Diagnostic Assessment of Assumptions for External Validity An Example Using Data in Metastatic Colorectal Cancer

Background: Methods developed to estimate intervention effects in external target populations assume that all important effect measure modifiers have been identified and appropriately modeled. Propensity score-based diagnostics can be used to assess the plausibility of these assumptions for weighting methods. Methods: We demonstrate the use of these diagnostics when assessing the transportability of treatment effects from the standard of care for metastatic colorectal cancer control arm in a phase III trial (HORIZON III) to a target population of 1,942 Medicare beneficiaries age 65+ years. Results: In an unadjusted comparison, control arm participants had lower mortality compared with target population patients treated with the standard of care therapy (trial vs. target hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.58, 0.89). Applying inverse odds of sampling weights attenuated the trial versus target HR (weighted HR = 0.96, 95% CI = 0.73, 1.26). However, whether unadjusted or weighted, hazards did not appear proportional. At 6 months of follow-up, mortality was lower in the weighted trial population than the target population (weighted trial vs. target risk difference [RD] = -0.07, 95% CI = -0.13, -0.01), but not at 12 months (weighted RD = 0.00, 95% CI = -0.09, 0.09). Conclusion: These diagnostics suggest that direct transport of treatment effects from HORIZON III to the Medicare population is not valid. How-ever, the proposed sampling model might allow valid transport of the treatment effects on longer-term mortality from HORIZON III to the Medicare population treated in clinical practice. See video abstract at, http://links.lww.com/EDE/B435.