Motivation: Biomedical studies increasingly produce multi-view high-dimensional datasets (e.g., multi-omics) that demand integrative analysis. Existing canonical correlation analysis (CCA) and generalized CCA methods address at most two of the following three key aspects simultaneously: (i) nonlinear dependence, (ii) sparsity for variable selection, and (iii) generalization to more than two data views. There is a pressing need for CCA methods that integrate all three aspects to effectively analyze multi-view high-dimensional data. Results: We propose three nonlinear, sparse, generalized CCA methods, HSIC-SGCCA, SA-KGCCA, and TS-KGCCA, for variable selection in multi-view high-dimensional data. These methods extend existing SCCA-HSIC, SA-KCCA, and TS-KCCA from two-view to multi-view settings. While SA-KGCCA and TS-KGCCA yield multi-convex optimization problems solved via block coordinate descent, HSIC-SGCCA introduces a necessary unit-variance constraint previously ignored in SCCA-HSIC, resulting in a nonconvex, non-multiconvex problem. We efficiently address this challenge by integrating the block prox-linear method with the linearized alternating direction method of multipliers. Simulations and TCGA-BRCA data analysis demonstrate that HSIC-SGCCA outperforms competing methods in multi-view variable selection. Availability and implementation: Code is available at https://github.com/Rows21/NSGCCA.

Drug development is a critical but notoriously resource- and time-consuming process. In this manuscript, we develop a novel generative artificial intelligence (genAI) method DiffSMol to facilitate drug development. DiffSmol generates 3D binding molecules based on the shapes of known ligands. DiffSMol encapsulates geometric details of ligand shapes within pre-trained, expressive shape embeddings and then generates new binding molecules through a diffusion model. DiffSMol further modifies the generated 3D structures iteratively via shape guidance to better resemble the ligand shapes. It also tailors the generated molecules toward optimal binding affinities under the guidance of protein pockets. Here, we show that DiffSMol outperforms the state-of-the-art methods on benchmark datasets. When generating binding molecules resembling ligand shapes, DiffSMol with shape guidance achieves a success rate 61.4%, substantially outperforming the best baseline (11.2%), meanwhile producing molecules with novel molecular graph structures. DiffSMol with pocket guidance also outperforms the best baseline in binding affinities by 13.2%, and even by 17.7% when combined with shape guidance. Case studies for two critical drug targets demonstrate very favorable physicochemical and pharmacokinetic properties of the generated molecules, thus, the potential of DiffSMol in developing promising drug candidates.

Conditional independence (CI) testing is a fundamental task in modern statistics and machine learning. The conditional randomization test (CRT) was recently introduced to test whether two random variables, $X$ and $Y$, are conditionally independent given a potentially high-dimensional set of random variables, $Z$. The CRT operates exceptionally well under the assumption that the conditional distribution $X|Z$ is known. However, since this distribution is typically unknown in practice, accurately approximating it becomes crucial. In this paper, we propose using conditional diffusion models (CDMs) to learn the distribution of $X|Z$. Theoretically and empirically, it is shown that CDMs closely approximate the true conditional distribution. Furthermore, CDMs offer a more accurate approximation of $X|Z$ compared to GANs, potentially leading to a CRT that performs better than those based on GANs. To accommodate complex dependency structures, we utilize a computationally efficient classifier-based conditional mutual information (CMI) estimator as our test statistic. The proposed testing procedure performs effectively without requiring assumptions about specific distribution forms or feature dependencies, and is capable of handling mixed-type conditioning sets that include both continuous and discrete variables. Theoretical analysis shows that our proposed test achieves a valid control of the type I error. A series of experiments on synthetic data demonstrates that our new test effectively controls both type-I and type-II errors, even in high dimensional scenarios.

Accurate prediction of chemical reaction yields is crucial for optimizing organic synthesis, potentially reducing time and resources spent on experimentation. With the rise of artificial intelligence (AI), there is growing interest in leveraging AI-based methods to accelerate yield predictions without conducting in vitro experiments. We present log-RRIM, an innovative graph transformer-based framework designed for predicting chemical reaction yields. Our approach implements a unique local-to-global reaction representation learning strategy. This approach initially captures detailed molecule-level information and then models and aggregates intermolecular interactions, ensuring that the impact of varying-sizes molecular fragments on yield is accurately accounted for. Another key feature of log-RRIM is its integration of a cross-attention mechanism that focuses on the interplay between reagents and reaction centers. This design reflects a fundamental principle in chemical reactions: the crucial role of reagents in influencing bond-breaking and formation processes, which ultimately affect reaction yields. log-RRIM outperforms existing methods in our experiments, especially for medium to high-yielding reactions, proving its reliability as a predictor. Its advanced modeling of reactant-reagent interactions and sensitivity to small molecular fragments make it a valuable tool for reaction planning and optimization in chemical synthesis. The data and codes of log-RRIM are accessible through https://github.com/ninglab/Yield_log_RRIM.

