Generative Flows on Synthetic Pathway for Drug Design

Generative models in drug discovery have recently gained attention as efficient alternatives to brute-force virtual screening. However, most existing models do not account for synthesizability, limiting their practical use in real-world scenarios. In this paper, we propose RxnFlow, which sequentially assembles molecules using predefined molecular building blocks and chemical reaction templates to constrain the synthetic chemical pathway. We then train on this sequential generating process with the objective of generative flow networks (GFlowNets) to generate both highly rewarded and diverse molecules. To mitigate the large action space of synthetic pathways in GFlowNets, we implement a novel action space subsampling method. This enables RxnFlow to learn generative flows over extensive action spaces comprising combinations of 1.2 million building blocks and 71 reaction templates without significant computational overhead. Additionally, RxnFlow can employ modified or expanded action spaces for generation without retraining, allowing for the introduction of additional objectives or the incorporation of newly discovered building blocks. We experimentally demonstrate that RxnFlow outperforms existing reaction-based and fragment-based models in pocket-specific optimization across various target pockets. Furthermore, RxnFlow achieves state-of-the-art performance on CrossDocked2020 for pocket-conditional generation, with an average Vina score of -8.85kcal/mol and 34.8% synthesizability.

UnPaSt: unsupervised patient stratification by differentially expressed biclusters in omics data

Most complex diseases, including cancer and non-malignant diseases like asthma, have distinct molecular subtypes that require distinct clinical approaches. However, existing computational patient stratification methods have been benchmarked almost exclusively on cancer omics data and only perform well when mutually exclusive subtypes can be characterized by many biomarkers. Here, we contribute with a massive evaluation attempt, quantitatively exploring the power of 22 unsupervised patient stratification methods using both, simulated and real transcriptome data. From this experience, we developed UnPaSt (https://apps.cosy.bio/unpast/) optimizing unsupervised patient stratification, working even with only a limited number of subtype-predictive biomarkers. We evaluated all 23 methods on real-world breast cancer and asthma transcriptomics data. Although many methods reliably detected major breast cancer subtypes, only few identified Th2-high asthma, and UnPaSt significantly outperformed its closest competitors in both test datasets. Essentially, we showed that UnPaSt can detect many biologically insightful and reproducible patterns in omic datasets.

Geometric-informed GFlowNets for Structure-Based Drug Design

The rise of cost involved with drug discovery and current speed of which they are discover, underscore the need for more efficient structure-based drug design (SBDD) methods. We employ Generative Flow Networks (GFlowNets), to effectively explore the vast combinatorial space of drug-like molecules, which traditional virtual screening methods fail to cover. We introduce a novel modification to the GFlowNet framework by incorporating trigonometrically consistent embeddings, previously utilized in tasks involving protein conformation and protein-ligand interactions, to enhance the model's ability to generate molecules tailored to specific protein pockets. We have modified the existing protein conditioning used by GFlowNets, blending geometric information from both protein and ligand embeddings to achieve more geometrically consistent embeddings. Experiments conducted using CrossDocked2020 demonstrated an improvement in the binding affinity between generated molecules and protein pockets for both single and multi-objective tasks, compared to previous work. Additionally, we propose future work aimed at further increasing the geometric information captured in protein-ligand interactions.

IceFormer: Accelerated Inference with Long-Sequence Transformers on CPUs

One limitation of existing Transformer-based models is that they cannot handle very long sequences as input since their self-attention operations exhibit quadratic time and space complexity. This problem becomes especially acute when Transformers are deployed on hardware platforms equipped only with CPUs. To address this issue, we propose a novel method for accelerating self-attention at inference time that works with pretrained Transformer models out-of-the-box without requiring retraining. We experiment using our method to accelerate various long-sequence Transformers, including a leading LLaMA 2-based LLM, on various benchmarks and demonstrate a greater speedup of 2.73x - 7.63x while retaining 98.6% - 99.6% of the accuracy of the original pretrained models. The code is available on our project website at https://yuzhenmao.github.io/IceFormer/.

