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Abstract Investigating the causal relationship between exposure and time-to-event outcome is an important topic in biomedical research. Previous literature has discussed the potential issues of using hazard ratio (HR) as the marginal causal effect measure due to noncollapsibility. In this article, we advocate using restricted mean survival time (RMST) difference as a marginal causal effect measure, which is collapsible and has a simple interpretation as the difference of area under survival curves over a certain time horizon. To address both measured and unmeasured confounding, a matched design with sensitivity analysis is proposed. Matching is used to pair similar treated and untreated subjects together, which is generally more robust than outcome modeling due to potential misspecifications. Our propensity score matched RMST difference estimator is shown to be asymptotically unbiased, and the corresponding variance estimator is calculated by accounting for the correlation due to matching. Simulation studies also demonstrate that our method has adequate empirical performance and outperforms several competing methods used in practice. To assess the impact of unmeasured confounding, we develop a sensitivity analysis strategy by adapting the E -value approach to matched data. We apply the proposed method to the Atherosclerosis Risk in Communities Study (ARIC) to examine the causal effect of smoking on stroke-free survival. 

Abstract Objective . Deep-learning (DL)-based dose engines have been developed to alleviate the intrinsic compromise between the calculation accuracy and efficiency of the traditional dose calculation algorithms. However, current DL-based engines typically possess high computational complexity and require powerful computing devices. Therefore, to mitigate their computational burdens and broaden their applicability to a clinical setting where resource-limited devices are available, we proposed a compact dose engine via knowledge distillation (KD) framework that offers an ultra-fast calculation speed with high accuracy for prostate Volumetric Modulated Arc Therapy (VMAT). Approach . The KD framework contains two sub-models: a large pre-trained teacher and a small to-be-trained student. The student receives knowledge transferred from the teacher for better generalization. The trained student serves as the final engine for dose calculation. The model input is patient computed tomography and VMAT dose in water, and the output is DL-calculated patient dose. The ground-truth \dose was computed by the Monte Carlo module of the Monaco treatment planning system. Twenty and ten prostate cases were included for model training and assessment, respectively. The model’s performance (teacher/student/student-only) was evaluated by Gamma analysis and inference efficiency. Main results . The dosimetric comparisons (input/DL-calculated/ground-truth doses) suggest that the proposed engine can effectively convert low-accuracy doses in water to high-accuracy patient doses. The Gamma passing rate (2%/2 mm, 10% threshold) between the DL-calculated and ground-truth doses was 98.64 ± 0.62% (teacher), 98.13 ± 0.76% (student), and 96.95 ± 1.02% (student-only). The inference time was 16 milliseconds (teacher) and 11 milliseconds (student/student-only) using a graphics processing unit device, while it was 936 milliseconds (teacher) and 374 milliseconds (student/student-only) using a central processing unit device. Significance . With the KD framework, a compact dose engine can achieve comparable accuracy to that of a larger one. Its compact size reduces the computational burdens and computing device requirements, and thus such an engine can be more clinically applicable.