用生成模型合成临床试验对照组数据,提升研究效率与隐私保护。
Toward Valid Generative Clinical Trial Data with Survival Endpoints
- 基于变分自编码器联合生成患者特征与生存结局,无需独立删失假设。
- 在真实与合成数据上验证,生成数据在保真度、效用和隐私上优于传统方法。
- 提出后处理筛选策略改善统计校准,适合肿瘤与罕见病临床研究使用。
临床试验面临患者群体分散、招募缓慢和成本高昂等挑战,尤其在肿瘤和罕见病的Ⅲ期试验中更为突出。尽管已有利用真实世界数据构建外部对照臂的研究,但利用生成式AI合成对照臂是更具潜力的替代方案。核心难点在于时间至事件结局(如生存期)的生成,这类终点在存在删失和小样本时难以建模。现有生成方法多基于GAN,依赖大量数据、不稳定且常假设删失独立。本文提出一种变分自编码器(VAE),在统一潜变量框架下联合生成混合类型协变量与生存结局,无需独立删失假设。我们在合成与真实试验数据集上评估该模型在两种场景下的表现:(i) 隐私约束下的数据共享,用合成对照组替代原始数据;(ii) 对照组增强,通过合成患者缓解治疗组与对照组之间的不平衡。结果表明,本方法在保真度、实用性及隐私保护指标上均优于GAN基线,并揭示了类型I错误率与检验效能的系统性偏差。我们提出一种后生成筛选流程,显著提升校准性能,凸显生成生存建模的进步与现存挑战。
原文摘要 · Abstract (English)
Clinical trials face mounting challenges: fragmented patient populations, slow enrollment, and unsustainable costs, particularly for late phase trials in oncology and rare diseases. While external control arms built from real-world data have been explored, a promising alternative is the generation of synthetic control arms using generative AI. A central challenge is the generation of time-to-event outcomes, which constitute primary endpoints in oncology and rare disease trials, but are difficult to model under censoring and small sample sizes. Existing generative approaches, largely GAN-based, are data-hungry, unstable, and rely on strong assumptions such as independent censoring. We introduce a variational autoencoder (VAE) that jointly generates mixed-type covariates and survival outcomes within a unified latent variable framework, without assuming independent censoring. Across synthetic and real trial datasets, we evaluate our model in two realistic scenarios: (i) data sharing under privacy constraints, where synthetic controls substitute for original data, and (ii) control-arm augmentation, where synthetic patients mitigate imbalances between treated and control groups. Our method outperforms GAN baselines on fidelity, utility, and privacy metrics, while revealing systematic miscalibration of type I error and power. We propose a post-generation selection procedure that improves calibration, highlighting both progress and open challenges for generative survival modeling.
Thank you to arXiv for use of its open access interoperability. PaperDance 不是 arXiv 官方产品;中文卡片由大模型生成,请以原文为准。