Assessing Delayed Treatment Benefits of Immunotherapy Using Long-Term Average Hazard: A Novel Test/Estimation Approach

Miki Horiguchi; Lu Tian; Kenneth L. Kehl; Hajime Uno

Home/Archive/arXiv

arXiv · 2403.10742

Assessing Delayed Treatment Benefits of Immunotherapy Using Long-Term Average Hazard: A Novel Test/Estimation Approach

Miki Horiguchi·Lu Tian·Kenneth L. Kehl·Hajime Uno

View original source ↗Read source document ↗Export metadata ↓

Abstract

Delayed treatment effects on time-to-event outcomes have often been observed in randomized controlled studies of cancer immunotherapies. In the case of delayed onset of treatment effect, the conventional test/estimation approach using the log-rank test for between-group comparison and Cox's hazard ratio to estimate the magnitude of treatment effect is not optimal, because the log-rank test is not the most powerful option, and the interpretation of the resulting hazard ratio is not obvious. Recently, alternative test/estimation approaches were proposed to address both the power issue and the interpretation problems of the conventional approach. One is a test/estimation approach based on long-term restricted mean survival time, and the other approach is based on average hazard with survival weight. This paper integrates these two ideas and proposes a novel test/estimation approach based on long-term average hazard (LT-AH) with survival weight. Numerical studies reveal specific scenarios where the proposed LT-AH method provides a higher power than the two alternative approaches. The proposed approach has test/estimation coherency and can provide robust estimates of the magnitude of treatment effect not dependent on study-specific censoring time distribution. Also, the proposed LT-AH approach can summarize the magnitude of the treatment effect in both absolute difference and relative terms using ``hazard'' (i.e., difference in LT-AH and ratio of LT-AH), meeting guideline recommendations and practical needs. This proposed approach can be a useful alternative to the traditional hazard-based test/estimation approach when delayed onset of survival benefit is expected.

Explore related subjects

stat.ME

Keep this discovery

BibTeX RIS

Miki Horiguchi, Lu Tian, Kenneth L. Kehl, Hajime Uno. 2024-03-16. Assessing Delayed Treatment Benefits of Immunotherapy Using Long-Term Average Hazard: A Novel Test/Estimation Approach. https://arxiv.org/abs/2403.10742

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related papers

arXiv2026

Surprise Reduction and Nullification in Bayesian and Inverse Bayesian Inference under Ambiguous Prediction-Error Attribution

In non-stationary environments, prediction errors may signal environmental change or transient outliers, and adaptive systems must track such changes without overreacting to outliers. We distinguish surprise reduction, which updates beliefs to fit observations, from surprise nullification, which weakens constraints imposed by the predictive structure, and formalize both within Bayesian and inverse Bayesian (BIB) inference. Belief and likelihood updates are derived from variational objectives sharing a nullification strength, determined endogenously by minimizing surprise under the candidate post-update predictive distribution. In the Gaussian case, nullification expands belief and likelihood variances by a common factor relative to standard Bayesian updating, leaving the ratio unchanged. BIB thus defers attribution of the prediction error, committing to neither latent-state change nor observation-process uncertainty. The nullification strength is carried over as a candidate and is maintained or released according to the predictive surprise of the next observation. In a mean estimation task with outliers and changepoints, no scanned parameter setting of a Sage-Husa-type adaptive Kalman filter, fixed-strength BIB variant, or belief-forgetting-only variant outperforms BIB in both changepoint tracking and post-outlier stability. An oracle-informed reduced Bayesian model tracks changepoints better but is less stable after outliers. Although BIB maintains no explicit hypotheses about changepoints or outliers, it generates event-dependent dynamics. The learning rate increases after changepoints, whereas after outliers, nullification is released, and this increase is suppressed. Deferring attribution and letting subsequent observations differentiate the responses may constitute a principle of adaptive inference in non-stationary environments.

stat.ME↗

arXiv2026

Generalized Ridge Refitting for the Lasso and Prediction Improvement Bounds

We study a class of Lasso based estimators obtained by applying a quadratic correction on the Lasso equicorrelation set. The penalty matrix determines both the magnitude and geometry of the correction and contains, among other cases, the isotropic Lasso--Ridge correction, least squares refitting, Gram proportional interpolation between the Lasso and least squares, and coordinate specific penalties. We first derive a closed form representation and isolate the positive gain component of the resulting prediction improvement. We then control the remaining stochastic linear term in expectation by localizing the random signed equicorrelation model around a deterministic reference support. This yields a finite sample expectation bound that explicitly accounts for the randomness induced by Lasso model selection. The resulting decomposition provides a unified framework for understanding when Lasso based quadratic corrections can improve prediction.

stat.ME↗

arXiv2026

Discretization in covariate-adaptive randomization: gains and losses

Covariate-adaptive randomization(CAR) is widely implemented in clinical trials to balance prognostic covariates across treatment arms. Continuous covariates are often discretized into strata in practice, yet their consequences are not clearly understood. This paper provides a comprehensive study of the impact of discretization on both the CAR design process and the inferential results thereafter. We establish the asymptotic properties of both imbalance measures and treatment effect estimators under discretized and non-discretized settings. Practical recommendations are given on when and how discretization should be employed. We show that discretization in design is generally recommended, as it enhances robustness against model misspecification. However, if the true model is known, the most efficient strategy is to balance covariates according to that model in the design. The theoretical results are corroborated by extensive simulation studies and an empirical application to a diabetes trial dataset. Together, the results clarify the gains and losses of discretization in CAR and pave the way for learning impact of discretization to other designs and beyond.

stat.ME↗