A targeted learning (TL) framework is developed to estimate the difference in the restricted mean survival time (RMST) for a clinical trial with time-to-event outcomes. The approach starts by defining the target estimand as the RMST difference between investigational and control treatments. Next, an efficient estimation method is introduced: a targeted minimum loss estimator (TMLE) utilizing pseudo-observations. Moreover, a version of the copy reference (CR) approach is developed to perform a sensitivity analysis for right-censoring. The proposed TL framework is demonstrated using a real data application.

The ICH E9(R1) guideline presents a framework for clinical trials to align planning, design, conduct, analysis, and interpretation (ICH, 2020). The three key steps in the framework are: estimand, estimator, and sensitivity analysis (Mallinckrodt et al., 2020). ICH E9(R1) highlights the importance of dealing with intercurrent events (ICEs), which are defined as: "Events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question of interest. It is necessary to address intercurrent events when describing the clinical question of interest in order to precisely define the treatment effect that is to be estimated." ICH E9(R1) proposes five strategies for dealing with ICEs in clinical trials with quantitative outcomes and categorical outcomes: treatment policy strategy, hypothetical strategy, composite variable strategy, while-on-treatment strategy, and principal stratum strategy.

Generating unique molecules with biochemically desired properties to serve as viable drug candidates is a difficult task that requires specialized domain expertise. In recent years, diffusion models have shown promising results in accelerating the drug design process through AI-driven molecular generation. However, training these models requires massive amounts of data, which are often isolated in proprietary silos. OpenFL is a federated learning framework that enables privacy-preserving collaborative training across these decentralized data sites. In this work, we present a federated discrete denoising diffusion model that was trained using OpenFL. The federated model achieves comparable performance with a model trained on centralized data when evaluating the uniqueness and validity of the generated molecules. This demonstrates the utility of federated learning in the drug design process. OpenFL is available at: https://github.com/securefederatedai/openfl

Age prediction using brain imaging, such as MRIs, has achieved promising results, with several studies identifying the model's residual as a potential biomarker for chronic disease states. In this study, we developed a brain age predictive model using a dataset of 1,220 U.S. veterans (18--80 years) and convolutional neural networks (CNNs) trained on two-dimensional slices of axial T2-weighted fast spin-echo and T2-weighted fluid attenuated inversion recovery MRI images. The model, incorporating a degree-3 polynomial ensemble, achieved an $R^{2}$ of 0.816 on the testing set. Images were acquired at the level of the anterior commissure and the frontal horns of the lateral ventricles. Residual analysis was performed to assess its potential as a biomarker for five ICD-coded conditions: hypertension (HTN), diabetes mellitus (DM), mild traumatic brain injury (mTBI), illicit substance abuse/dependence (SAD), and alcohol abuse/dependence (AAD). Residuals grouped by the number of ICD-coded conditions demonstrated different trends that were statistically significant ($p = 0.002$), suggesting a relationship between disease states and predicted brain age. This association was particularly pronounced in patients over 49 years, where negative residuals (indicating advanced brain aging) correlated with the presence of multiple ICD codes. These findings support the potential of residuals as biomarkers for detecting latent health conditions.

Kernel ridge regression (KRR) has recently attracted renewed interest due to its potential for explaining the transient effects, such as double descent, that emerge during neural network training. In this work, we study how the alignment between the target function and the kernel affects the performance of the KRR. We focus on the truncated KRR (TKRR) which utilizes an additional parameter that controls the spectral truncation of the kernel matrix. We show that for polynomial alignment, there is an \emph{over-aligned} regime, in which TKRR can achieve a faster rate than what is achievable by full KRR. The rate of TKRR can improve all the way to the parametric rate, while that of full KRR is capped at a sub-optimal value. This shows that target alignemnt can be better leveraged by utilizing spectral truncation in kernel methods. We also consider the bandlimited alignment setting and show that the regularization surface of TKRR can exhibit transient effects including multiple descent and non-monotonic behavior. Our results show that there is a strong and quantifable relation between the shape of the \emph{alignment spectrum} and the generalization performance of kernel methods, both in terms of rates and in finite samples.

