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Research Article
Here, we evaluated the associations of the red blood cell distribution width-to-albumin ratio with migraine prevalence and all-cause mortality among individuals with migraine using data from NHANES 1999–2004. We found that higher RAR levels were significantly associated with an increased likelihood of migraine and higher risk of all-cause mortality among migraine participants.
Migraine is a common primary neurovascular disorder associated with substantial morbidity and systemic inflammatory alterations. The red blood cell distribution width-to-albumin ratio (RDW-to-albumin ratio, RAR) is an emerging marker of systemic inflammation and nutritional status; however, standardized approaches for evaluating its association with migraine outcomes in large population datasets are limited. Using data from the National Health and Nutrition Examination Survey (NHANES) 1999–2004, this study evaluated the relationship between RAR and migraine prevalence, as well as all-cause mortality among individuals with migraine. A total of 8,781 participants were included in the cross-sectional analysis, and 1,762 participants with migraine were followed for mortality outcomes. Multivariable logistic and Cox regression models were used to assess the associations. After adjusting for potential confounders, higher RAR levels were significantly associated with an increased likelihood of migraine. Among participants with migraine, elevated RAR was also independently associated with higher all-cause mortality. These findings suggest that RAR may serve as a simple and accessible biomarker for identifying individuals at higher risk of migraine and adverse outcomes, highlighting its potential value in risk stratification and clinical management.
Migraine is a prevalent primary neurovascular disorder typically characterized by unilateral pulsatile headache with associated symptoms, such as nausea, vomiting, photophobia, and phonophobia1. Globally, it ranks among the leading causes of disability and disease burden, adversely affecting the quality of life and socioeconomic productivity2. Migraine attacks are recurrent and triggered by multiple factors, and they increase the risk of comorbidities, including cardiovascular disease, anxiety, and depression3,4. Over time, repeated attacks may induce structural or functional changes in the central nervous system, highlighting the clinical importance of early identification and risk stratification. Emerging evidence suggests that systemic inflammation plays a key role in migraine pathophysiology, linking neurovascular dysfunction to disease initiation and progression5.
Red blood cell distribution width (RDW), a routine hematologic parameter, reflects the variability in erythrocyte size and has been linked to systemic inflammation, oxidative stress, and adverse outcomes in various diseases6,7,8. Serum albumin, the most abundant plasma protein, plays an essential role in maintaining colloid osmotic pressure, exerting anti-inflammatory and antioxidant effects, and modulating platelet aggregation9,10. Albumin levels are influenced by both nutritional status and inflammatory activity, making it a widely used marker of systemic health and prognosis11.
Recently, composite inflammatory-nutritional biomarkers have gained significant clinical attention. Among them, the red blood cell distribution width-to-albumin ratio (RAR) has emerged as a novel index that integrates systemic inflammation and nutritional status12. While previous studies have extensively investigated RDW or albumin individually, RDW primarily reflects inflammatory burden, whereas hypoalbuminemia typically indicates heightened inflammation or malnutrition8,9. By integrating these two dimensions, RAR provides a more stable and comprehensive assessment of systemic health, offering potential advantages over RDW or albumin alone. Indeed, recent evidence demonstrates that composite indices like RAR and the hemoglobin-to-red blood cell distribution width ratio (HRR) have substantial clinical relevance in inflammatory cardiac conditions, such as pericarditis and myocarditis, highlighting their robust biological plausibility as prognostic inflammatory markers13,14. Furthermore, an expanding body of literature indicates that elevated RAR is associated with the prevalence of various systemic diseases, such as cardiovascular disorders, renal diseases, gastrointestinal perforation, and depression14,15,16,17. RAR has also been shown to serve as a reliable predictor of poor prognosis across diverse clinical settings, including its association with increased mortality risk in populations with pre-hypertension and hypertension18. These findings highlight the potential of RAR as a versatile biomarker, not only in the context of systemic diseases but also in predicting adverse clinical outcomes, thereby justifying its examination in relation to migraine. Given the shared pathophysiological mechanisms of systemic inflammation between these conditions and migraine, we hypothesized that RAR might serve as a valuable and comprehensive biomarker for evaluating migraine prevalence and its associated all-cause mortality.
Using data from the National Health and Nutrition Examination Survey (NHANES), this study systematically examined the association of RAR with migraine prevalence in a large, nationally representative cohort. We further evaluated the relationship between RAR and all-cause mortality among individuals with migraine, explored potential non-linear dose-response patterns, and assessed the predictive value of RAR for long-term outcomes. We hypothesized that elevated RAR levels are significantly associated with both an increased prevalence of migraine and higher all-cause mortality. Ultimately, this study aims to determine whether RAR can serve as a simple, accessible biomarker to assist clinicians in risk stratification, guiding early intervention strategies, and improving prognostic assessment in routine migraine care.
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The NHANES data-collection protocols were approved by the National Center for Health Statistics (NCHS) Research Ethics Review Board (ERB). As the NHANES datasets are publicly available, researchers do not need additional approval from their own institutional review boards (IRBs).
Study population and eligibility criteria
The NHANES employs a multistage, stratified probability sampling design and collects comprehensive health and nutritional information through household interviews, standardized physical examinations, and laboratory assessments at Mobile Examination Centers (MEC). Publicly available data from the 1999 to 2004 survey-cycles was analyzed. As the data were fully anonymized and publicly accessible, this retrospective study did not require additional ethical approval. The study consisted of two components: (1) a cross-sectional analysis examining the association between the RAR and migraine occurrence, and (2) a prospective cohort analysis evaluating the relationship between RAR levels and all-cause mortality among individuals with migraine to assess its prognostic value. Figure 1 illustrates the overall study design and participant selection workflow, as required by JoVE guidelines. Briefly, a total of 15,332 participants aged ≥ 20 years were initially considered. After applying exclusion criteria and accounting for missing data, 8,781 participants were included in the cross-sectional analysis. Missing data were handled using a complete-case analysis, where participants with missing values for key variables (RAR, migraine status, or covariates) were excluded to ensure reproducibility. For the cohort analysis, participants identified as having migraine (n = 1,762) were followed longitudinally to investigate the association between RAR and mortality risk.