In this paper, we propose a novel framework, the Sampling-guided Heterogeneous Graph Neural Network (SHT-GNN), to effectively tackle the challenge of missing data imputation in longitudinal studies. Unlike traditional methods, which often require extensive preprocessing to handle irregular or inconsistent missing data, our approach accommodates arbitrary missing data patterns while maintaining computational efficiency. SHT-GNN models both observations and covariates as distinct node types, connecting observation nodes at successive time points through subject-specific longitudinal subnetworks, while covariate-observation interactions are represented by attributed edges within bipartite graphs. By leveraging subject-wise mini-batch sampling and a multi-layer temporal smoothing mechanism, SHT-GNN efficiently scales to large datasets, while effectively learning node representations and imputing missing data. Extensive experiments on both synthetic and real-world datasets, including the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, demonstrate that SHT-GNN significantly outperforms existing imputation methods, even with high missing data rates. The empirical results highlight SHT-GNN's robust imputation capabilities and superior performance, particularly in the context of complex, large-scale longitudinal data.

In this paper, we aim to address a significant challenge in the field of missing data imputation: identifying and leveraging the interdependencies among features to enhance missing data imputation for tabular data. We introduce a novel framework named the Bipartite and Complete Directed Graph Neural Network (BCGNN). Within BCGNN, observations and features are differentiated as two distinct node types, and the values of observed features are converted into attributed edges linking them. The bipartite segment of our framework inductively learns embedding representations for nodes, efficiently utilizing the comprehensive information encapsulated in the attributed edges. In parallel, the complete directed graph segment adeptly outlines and communicates the complex interdependencies among features. When compared to contemporary leading imputation methodologies, BCGNN consistently outperforms them, achieving a noteworthy average reduction of 15% in mean absolute error for feature imputation tasks under different missing mechanisms. Our extensive experimental investigation confirms that an in-depth grasp of the interdependence structure substantially enhances the model's feature embedding ability. We also highlight the model's superior performance in label prediction tasks involving missing data, and its formidable ability to generalize to unseen data points.

Chemistry plays a crucial role in many domains, such as drug discovery and material science. While large language models (LLMs) such as GPT-4 exhibit remarkable capabilities on natural language processing tasks, existing work shows their performance on chemistry tasks is discouragingly low. In this paper, however, we demonstrate that our developed LLMs can achieve very strong results on a comprehensive set of chemistry tasks, outperforming the most advanced GPT-4 across all the tasks by a substantial margin and approaching the SoTA task-specific models. The key to our success is a large-scale, comprehensive, high-quality dataset for instruction tuning named SMolInstruct. It contains 14 meticulously selected chemistry tasks and over three million high-quality samples, laying a solid foundation for training and evaluating LLMs for chemistry. Based on SMolInstruct, we fine-tune a set of open-source LLMs, among which, we find that Mistral serves as the best base model for chemistry tasks. We further conduct analysis on the impact of trainable parameters, providing insights for future research.

Retrosynthesis is the process of determining the set of reactant molecules that can react to form a desired product. Semi-template-based retrosynthesis methods, which imitate the reverse logic of synthesis reactions, first predict the reaction centers in the products, and then complete the resulting synthons back into reactants. These methods enable necessary interpretability and high practical utility to inform synthesis planning. We develop a new offline-online reinforcement learning method RLSynC for synthon completion in semi-template-based methods. RLSynC assigns one agent to each synthon, all of which complete the synthons by conducting actions step by step in a synchronized fashion. RLSynC learns the policy from both offline training episodes and online interactions which allow RLSynC to explore new reaction spaces. RLSynC uses a forward synthesis model to evaluate the likelihood of the predicted reactants in synthesizing a product, and thus guides the action search. We compare RLSynC with the state-of-the-art retrosynthesis methods. Our experimental results demonstrate that RLSynC can outperform these methods with improvement as high as 14.9% on synthon completion, and 14.0% on retrosynthesis, highlighting its potential in synthesis planning.

Ligand-based drug design aims to identify novel drug candidates of similar shapes with known active molecules. In this paper, we formulated an in silico shape-conditioned molecule generation problem to generate 3D molecule structures conditioned on the shape of a given molecule. To address this problem, we developed a translation-and rotation-equivariant shape-guided generative model ShapeMol . ShapeMol consists of an equivariant shape encoder that maps molecular surface shapes into latent embeddings, and an equivariant diffusion model that generates 3D molecules based on these embeddings. Experimental results show that ShapeMol can generate novel, diverse, drug-like molecules that retain 3D molecular shapes similar to the given shape condition. These results demonstrate the potential of ShapeMol in designing drug candidates of desired 3D shapes binding to protein target pockets.

Retrosynthesis is a procedure where a target molecule is transformed into potential reactants and thus the synthesis routes can be identified. Recently, computational approaches have been developed to accelerate the design of synthesis routes. In this paper, we develop a generative framework $\mathsf{G^2Retro}$ for one-step retrosynthesis prediction. $\mathsf{G^2Retro}$ imitates the reversed logic of synthetic reactions. It first predicts the reaction centers in the target molecules (products), identifies the synthons needed to assemble the products, and transforms these synthons into reactants. $\mathsf{G^2Retro}$ defines a comprehensive set of reaction center types, and learns from the molecular graphs of the products to predict potential reaction centers. To complete synthons into reactants, $\mathsf{G^2Retro}$ considers all the involved synthon structures and the product structures to identify the optimal completion paths, and accordingly attaches small substructures sequentially to the synthons. Here we show that $\mathsf{G^2Retro}$ is able to better predict the reactants for given products in the benchmark dataset than the state-of-the-art methods.