Table 1.
Baseline and on-RCT clinical characteristics of the patients included (and those not included) in the detailed LTF evaluation after 16 years*.
Table 2.
Recursive Partitioning associating each predictor variable independently with “any negative-outcome” (p<0.20 to split).
Figure 1.
The effect of MPR transformation on the bias introduced by informative-censoring of exposure (see text).
In panel A are the results of the RP analysis incorporating all of the baseline variables and the unweighted raw exposures (measured in years). In this analysis the exposure variable (in years) dominates all other variables with a p-value of 10−16. However, in panel B, where the same analysis is conducted using the unweighted-MPRs (in place of the unweighted “raw” exposures), the entire “spurious” treatment-effect disappears and the resulting tree is identical to that found when all predictor variables (but not treatment) are included in the RP-analysis. In both Panels, the Kaplan-Meier survival estimates are displayed below each of the identified subgroups (splits). X-axis is time in years. Y-axis is survival in % (1 = 100%).
Figure 2.
Optimal split determined by the recursive partitioning algorithm considering all predictor variables (Table 2) together with all possible weighted-MPR exposures to IFNβ-1b.
Two highly significant split-levels were identified by the algorithm based on EDSS at the start of therapy and weighted IFNβ-1b exposure during the LTF. The first split (as in the Supplemental Material; Appendix S1; Figure S6) occurred at EDSS = 2, whereas a second level split occurred only for the EDSS>2 branch and was based on DMT exposure. Importantly, the algorithm for this analysis selected precisely the same weighting-scheme (bTN4SN2) that was selected in the Supplemental Material (Appendix S1; Figure S7). Survival curves are displayed below the identified subgroups and survival is best in the EDSS≤2 and the high-exposure groups. The split-point for DMT exposure is slightly different than that identified in the Supplemental Material (Appendix S1; Figure S7) because, in this instance, the split-point was determined only from the subgroup of patients with an EDSS>2. Note: the number (0.028) cannot be interpreted in time units because it represents a mathematical transformation from the raw exposure in years. In both Panels, the Kaplan-Meier survival estimates are displayed below each of the identified subgroups (splits). X-axis is time in years. Y-axis is survival in % (1 = 100%).
Figure 3.
Propensity adjusted Cox proportional hazard estimates for the effect of treatment on each of the “hard” negative-outcomes examined in the study.
The results for our principal analysis (i.e., for “any negative-outcome”) are shown on the far left. For each of these outcomes, there is approximately a 60% to 70% long-term benefit to therapy. Error bars indicate the 95% CI for each the different outcomes.