Probabilistic Quantitative Bias Analysis for Misclassification and Uncontrolled Confounding: A Methodological Tutorial Using Real-World Data.

BACKGROUND

Observational studies and clinical trials are vulnerable to multiple sources of bias that can distort study findings. This methodological tutorial demonstrates the application of probabilistic quantitative bias analysis (QBA) to adjust for exposure misclassification, outcome misclassification, and uncontrolled confounding, using the association between obesity (exposure) and hypertension (outcome) as an exemplar.

METHODS

Publicly available data from the National Health and Nutrition Examination Survey were temporally split into an analysis dataset to estimate the association of interest (2021-2023, n = 5165) and a validation dataset to derive bias parameters (2003-2016, n = 33,103). Misclassification was introduced by using self-reported measures to define obesity and hypertension rather than measured objective assessments (height, weight, and blood pressure). Uncontrolled confounding was introduced by omitting adjustment for socioeconomic status. Bias parameters were estimated and applied in a Monte Carlo-based probabilistic QBA to obtain bias-adjusted measures of association by age group and sex.

RESULTS

After correcting for nondifferential misclassification of obesity, bias-adjusted estimates were consistently larger than conventional estimates across all age and sex subgroups, indicating that self-reported height and weight attenuated the obesity-hypertension association. Accounting for differential misclassification of hypertension generally yielded smaller bias-adjusted estimates, suggesting that self-reported hypertension overestimated the association, except among males 40-59 years of age, where it was attenuated. Adjustment for uncontrolled confounding by socioeconomic status resulted in larger bias-adjusted estimates, particularly in older adults, indicating further attenuation due to residual confounding.

CONCLUSIONS

QBA offers a practical approach to assess and account for bias, improving the interpretation and reliability of results in cardiovascular studies.