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Comparison of methods for assessing effects of risk factors on disease progression in Mendelian randomization under index event bias
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DOI：10.1016/j.ajhg.2026.06.004.png)
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Abstract
En 中文
Mendelian randomization has emerged as a transformative approach for inferring causal relationships between risk factors and disease outcomes. However, applying Mendelian randomization to disease progression—a critical step in validating therapeutic targets—is hampered by index event bias. This form of selection bias occurs because analyses of disease progression are necessarily restricted to individuals who have already experienced the disease event. Here, we present a comprehensive evaluation of statistical methods designed to mitigate index event bias, including inverse-probability weighting, Heckman’s method, the Slope-Hunter method, and multivariable methods. We compare their performance in simulations and applied examples. Inverse-probability weighting methods reduce bias but require individual-level data and will only fully eliminate bias when the disease event model is correctly specified. The Slope-Hunter method performed poorly in all simulation scenarios, even when its assumptions were fully satisfied. Multivariable methods worked best when including genetic variants that affect the incident disease event. However, if these genetic variants also affect disease progression directly, then the analysis will suffer from pleiotropy. Hence, if the same biological mechanisms affect disease incidence and progression, then multivariable methods will have little utility. In such a case, however, analyses of disease progression are less critical, as conclusions reached from analyses of disease incidence are likely to hold for disease progression. Our findings indicate that no single method is a universal solution to provide reliable results for the investigation of disease progression. Instead, we propose a strategic framework for method selection based on data availability and biological context.
Keywords:
genetic epidemiology
causal inference
index event bias
methods comparison
collider bias
selection bias
Mendelian randomization
disease progression
drug development
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