Establishing Long-Term Efficacy in Chronic Disease: Use of Recursive Partitioning and Propensity Score Adjustment to Estimate Outcome in MS

CONTEXT Establishing the long-term benefit of therapy in chronic diseases has been challenging. Long-term studies require non-randomized designs and, thus, are often confounded by biases. For example, although disease-modifying therapy in MS has a convincing benefit on several short-term outcome-measures in randomized trials, its impact on long-term function remains uncertain. OBJECTIVE Data from the 16-year Long-Term Follow-up study of interferon-beta-1b is used to assess the relationship between drug-exposure and long-term disability in MS patients. DESIGN/SETTING To mitigate the bias of outcome-dependent exposure variation in non-randomized long-term studies, drug-exposure was measured as the medication-possession-ratio, adjusted up or down according to multiple different weighting-schemes based on MS severity and MS duration at treatment initiation. A recursive-partitioning algorithm assessed whether exposure (using any weighing scheme) affected long-term outcome. The optimal cut-point that was used to define "high" or "low" exposure-groups was chosen by the algorithm. Subsequent to verification of an exposure-impact that included all predictor variables, the two groups were compared using a weighted propensity-stratified analysis in order to mitigate any treatment-selection bias that may have been present. Finally, multiple sensitivity-analyses were undertaken using different definitions of long-term outcome and different assumptions about the data. MAIN OUTCOME MEASURE Long-Term Disability. RESULTS In these analyses, the same weighting-scheme was consistently selected by the recursive-partitioning algorithm. This scheme reduced (down-weighted) the effectiveness of drug exposure as either disease duration or disability at treatment-onset increased. Applying this scheme and using propensity-stratification to further mitigate bias, high-exposure had a consistently better clinical outcome compared to low-exposure (Cox proportional hazard ratio = 0.30-0.42; p<0.0001). CONCLUSIONS Early initiation and sustained use of interferon-beta-1b has a beneficial impact on long-term outcome in MS. Our analysis strategy provides a methodological framework for bias-mitigation in the analysis of non-randomized clinical data. TRIAL REGISTRATION Clinicaltrials.govNCT00206635.