normalized Vitamin D Status and Long-Term Mortality and Multisystem Disease Risk in the UK Biobank}},
author = {A. Israel and A. Weizman and S. Ashkenazi and E. Magen and E. Merzon and S. Vinker and N. Rappoport},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.26364983},
url = {https://www.medrxiv.org/content/10.64898/2026.10.07.26364983v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Seasonally Normalized Vitamin D Status and Long-Term Mortality and Multisystem Disease Risk in the UK Biobank
AU - A. Israel
AU - A. Weizman
AU - S. Ashkenazi
AU - E. Magen
AU - E. Merzon
AU - S. Vinker
AU - N. Rappoport
PY - 2026
DA - 2026/10/07
PB - medRxiv
DO - 10.64898/2026.10.07.26364983
UR - https://www.medrxiv.org/content/10.64898/2026.10.07.26364983v1
AB - BackgroundVitamin D deficiency has been associated with mortality and chronic disease. In a recent study of Israeli Leumit Health Services (LHS) and US TriNetX populations, severe deficiency was reproducibly associated with mortality and multisystem morbidity, while longitudinal supplementation reconstructed from pharmacy dispensing was associated with lower risk. MethodsWe sought to reproduce these associations and address a wide range of potential confounders in the deeply phenotyped UK Biobank. Baseline circulating 25-hydroxyvitamin D [25(OH)D] was standardized to a common late-winter nadir using an eight-harmonic model, and participants were categorized according to nadir-equivalent 25(OH)D as <5, 5-10, 10-15, 15-20, or [≥]20 ng/mL. Primary survival analyses used one-year delayed entry and complete-case multivariable adjustment. ResultsAnalyses included 412,020 participants and 31,197 deaths. Mortality hazard ratios were 2.03 (95% CI 1.90-2.18), 1.34 (1.29-1.39), 1.08 (1.04-1.11), respectively, for <5, 5-10 and 10-15, versus [≥]20 ng/mL. Associations previously observed in LHS and TriNetX were reproduced, notably for diabetes, myocardial infarction, cerebrovascular disease, dementia, diabetic retinopathy, and end-stage renal disease, whereas skin malignancies showed the opposite gradient, consistent with greater ultraviolet exposure. DAG-informed causal analyses using generalized overlap weighting achieved acceptable balance across measured covariates; weighted 10-year mortality was 9.7% with very severe deficiency versus 4.8% with [≥]20 ng/mL, supporting a causal interpretation. Estimates remained stable with landmark lags extending to 5 years after measurement. ConclusionsSeasonally normalized 25(OH)D identifies a reproducible state of systemic vulnerability while reducing exposure misclassification caused by calendar timing of measurement. An interactive implementation of the normalization model is available: https://vitamind.medil.ai.
ER -