Causal Inference in Non-Allergic Asthma Associated with Obesity: Application of the Bradford Hill Viewpoints to a Complex Epidemiological Association
Abstract
The association between obesity and a distinct, non-allergic, late-onset, neutrophilic asthma phenotype has been recognised for over two decades. However, establishing obesity as a causal factor rather than a comorbidity remains methodologically chal-lenging. Randomised allocation to obesity is neither feasible nor ethical. The relationship is mediated by a complex network of mechanical, immunometabolic, microbial, hor-monal, and epigenetic mechanisms. This review applies Sir Austin Bradford Hill’s nine viewpoints (1965) as a structured framework for causal inference to the 2020–2026 evi-dence linking obesity to non-T2 asthma. Evidence for strength (effect sizes 1.4–6.8; E-values 4.8–13.4; Mendelian-randomisation summary risk ratio 1.05 per 1 kg/m²), con-sistency (replication across continents, age groups, sexes, and study designs), temporality (cohort and life-course Mendelian-randomisation evidence), biological gradient (BMI dose–response with TNFα, IL-17A, and Th17 frequency), plausibility (a twelve-layer architecture from adipose dysfunction to bronchial epithelium), coherence with the natural history of the phenotype, experimental support (bariatric surgery, lifestyle weight loss, GLP-1 receptor agonist pharmaco-epidemiology, murine and in vitro stud-ies), and analogy with other obesity-related Th17 diseases collectively support a causal interpretation. Specificity, the weakest of Hill’s viewpoints, is satisfied at the phenotype level. Hill’s viewpoints are situated…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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