The New England Journal of Statistics in Data Science

Efficacy testing is a cornerstone of clinical trials, ensuring that medical interventions achieve their intended therapeutic effects. Over the decades, a wide range of statistical methodologies have been developed to address the complexities of clinical trial data, including parametric, nonparametric, Bayesian, and machine learning approaches. Parametric methods, such as t-tests, ANOVA, and LMMs, have traditionally been the foundation of efficacy testing due to their efficiency under well-defined assumptions. Nonparametric techniques, including the Friedman test, Brunner-Munzel test, and modern extensions like nparLD, have emerged as robust alternatives, particularly for skewed, ordinal, or non-normal data. Bayesian methodologies have enabled the incorporation of prior information and uncertainty quantification, while machine learning techniques, such as deep learning and reinforcement learning, are revolutionizing trial designs and outcome predictions. Despite these advancements, significant gaps remain, including challenges in handling high-dimensional data, missingness, and ensuring equitable efficacy testing across diverse populations. This review provides a comprehensive overview of these statistical methods, highlighting their applications, strengths, limitations, and future directions. By bridging traditional statistical frameworks with modern computational techniques, the field can continue to advance toward more reliable and personalized clinical trial methodologies.

The timing of longitudinal measurements may depend upon outcome or disease severity. In biomedical studies relying on clinical encounter data, patients often have dense, irregular collections of visit data when suffering a worse health condition. In parallel, the longitudinal measurements may be impacted by the period of irregular visiting. Ignoring the impact of the outcome-dependent visiting process when constructing a longitudinal disease progression model can produce biased results. We propose a Bayesian joint model linking a mixed-effects model for the longitudinal marker and Weibull proportional hazards model with a log frailty for the visiting process, adjusting both longitudinal marker and event processes with covariates. We examine different random effect structures and performance characterizing disease trajectory. Motivated by clinical data on cystic fibrosis lung disease, we estimate the longitudinal process for lung function decline. Individuals with lower lung function tend to have more frequent clinical visits than those with higher lung function. Simulation studies suggest that incorporating a time-dependent Gaussian process is more important for model fit than adding the survival model via joint modeling; the random intercepts model exhibits maximum bias, especially when there is an outcome-dependent visiting process.

Time-to-event (TTE) endpoints are widely used in drug development and biomedical research. Traditional statistical models, for example the Cox regression model, have been used to predict TTE outcomes. Recent studies have also employed flexible machine learning (ML) methods, for example, tree models, to obtain superior prediction performance. In addition, post-baseline time-varying predictors have recently been reported to improve prediction using ML methods. In this study, we applied the Cox model and ML methods to predict the onset of TTE with both baseline and post-baseline predictors. We evaluated the predictive performance of these models using various metrics, including the time-dependent area under the receiver operating characteristic curve (AUC), the concordance index (C-index), and integrated Brier scores. We also used these metrics as criteria to guide the selection of predictors in the predictive models. Our findings indicate that the Cox model remains a robust choice, often comparable to ML methods in moderate sample sizes, provided the proportional hazards assumption holds. However, tree-based methods demonstrate superior performance in capturing complex, nonlinear interactions, albeit requiring larger sample sizes to stabilize predictions.

This study explores the application of the t-link model in high-dimensional variable selection for binary regression. The t-link model provides flexibility in binary modeling and offers robust inference in the presence of outliers, making it a preferable alternative to the commonly used probit and logit links. To address the computational challenges posed by a large number of covariates, the skinny Gibbs algorithm is employed, and the consistency of variable selection under this approximate algorithm is established. These advancements in both computational and theoretical perspectives enhance the practicality and ease of implementing the t-link model. The performance of the t-link model, with a specified degrees of freedom, is compared to logit link and the probit link through simulation studies and an application to PCR data. The results demonstrate the robustness and computational efficiency of the proposed method.

