TAD-SIE: Sample Size Estimation for Clinical Randomized Controlled Trials using a Trend-Adaptive Design with a Synthetic-Intervention-Based Estimator

Phase-3 clinical trials provide the highest level of evidence on drug safety and effectiveness needed for market approval by implementing large randomized controlled trials (RCTs). However, 30-40% of these trials fail mainly because such studies have inadequate sample sizes, stemming from the inability to obtain accurate initial estimates of average treatment effect parameters. To remove this obstacle from the drug development cycle, we present a new algorithm called Trend-Adaptive Design with a Synthetic-Intervention-Based Estimator (TAD-SIE) that appropriately powers a parallel-group trial, a standard RCT design, by leveraging a state-of-the-art hypothesis testing strategy and a novel trend-adaptive design (TAD). Specifically, TAD-SIE uses SECRETS (Subject-Efficient Clinical Randomized Controlled Trials using Synthetic Intervention) for hypothesis testing, which simulates a cross-over trial in order to boost power; doing so, makes it easier for a trial to reach target power within trial constraints (e.g., sample size limits). To estimate sample sizes, TAD-SIE implements a new TAD tailored to SECRETS given that SECRETS violates assumptions under standard TADs. In addition, our TAD overcomes the ineffectiveness of standard TADs by allowing sample sizes to be increased across iterations without any condition while controlling significance level with futility stopping. On a real-world Phase-3 clinical RCT (i.e., a two-arm parallel-group superiority trial with an equal number of subjects per arm), TAD-SIE reaches typical target operating points of 80% or 90% power and 5% significance level in contrast to baseline algorithms that only get at best 59% power and 4% significance level.

SECRETS: Subject-Efficient Clinical Randomized Controlled Trials using Synthetic Intervention

The randomized controlled trial (RCT) is the gold standard for estimating the average treatment effect (ATE) of a medical intervention but requires 100s-1000s of subjects, making it expensive and difficult to implement. While a cross-over trial can reduce sample size requirements by measuring the treatment effect per individual, it is only applicable to chronic conditions and interventions whose effects dissipate rapidly. Another approach is to replace or augment data collected from an RCT with external data from prospective studies or prior RCTs, but it is vulnerable to confounders in the external or augmented data. We propose to simulate the cross-over trial to overcome its practical limitations while exploiting its strengths. We propose a novel framework, SECRETS, which, for the first time, estimates the individual treatment effect (ITE) per patient in the RCT study without using any external data by leveraging a state-of-the-art counterfactual estimation algorithm, called synthetic intervention. It also uses a new hypothesis testing strategy to determine whether the treatment has a clinically significant ATE based on the estimated ITEs. We show that SECRETS can improve the power of an RCT while maintaining comparable significance levels; in particular, on three real-world clinical RCTs (Phase-3 trials), SECRETS increases power over the baseline method by $\boldsymbol{6}$-$\boldsymbol{54\%}$ (average: 21.5%, standard deviation: 15.8%).

Semi-Supervised Learning for Fetal Brain MRI Quality Assessment with ROI consistency

Fetal brain MRI is useful for diagnosing brain abnormalities but is challenged by fetal motion. The current protocol for T2-weighted fetal brain MRI is not robust to motion so image volumes are degraded by inter- and intra- slice motion artifacts. Besides, manual annotation for fetal MR image quality assessment are usually time-consuming. Therefore, in this work, a semi-supervised deep learning method that detects slices with artifacts during the brain volume scan is proposed. Our method is based on the mean teacher model, where we not only enforce consistency between student and teacher models on the whole image, but also adopt an ROI consistency loss to guide the network to focus on the brain region. The proposed method is evaluated on a fetal brain MR dataset with 11,223 labeled images and more than 200,000 unlabeled images. Results show that compared with supervised learning, the proposed method can improve model accuracy by about 6\% and outperform other state-of-the-art semi-supervised learning methods. The proposed method is also implemented and evaluated on an MR scanner, which demonstrates the feasibility of online image quality assessment and image reacquisition during fetal MR scans.