The New England Journal of Statistics in Data Science

Historically, the primary objective of Phase I clinical trials has been to pick an optimal dose in terms of patient safety, referred to as the maximum tolerated dose (MTD). Most of these trials recommend a “one-size-fits-all” dose for the patient population being studied, while also solely focusing on short-term adverse events. Often patient heterogeneity exists so that group-specific dose selection is of interest. To address the issue of patient heterogeneity, several dose-finding methods have been proposed, including the shift model framework based on the Continual Reassessment Method (CRM). Additionally, for many cancer therapies, relevant toxicities may be defined by participants experiencing adverse events at any point over a long evaluation window, resulting in pending outcomes when new participants need to be assigned a dose. By leveraging the CRM, the time-to-event continual reassessment method (TITE-CRM) provides a feasible approach for addressing this issue. Motivated by a Phase I trial involving radiotherapy that included two patient groups conducted at the University of Virginia, we have developed a hybrid design that combines elements from the TITE-CRM and the shift model framework. This approach helps address patient heterogeneity and late-onset toxicity simultaneously. We illustrate how to perform a dose-finding trial using the proposed design, and compare its operating characteristics to other suggested methods in the field by conducting a simulation study. The shift model TITE-CRM is shown to be a practical design with good operating characteristics in regard to selecting the correct MTD in each group. An R package is also being developed, allowing investigators to provide group-specific MTD recommendations by applying the proposed design, in addition to providing operating characteristics for custom simulation settings.

Estimating a prediction function is a fundamental component of many data analyses. The super learner ensemble, a particular implementation of stacking, has desirable theoretical properties and has been used successfully in many applications. Dimension reduction can be accomplished by using variable screening algorithms (screeners), including the lasso, within the ensemble prior to fitting other prediction algorithms. However, the performance of a super learner using the lasso for dimension reduction has not been fully explored in cases where the lasso is known to perform poorly. We provide empirical results that suggest that a diverse set of candidate screeners should be used to protect against poor performance of any one screener, similar to the guidance for choosing a library of prediction algorithms for the super learner. These results are further illustrated through the analysis of HIV-1 antibody data.

The high cost of drug development and the relatively low success rates of phase III clinical trials highlight the need for improved and reasonably sized phase II trial designs, especially when responses observed in treatment and control could not lead to a clear-cut decision warranting further studies. To this end, we propose a three-outcome dual-criterion randomized (TDR) trial design, which implements inconclusive region sculpting using boundaries defined by both statistically significant differences between treatment and control as well as the clinical relevance of treatment responses. We provide statistical justifications for the TDR design in both one-stage and two-stage trial settings. Additionally, we evaluate its operating characteristics through a comparison with existing designs. The proposed design is shown able to achieve sample size saving and type II error reduction while controlling the type I error at a marginal cost of power reduction. Lastly, robustness under various deviations from the assumed control response rate is also demonstrated.

Machine learning models, particularly the black-box models, are widely favored for their outstanding predictive capabilities. However, they often face scrutiny and criticism due to the lack of interpretability. Paradoxically, their strong predictive capabilities may indicate a deep understanding of the underlying data, implying significant potential for interpretation. Leveraging the emerging concept of knowledge distillation, we introduce the method of knowledge distillation decision tree (KDDT). This method enables the distillation of knowledge about the data from a black-box model into a decision tree, thereby facilitating the interpretation of the black-box model. Essential attributes for a good interpretable model include simplicity, stability, and predictivity. The primary challenge of constructing an interpretable tree lies in ensuring structural stability under the randomness of the training data. KDDT is developed with the theoretical foundations demonstrating that structure stability can be achieved under mild assumptions. Furthermore, we propose the hybrid KDDT to achieve both simplicity and predictivity. An efficient algorithm is provided for constructing the hybrid KDDT. Simulation studies and a real-data analysis validate the hybrid KDDT’s capability to deliver accurate and reliable interpretations. KDDT is an excellent interpretable model with great potential for practical applications.