Measurement and categorization of RAR
RDW in NHANES was measured as part of standard laboratory complete blood count procedures conducted by trained personnel. All laboratory values, including RDW and albumin, were obtained from a single baseline measurement for each participant. Serum albumin levels were determined using the bromocresol purple (BCP) method under standardized pH conditions. The RAR was calculated as RDW (%) divided by serum albumin (g·dL-1) and has been widely applied in previous studies as a composite marker of inflammation and nutritional status19. For the cross-sectional analysis, participants were categorized into quartiles (Q1–Q4) based on the distribution of RAR in the overall study population: Q1 (≤ 2.73), Q2 (> 2.73–2.93), Q3 (> 2.93–3.18), and Q4 (> 3.18). In the cohort analysis, which included only participants with migraine, the RAR distribution differed; quartiles were recalculated within this subgroup: Q1 (≤ 2.74), Q2 (> 2.74–2.95), Q3 (> 2.95–3.23), and Q4 (> 3.23).
Migraine assessment
Migraine (or severe headache) in NHANES was assessed via questionnaire: participants were asked, “During the past 3 months, did you have severe headaches or migraines?” Previous studies, including the Migraine Prevalence and Prevention study and multiple NHANES-based national surveys, have demonstrated good concordance between self-reported severe headache and clinically diagnosed migraine20,21,22. Therefore, questionnaire-based identification provides a reasonable and comparable approach to identifying individuals with potential migraine in population studies.
Mortality assessment
Follow-up began on the MEC examination date and continued until death or December 31, 2019. Mortality outcomes were classified according to ICD-10 codes to assess all-cause mortality.
Covariate assessment
Potential confounders were selected based on the previous literature and their clinical relevance23,24,25. Demographic variables included age, sex, race/ethnicity (Mexican American, non-Hispanic White, non-Hispanic Black, other), education (< high school, high school, > high school), marital status (married/living with a partner vs. not married), and family income-to-poverty ratio (PIR: < 1, 1–3, > 3). Lifestyle factors included smoking status (current, former, and never) and alcohol consumption (ever vs. never). Physical status was represented by BMI (< 25, 25–30, and > 30), and medical conditions included self-reported diabetes and hypertension.
Statistical analysis
All analyses accounted for the complex survey design of NHANES by incorporating MEC weights, primary sampling units (clusters), and strata, ensuring nationally representative and reproducible estimates. Continuous variables were expressed as weighted medians with interquartile ranges (IQR) and compared using the Kruskal–Wallis test, whereas categorical variables were presented as weighted percentages and compared using the Rao–Scott chi-square test. Weighted logistic regression models were used in the cross-sectional analysis to evaluate the associations between RAR and migraine, with results presented as odds ratios (ORs) and 95% confidence intervals (CIs). In the cohort analysis, Cox proportional hazards models were applied to assess the association between RAR quartiles and all-cause mortality, with results reported as hazard ratios (HRs) and 95% CIs. Three hierarchical models were constructed: Model 0 was unadjusted; Model 1 was adjusted for demographic factors; Model 2 was further adjusted for lifestyle and physical factors (smoking, alcohol, BMI); and Model 3 was additionally adjusted for medical conditions (hypertension and diabetes). Restricted cubic spline (RCS) regression, utilizing 3 knots placed at the 10th, 50th, and 90th percentiles of the RAR distribution, was applied to explore potential non-linear relationships between RAR and migraine or mortality. Kaplan–Meier survival curves were generated to compare survival across RAR quartiles, and time-dependent receiver operating characteristic (ROC) curves were used to assess the predictive performance of RAR for mortality outcomes. Subgroup analyses were performed using interaction terms, with a two-sided P < 0.05 considered statistically significant. All analyses were conducted using R software (version 4.2.2).
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Cross-sectional study: Baseline characteristics
A total of 8,781 participants were included in the cross-sectional analysis, comprising 7,019 individuals without migraine and 1,762 individuals with migraine. Participants were categorized into quartiles based on their RAR levels. The median age of the overall population was 44 years (IQR: 33–56 years), and age increased progressively across the RAR quartiles from Q1 to Q4. Significant differences in sex, race/ethnicity, education level, marital status...
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This nationally representative study based in the U.S. NHANES dataset systematically evaluated the associations of the RAR with the risk of migraine and all-cause mortality. Our findings demonstrated that higher RAR levels were significantly associated with increased migraine risk, even after adjusting for demographic characteristics, lifestyle factors, and clinical comorbidities. Moreover, RAR independently predicted all-cause mortality among patients with migraine, with elevated RAR levels conferring a markedly higher ...
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The authors declare that they have no conflicts of interest.
We sincerely thank all authors for their contributions to the study, including conceptualization, data collection, analysis, interpretation, and manuscript preparation.
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| Name | Company | Catalog Number | Comments |
|---|---|---|---|
| R software, version 4.2.2 | R Foundation for Statistical Computing | Not applicable | Statistical analysis and visualization |
| Coulter automated hematology analyzer | Beckman Coulter | Not applicable | Used for complete blood count (CBC) and other hematology analyses. |
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