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When the distribution of treatment effect modifiers differs between the trial sample and target population, inverse probability weighting (IPSW) can be applied to achieve an unbiased estimate of the population average treatment effect in the target population. The statistical validity of IPSW is threatened when there are missing data in the target population, including potential missingness in trial sample. However, missing data methods have not been adequately discussed in the current literature. We conducted a set of simulation studies to determine how to apply multiple imputation (MI) in the context of IPSW. We specifically addressed questions such as which variables to include in the imputation model and whether they should come from trial or non-trial portion of the target population. Based on our findings, we recommend including all potential effect modifiers and trial indicator from both trial and non-trial populations, as well as treatment and outcome variables from trial sample in the imputation model as main effects. Additionally, we have illustrated ideas by transporting findings from the Frequent Hemodialysis Network (FHN) Daily Trial to the United States Renal Stage System (USRDS) population.

Generalizability and transportability methods have been proposed to address the external validity bias of randomized clinical trials that results from differences in the distribution of treatment effect modifiers between trial and target populations. However, such studies present many challenges. We review and summarize state-of-the-art methodological considerations. We additionally provide investigators with a step-by-step guide to address these challenges, illustrated through a published case study. When conducted with rigor, such studies may play an integral role in regulatory decisions by providing key real-world evidence.

Propensity score matching (PSM) has been widely used to mitigate confounding in observational studies, although complications arise when the covariates used to estimate the PS are only partially observed. Multiple imputation (MI) is a potential solution for handling missing covariates in the estimation of the PS. Unfortunately, it is not clear how to best apply MI strategies in the context of PSM. We conducted a simulation study to compare the performances of popular non-MI missing data methods and various MI-based strategies under different missing data mechanisms (MDMs). We found that commonly applied missing data methods resulted in biased and inefficient estimates, and we observed large variation in performance across MI-based strategies. Based on our findings, we recommend 1) deriving the PS after applying MI (referred to as MI-derPassive); 2) conducting PSM within each imputed data set followed by averaging the treatment effects to arrive at one summarized finding (INT-within) for mild MDMs and averaging the PSs across multiply imputed datasets before obtaining one treatment effect using PSM (INT-across) for more complex MDMs; 3) a bootstrapped-based variance to account for uncertainty of PS estimation, matching, and imputation; and 4) inclusion of key auxiliary variables in the imputation model.

Objectives: Most cancer data sources lack information on metastatic recurrence. Electronic medical records (EMRs) and population-based cancer registries contain complementary information on cancer treatment and outcomes, yet are rarely used synergistically. To enable detection of metastatic breast cancer (MBC), we applied a semi-supervised machine learning framework to linked EMR-California Cancer Registry (CCR) data. Materials and Methods: We studied 11,459 female patients treated at Stanford Health Care who received an incident breast cancer diagnosis from 2000-2014. The dataset consisted of structured data and unstructured free-text clinical notes from EMR, linked to CCR, a component of the Surveillance, Epidemiology and End Results (SEER) database. We extracted information on metastatic disease from patient notes to infer a class label and then trained a regularized logistic regression model for MBC classification. We evaluated model performance on a gold standard set of set of 146 patients. Results: There are 495 patients with de novo stage IV MBC, 1,374 patients initially diagnosed with Stage 0-III disease had recurrent MBC, and 9,590 had no evidence of metastatis. The median follow-up time is 96.3 months (mean 97.8, standard deviation 46.7). The best-performing model incorporated both EMR and CCR features. The area under the receiver-operating characteristic curve=0.925 [95% confidence interval: 0.880-0.969], sensitivity=0.861, specificity=0.878 and overall accuracy=0.870. Discussion and Conclusion: A framework for MBC case detection combining EMR and CCR data achieved good sensitivity, specificity and discrimination without requiring expert-labeled examples. This approach enables population-based research on how patients die from cancer and may identify novel predictors of cancer recurrence.