arXiv subjects

Georgios Antonios Margonis

Publications and source records attributed to Georgios Antonios Margonis.

5 recordsLinked to original sources

arXiv2026

Robustifying and Selecting Cohort-Appropriate Prognostic Models under Distributional Shifts

External validation is widely regarded as the gold standard for prognostic model evaluation. In this study, we challenge the assumption that successful external calibration guarantees model generalizability and propose two complementary strategies to improve transportability of prognostic models across cohorts. Using six real-world surgical cohorts from tertiary academic centers, we tested whether successful external calibration depends largely on similarity in covariates and outcomes between training and validation cohorts, quantified using Kullback-Leibler (KL) divergence, with calibration assessed by the Integrated Calibration Index (ICI). From the model-developer's perspective, we trained the "best-on-average" prognostic model by tuning toward a meta-analysis-derived covariate and outcome distribution as an approximation of the broader target population. From the end-user perspective, we proposed a simple measure for cohort outcome similarity to identify, among published models, the one most suitable for a given target cohort in terms of both calibration and clinical utility. External calibration worsened as distributional mismatch increased. Higher KL divergence was associated with higher ICI in both surgery-alone (Spearman $ρ=0.614$, $p=0.004$) and surgery + adjuvant chemotherapy cohorts (Spearman $ρ=0.738$, $p<0.001$). Meta-analysis-informed weighting improved calibration in most settings without materially affecting discrimination, with the clearest benefit when evaluated on the aggregated external population ($p=0.037$). Models developed in more similar cohorts achieved lower ICI in surgery-alone (Spearman $ρ=0.803$, $p<0.001$) and surgery + adjuvant chemotherapy cohorts (Spearman $ρ=0.737$, $p<0.001$), and provided greater clinical utility on DCA.

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arXiv2026

Observing the unobserved confounding through its effects: toward randomized trial-like estimates from real-world survival data

Background: Randomized controlled trials (RCTs) are costly, time-consuming, and often infeasible, while treatment-effect estimation from observational data is limited by unobserved confounding. Methods: We developed a three-step framework to address unobserved confounding in observational survival data. First, we infer a latent prognostic factor (U) from restricted mean survival time (RMST) discrepancies between patients with similar observed factors, the same treatment, and divergent outcomes, leveraging the idea that the aggregate effect of unmeasured factors can be inferred even if individual factors cannot. Second, we balance U with observed baseline covariates using prognostic matching, entropy balancing, or inverse probability of treatment weighting. Third, we apply multivariable survival analysis to estimate hazard ratios (HRs). We evaluated the framework in three observational cohorts with RCT benchmarks, two RCT cohorts, and six multicenter observational cohorts. Results: In three observational cohorts (nine comparisons), balancing U improved agreement with trial HRs in all cases; in the strongest settings, it reduced absolute log-HR error by approximately ten-fold versus using observed covariates alone (mean reduction 0.344; p=0.001). In two RCT cohorts, U was balanced across arms (most SMDs <0.1) and adjustment had minimal impact on log-HRs (mean absolute change 0.08). Across six multicenter cohorts, balancing U within centers reduced cross-center dispersion in chemotherapy log-HR estimates (mean reduction 0.147; p=0.016); when populations were directly balanced across centers to account for case-mix differences, cross-center survival differences were narrowed in 75%-100% of comparisons. Conclusions: Inferring and balancing a latent prognostic signal may reduce unobserved confounding and improve treatment-effect estimation from real-world data.

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arXiv2025

Improving Survival Models in Healthcare by Balancing Imbalanced Cohorts: A Novel Approach

We explore whether survival model performance in underrepresented high- and low-risk subgroups - regions of the prognostic spectrum where clinical decisions are most consequential - can be improved through targeted restructuring of the training dataset. Rather than modifying model architecture, we propose a novel risk-stratified sampling method that addresses imbalances in prognostic subgroup density to support more reliable learning in underrepresented tail strata. We introduce a novel methodology that partitions patients by baseline prognostic risk and applies matching within each stratum to equalize representation across the risk distribution. We implement this framework on a cohort of 1,799 patients with resected colorectal liver metastases (CRLM), including 1,197 who received adjuvant chemotherapy and 602 who did not. All models used in this study are Cox proportional hazards models trained on the same set of selected variables. Model performance is assessed via Harrell's C index, time-dependent AUC, and Integrated Calibration Index (ICI), with internal validation using Efron's bias-corrected bootstrapping. External validation is conducted on two independent CRLM datasets. Cox models trained on risk-balanced cohorts showed consistent improvements in internal validation compared to models trained on the full dataset while noticeably enhancing stratified C-index values in underrepresented high- and low-risk strata of the external cohorts. Our findings suggest that survival model performance in observational oncology cohorts can be meaningfully improved through targeted rebalancing of the training data across prognostic risk strata. This approach offers a practical and model-agnostic complement to existing methods, especially in applications where predictive reliability across the full risk continuum is critical to downstream clinical decisions.

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arXiv2024

The R.O.A.D. to clinical trial emulation

Observational studies provide the only evidence on the effectiveness of interventions when randomized controlled trials (RCTs) are impractical due to cost, ethical concerns, or time constraints. While many methodologies aim to draw causal inferences from observational data, there is a growing trend to model observational study designs after RCTs, a strategy known as "target trial emulation." Despite its potential, causal inference through target trial emulation cannot fully address the confounding bias in real-world data due to the lack of randomization. In this work, we present a novel framework for target trial emulation that aims to overcome several key limitations, including confounding bias. The framework proceeds as follows: First, we apply the eligibility criteria of a specific trial to an observational cohort. We then "correct" this cohort by extracting a subset that matches both the distribution of covariates and the baseline prognosis of the control group in the target RCT. Next, we address unmeasured confounding by adjusting the prognosis estimates of the treated group to align with those observed in the trial. Following trial emulation, we go a step further by leveraging the emulated cohort to train optimal decision trees, to identify subgroups of patients with heterogeneity in treatment effects (HTE). The absence of confounding is verified using two external models, and the validity of the treatment recommendations is independently confirmed by the team responsible for the original trial we emulate. To our knowledge, this is the first framework to successfully address both observed and unobserved confounding, a challenge that has historically limited the use of randomized trial emulation and causal inference. Additionally, our framework holds promise in advancing precision medicine by identifying patient subgroups that benefit most from specific treatments.

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arXiv2023

The R.O.A.D. to precision medicine

We propose a prognostic stratum matching framework that addresses the deficiencies of Randomized trial data subgroup analysis and transforms ObservAtional Data to be used as if they were randomized, thus paving the road for precision medicine. Our approach counters the effects of unobserved confounding in observational data by correcting the estimated probabilities of the outcome under a treatment through a novel two-step process. These probabilities are then used to train Optimal Policy Trees (OPTs), which are decision trees that optimally assign treatments to subgroups of patients based on their characteristics. This facilitates the creation of clinically intuitive treatment recommendations. We applied our framework to observational data of patients with gastrointestinal stromal tumors (GIST) and validated the OPTs in an external cohort using the sensitivity and specificity metrics. We show that these recommendations outperformed those of experts in GIST. We further applied the same framework to randomized clinical trial (RCT) data of patients with extremity sarcomas. Remarkably, despite the initial trial results suggesting that all patients should receive treatment, our framework, after addressing imbalances in patient distribution due to the trial's small sample size, identified through the OPTs a subset of patients with unique characteristics who may not require treatment. Again, we successfully validated our recommendations in an external cohort.

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