Social networks primarily focus on the phenomenon of the contagion effect when examining behavior patterns within specific social groups. However, the impact of peer effects is characterized by the tendency to imitate the behaviors of friends and the selection process, where individuals tend to affiliate with others sharing similar traits, significantly contributing to shaping social behaviors that are frequently interconnecting. This article presents a Bayesian approach that uses latent-space estimation methods to detect and examine contagion effects, considering the impact of social selection. The research provides a methodological explanation, followed by a sequence of simulation trials designed to explore operational functionalities and possible real-world applications. To illustrate the potential correlation between changes in alcohol use and the influence of social networks, this study concludes by presenting an example of adolescent drinking behavior.

In extreme value analysis, the impact of rounding in data, a form of quantization, on statistical inferences beyond point estimation has not been comprehensively studied. This paper addresses these challenges by considering rounded data as interval-censored. The maximum likelihood estimators of the model parameters tailored to account for interval censoring are asymptotically unbiased and efficient. Further, we adapt classic goodness-of-fit tests, such as the Anderson-Darling test, for rounded data based on the maximum likelihood estimator. The resulting tests have appropriate sizes and considerable power. One application of such tests is threshold selection for the peak over threshold approach in extreme value analysis. The efficacy of our estimation approach and the goodness-of-fit tests are demonstrated through a simulation study involving data rounded from generalized Pareto distributions. Applying this method to precipitation data from 18 stations in eastern Washington, an area with typically low precipitation and expecting a significant rounding effect, we observe narrower interval estimates of return levels.

Clinical trial design for rare diseases can be challenging due to limited data, heterogeneous clinical manifestations and progression, and a frequent lack of adequate knowledge about the disease. Multiple endpoints are usually used to collectively assess the effectiveness of the investigational drug on multiple aspects of the disease. Here we propose an adaptive design based on the promising zone framework, allowing for sample size re-estimation (SSR) using interim data for a clinical trial involving multiple endpoints. The proposed SSR procedure incorporates two global tests: the ordinary least squares (OLS) test and the nonparametric permutation test. We consider two SSR approaches: one is based on power (SSR-Power) and the other on conditional power (SSR-CP). Simulation results show that the adaptive design achieves type I error control and satisfactory power. Compared with the permutation test, the OLS test has improved type I error control when the sample size is small and the timing of the interim analysis is early; while the permutation test achieves slightly higher power in most scenarios. Regarding the SSR methods, SSR-CP consistently achieves higher power than SSR-Power but often requires a larger sample size and more frequently reaches the maximum allowable sample size. The proposed design is particularly useful when the trial has a small initial sample size and has opportunity to adjust the sample size at an interim analysis to achieve adequate power.

Background: Generalized estimating equations (GEE) and mixed-model repeated measures (MMRM) can handle longitudinal continuous outcomes when modeling the mean with time included categorically. Due to small sample sizes in rare diseases, a compound symmetry (CS) covariance pattern is sometimes adopted. In this setting, there is scant literature in the rare disease community that provide practical advice about the use of both methods based on real datasets from trials conducted in rare diseases, including when to use the sandwich variance estimator with or without a bias correction.

Cell boundary information is crucial for analyzing cell behaviors from time-lapse microscopy videos. Existing supervised cell segmentation tools, such as ImageJ, require tuning various parameters and rely on restrictive assumptions about the shape of the objects. While recent supervised segmentation tools based on convolutional neural networks enhance accuracy, they depend on high-quality labeled images, making them unsuitable for segmenting new types of objects not in the database. We developed a novel unsupervised cell segmentation algorithm based on fast Gaussian processes for noisy microscopy images without the need for parameter tuning or restrictive assumptions about the shape of the object. We derived robust thresholding criteria adaptive for heterogeneous images containing distinct brightness at different parts to separate objects from the background, and employed watershed segmentation to distinguish touching cell objects. Both simulated studies and real-data analysis of large microscopy images demonstrate the scalability and accuracy of our approach compared with the alternatives.