Kernels ensuing from tree ensembles such as random forest (RF) or gradient boosted trees (GBT), when used for kernel learning, have been shown to be competitive to their respective tree ensembles (particularly in higher dimensional scenarios). On the other hand, it has been also shown that performance of the kernel algorithms depends on the degree of the kernel-target alignment. However, the kernel-target alignment for kernel learning based on the tree ensembles has not been investigated and filling this gap is the main goal of our work. Using the eigenanalysis of the kernel matrix, we demonstrate that for continuous targets good performance of the tree-based kernel learning is associated with strong kernel-target alignment. Moreover, we show that well performing tree ensemble based kernels are characterized by strong target aligned components that are expressed through scalar products between the eigenvectors of the kernel matrix and the target. This suggests that when tree ensemble based kernel learning is successful, relevant information for the supervised problem is concentrated near lower dimensional manifold spanned by the target aligned components. Persistence of the strong target aligned components in tree ensemble based kernels is further supported by sensitivity analysis via landmark learning. In addition to a comprehensive simulation study, we also provide experimental results from several real life data sets that are in line with the simulations.

Tree based ensembles such as Breiman's random forest (RF) and Gradient Boosted Trees (GBT) can be interpreted as implicit kernel generators, where the ensuing proximity matrix represents the data-driven tree ensemble kernel. Kernel perspective on the RF has been used to develop a principled framework for theoretical investigation of its statistical properties. Recently, it has been shown that the kernel interpretation is germane to other tree-based ensembles e.g. GBTs. However, practical utility of the links between kernels and the tree ensembles has not been widely explored and systematically evaluated. Focus of our work is investigation of the interplay between kernel methods and the tree based ensembles including the RF and GBT. We elucidate the performance and properties of the RF and GBT based kernels in a comprehensive simulation study comprising of continuous and binary targets. We show that for continuous targets, the RF/GBT kernels are competitive to their respective ensembles in higher dimensional scenarios, particularly in cases with larger number of noisy features. For the binary target, the RF/GBT kernels and their respective ensembles exhibit comparable performance. We provide the results from real life data sets for regression and classification to show how these insights may be leveraged in practice. Overall, our results support the tree ensemble based kernels as a valuable addition to the practitioner's toolbox. Finally, we discuss extensions of the tree ensemble based kernels for survival targets, interpretable prototype and landmarking classification and regression. We outline future line of research for kernels furnished by Bayesian counterparts of the frequentist tree ensembles.

Breiman's random forest (RF) can be interpreted as an implicit kernel generator,where the ensuing proximity matrix represents the data-driven RF kernel. Kernel perspective on the RF has been used to develop a principled framework for theoretical investigation of its statistical properties. However, practical utility of the links between kernels and the RF has not been widely explored and systematically evaluated.Focus of our work is investigation of the interplay between kernel methods and the RF. We elucidate the performance and properties of the data driven RF kernels used by regularized linear models in a comprehensive simulation study comprising of continuous, binary and survival targets. We show that for continuous and survival targets, the RF kernels are competitive to RF in higher dimensional scenarios with larger number of noisy features. For the binary target, the RF kernel and RF exhibit comparable performance. As the RF kernel asymptotically converges to the Laplace kernel, we included it in our evaluation. For most simulation setups, the RF and RFkernel outperformed the Laplace kernel. Nevertheless, in some cases the Laplace kernel was competitive, showing its potential value for applications. We also provide the results from real life data sets for the regression, classification and survival to illustrate how these insights may be leveraged in practice.Finally, we discuss further extensions of the RF kernels in the context of interpretable prototype and landmarking classification, regression and survival. We outline future line of research for kernels furnished by Bayesian counterparts of the RF.

Job title: Business Systems Analyst with RPA or Machine Learning EXP Location: North Chicago, IL Duration: 6 months Preferred: • Proven BSA who has worked on RPA or Machine Learning applications Required • Over 8 years' experience in Business Analysis • Experience in Waterfall and Agile Software Development Life Cycle (SDLC) methodologies • Experience in working in an Agile environment • Experience in data modeling, workflow modeling, and use case development.