Optimizing Clinical Trial Protocols Using EHR-Derived Heterogeneous Treatment Effects

Target trial emulation (TTE) enables causal questions to be studied with observational data when randomized controlled trials (RCTs) are infeasible. Yet treatment-effect methods often address causal estimation, missingness, and temporal structure separately, limiting their robustness in electronic health records (EHRs), where time-varying confounding and missing-not-at-random (MNAR) biomarkers can reach 50%--80%. We propose a two-stage pipeline for treatment effect estimation from incomplete longitudinal EHRs. First, CausalFlow-T, a directed acyclic graph (DAG)-constrained normalizing flow with long short-term memory (LSTM)-encoded patient history, performs exact invertible counterfactual inference, avoiding approximation errors from variational inference and separating confounding through explicit causal structure. Ablations on four synthetic and one semi-synthetic benchmark with known counterfactuals show that DAG constraints and exact inference address distinct failure modes: neither compensates for the other. Second, because CausalFlow-T requires completed inputs, we introduce an LLM-driven evolutionary imputer that proposes executable imputation operators rather than individual entries, and evaluate it with three large language model (LLM) backends, including two open-source models. Across 30%--80% MNAR missingness, this imputer achieves the best pooled rank over biomarker and causal metrics, leading in point-wise accuracy and temporal extrapolation while preserving average treatment effect (ATE) recovery as statistical baselines degrade. On Swiss primary-care EHRs from adults with type 2 diabetes initiating a GLP-1 receptor agonist or SGLT-2 inhibitor, the pipeline estimates a per-protocol weight-loss difference of -0.98 kg [95% CI -1.01, -0.96] favoring GLP-1 receptor agonists, consistent with randomized evidence and obtained from realistically incomplete real-world EHRs.

Progression to dialysis or end-stage renal disease is a rare but clinically important outcome. Clinicians need evidence on how medication exposures influence downstream risk. We constructed a fixed-window EHR cohort (90-day observation, 730-day prediction; N=81401; dialysis/ESRD prevalence: 1.1%) and modeled sequences of diagnoses, procedures, and medications with kidney laboratory trends (creatinine, BUN, eGFR). A transformer-based causal multi-head model was trained to estimate drug- and ingredient-level average treatment effects (ATEs) using counterfactual exposure removal and insertion under a full medication history setup. On test set, predictive performance reached an AUC of 0.694 and PR-AUC of 0.094. At the selected decision threshold (0.883), the model achieved an F1 score of 0.201 with a Brier score of 0.018. Post-hoc causal analyses of lab changes (eGFR, creatinine, BUN) using IPTW, AIPW, naive, and covariate-adjusted OLS methods assessed clinical directionality. Results showed partial protective-direction support for ACE/ARB exposures and worsening-direction signals for loop diuretics.

Estimating heterogeneous treatment effects (CATE) requires simultaneously detecting effect modification and quantifying estimation uncertainty. Existing tree-based methods make an uneasy trade-off: significance-based approaches (Radcliffe and Surry 2011) identify subgroup interactions directly but lack valid inference; honest causal trees (Athey and Imbens 2016) deliver nominal confidence interval coverage but use outcome-agnostic splitting criteria that sacrifice interaction sensitivity. We introduce a hybrid algorithm that fuses significance-based splitting with honest sample-splitting and cross-validation. Our splitting criterion uses the squared $t$-statistic for the treatment $\times$ side interaction ($t^2$), which is shown to be directly aligned with the honest $\text{EMSE}_τ$ criterion when the interaction is strong. Post-hoc honest cross-validation selects the cost-complexity penalty, giving a single principled estimator with nominal CI coverage at the leaf level. For forests, we retain bootstrap count vectors to enable an infinitesimal jackknife (IJ) variance estimate of Monte-Carlo convergence rather than formal pointwise inference. On the three synthetic designs from (Athey and Imbens 2016) the single tree achieves approximately 90% leaf-average CI coverage at the 90% nominal level across all three designs (200 replications each); on the Criteo, Hillstrom and Starbucks uplift datasets we match Qini coefficient performance of S-, T-learner and GRF baselines. An open-source Python package with reproducible seeds, sklearn-compatible API, and full test coverage accompanies this work (https://codeberg.org/hadjipantelis/rattus).