Conventional methods for analyzing composite endpoints in clinical trials often only focus on the time to the first occurrence of all events in the composite. Therefore, they have inherent limitations because the individual patients’ first event can be the outcome of lesser clinical importance. To overcome this limitation, the concept of the win ratio (WR), which accounts for the relative priorities of the components and gives appropriate priority to the more clinically important event, was examined. For example, because mortality has a higher priority than hospitalization, it is reasonable to give a higher priority when obtaining the WR. In this paper, we evaluate three innovative WR methods (stratified matched, stratified unmatched, and unstratified unmatched) for two and multiple components under binary and survival composite endpoints. We compare these methods to traditional ones, including the Cox regression, O’Brien’s rank-sum-type test, and the contingency table for controlling study Type I error rate. We also incorporate these approaches into two-stage enrichment designs with the possibility of sample size adaptations to gain efficiency for rare disease studies.

In oncology therapy development, Simon’s two-stage design is commonly employed in early-phase clinical trials to assess the preliminary efficacy of a single dose, typically the maximum tolerable dose (MTD) or the maximum assessed dose (MAD). In this design, a dose may be terminated at the first stage if the anti-tumor activity is insufficient or it may proceed to the second stage for further evaluation with more subjects. To enhance the design for better benefit-risk profile dose selection and to meet the increasing needs for study designs that explore dose-response relationships, we extend Simon’s two-stage design to evaluate two doses and to include early termination for success in addition to futility. The proposed method derives decision rules and sample sizes for optimal study designs that minimize the expected or overall sample sizes while controlling type I error and meeting desired power.

While randomized trials may be the gold standard for evaluating the effectiveness of the treatment intervention, in some special circumstances, single-arm clinical trials utilizing external control may be considered. The causal treatment effect of interest for single-arm trials is usually the average treatment effect on the treated (ATT) rather than the average treatment effect (ATE). Although methods have been developed to estimate the ATT, the selection and use of these methods require a thorough comparison and in-depth understanding of the advantages and disadvantages of these methods. In this study, we conducted simulations under different identifiability assumptions to compare the performance metrics (e.g., bias, standard deviation (SD), mean squared error (MSE), type I error rate) for a variety of methods, including the regression model, propensity score matching (PSM), Mahalanobis distance matching (MDM), coarsened exact matching, inverse probability weighting, augmented inverse probability weighting (AIPW), AIPW with SuperLearner, and targeted maximum likelihood estimator (TMLE) with SuperLearner.

The evolving focus in statistics and data science education highlights the growing importance of computing. This paper presents the Data Jamboree, a live event that combines computational methods with traditional statistical techniques to address real-world data science problems. Participants, ranging from novices to experienced users, followed workshop leaders in using open-source tools like Julia, Python, and R to perform tasks such as data cleaning, manipulation, and predictive modeling. The Jamboree showcased the educational benefits of working with open data, providing participants with practical, hands-on experience. We compared the tools in terms of efficiency, flexibility, and statistical power, with Julia excelling in performance, Python in versatility, and R in statistical analysis and visualization. The paper concludes with recommendations for designing similar events to encourage collaborative learning and critical thinking in data science.

Observations of groundwater pollutants, such as arsenic or Perfluorooctane sulfonate (PFOS), are riddled with left censoring. These measurements have an impact on the health and lifestyle of the populace. Left censoring of these spatially correlated observations is usually addressed by applying Gaussian processes (GPs), which have theoretical advantages. However, this comes with a challenging computational complexity of $\mathcal{O}({n^{3}})$, impractical for large datasets. Additionally, a sizable proportion of the left-censored data creates further bottlenecks since the likelihood computation now involves an intractable high-dimensional integral of the multivariate Gaussian density. In this article, we tackle these two problems simultaneously by approximating the GP with a Gaussian Markov random field (GMRF) approach that exploits an explicit link between a GP with Matérn correlation function and a GMRF using stochastic partial differential equations (SPDEs). We introduce a GMRF-based measurement error into the model, which alleviates the likelihood computation for the censored data, drastically improving the computational speed while maintaining admirable accuracy. Our approach demonstrates robustness and substantial computational scalability compared to state-of-the-art methods for censored spatial responses across various simulation settings. Finally, the fit of this fully Bayesian model to the concentration of PFOS in groundwater available at 24,959 sites across California, where 46.62% responses are censored, produces prediction surface and uncertainty quantification in real-time, thereby substantiating the applicability and scalability of the proposed method. Code for implementation is made available via GitHub.