Figure 1.

The hypothesized causal relationships in the treatment of multiple sclerosis, with 3 time points: j = 0, 1, 2. Here E_j denotes the binary β-interferon exposure variable that is measured immediately after the time-dependent confounders R_j (cumulative relapses) and D_j (disability progression index—that is, Expanded Disability Status Scale (EDSS) score) for the jth time period. The time-dependent confounder R_j at time j is affected by prior treatment E_j−1. According to the causal diagram, R₀ imposes confounding on the E₀-D relationship (since relapse frequency may dictate the subsequent treatment choice and residual disability left by frequent relapses may accumulate over time, leading to irreversible disability), but R₁ is an intermediate variable for the same relationship (51, 52) (since the prior β-interferon treatment may reduce relapse frequency, which may allow the patient more time to recover from residual disability left by past relapses and may contribute to slower progression of disability over time).