Adversarially Balanced Representation for Continuous Treatment Effect Estimation

Individual treatment effect (ITE) estimation requires adjusting for the covariate shift between populations with different treatments, and deep representation learning has shown great promise in learning a balanced representation of covariates. However the existing methods mostly consider the scenario of binary treatments. In this paper, we consider the more practical and challenging scenario in which the treatment is a continuous variable (e.g. dosage of a medication), and we address the two main challenges of this setup. We propose the adversarial counterfactual regression network (ACFR) that adversarially minimizes the representation imbalance in terms of KL divergence, and also maintains the impact of the treatment value on the outcome prediction by leveraging an attention mechanism. Theoretically we demonstrate that ACFR objective function is grounded in an upper bound on counterfactual outcome prediction error. Our experimental evaluation on semi-synthetic datasets demonstrates the empirical superiority of ACFR over a range of state-of-the-art methods.

TacoGFN: Target Conditioned GFlowNet for Structure-Based Drug Design

We seek to automate the generation of drug-like compounds conditioned to specific protein pocket targets. Most current methods approximate the protein-molecule distribution of a finite dataset and, therefore struggle to generate molecules with significant binding improvement over the training dataset. We instead frame the pocket-conditioned molecular generation task as an RL problem and develop TacoGFN, a target conditional Generative Flow Network model. Our method is explicitly encouraged to generate molecules with desired properties as opposed to fitting on a pre-existing data distribution. To this end, we develop transformer-based docking score prediction to speed up docking score computation and propose TacoGFN to explore molecule space efficiently. Furthermore, we incorporate several rounds of active learning where generated samples are queried using a docking oracle to improve the docking score prediction. This approach allows us to accurately explore as much of the molecule landscape as we can afford computationally. Empirically, molecules generated using TacoGFN and its variants significantly outperform all baseline methods across every property (Docking score, QED, SA, Lipinski), while being orders of magnitude faster.

Semi-Supervised Junction Tree Variational Autoencoder for Molecular Property Prediction

Recent advances in machine learning have enabled accurate prediction of chemical properties. However, supervised machine learning methods in this domain often suffer from the label scarcity problem, due to the expensive nature of labeling chemical property experimentally. This research modifies state-of-the-art molecule generation method - Junction Tree Variational Autoencoder (JT-VAE) to facilitate semi-supervised learning on chemical property prediction. Furthermore, we force some latent variables to take on consistent and interpretable purposes such as representing toxicity via this partial supervision. We leverage JT-VAE architecture to learn an interpretable representation optimal for tasks ranging from molecule property prediction to conditional molecule generation, using a partially labelled dataset.

Subgroup Discovery in Unstructured Data

Subgroup discovery is a descriptive and exploratory data mining technique to identify subgroups in a population that exhibit interesting behavior with respect to a variable of interest. Subgroup discovery has numerous applications in knowledge discovery and hypothesis generation, yet it remains inapplicable for unstructured, high-dimensional data such as images. This is because subgroup discovery algorithms rely on defining descriptive rules based on (attribute, value) pairs, however, in unstructured data, an attribute is not well defined. Even in cases where the notion of attribute intuitively exists in the data, such as a pixel in an image, due to the high dimensionality of the data, these attributes are not informative enough to be used in a rule. In this paper, we introduce the subgroup-aware variational autoencoder, a novel variational autoencoder that learns a representation of unstructured data which leads to subgroups with higher quality. Our experimental results demonstrate the effectiveness of the method at learning subgroups with high quality while supporting the interpretability of the concepts.

A Comprehensive Survey on Deep Clustering: Taxonomy, Challenges, and Future Directions

Clustering is a fundamental machine learning task which has been widely studied in the literature. Classic clustering methods follow the assumption that data are represented as features in a vectorized form through various representation learning techniques. As the data become increasingly complicated and complex, the shallow (traditional) clustering methods can no longer handle the high-dimensional data type. With the huge success of deep learning, especially the deep unsupervised learning, many representation learning techniques with deep architectures have been proposed in the past decade. Recently, the concept of Deep Clustering, i.e., jointly optimizing the representation learning and clustering, has been proposed and hence attracted growing attention in the community. Motivated by the tremendous success of deep learning in clustering, one of the most fundamental machine learning tasks, and the large number of recent advances in this direction, in this paper we conduct a comprehensive survey on deep clustering by proposing a new taxonomy of different state-of-the-art approaches. We summarize the essential components of deep clustering and categorize existing methods by the ways they design interactions between deep representation learning and clustering. Moreover, this survey also provides the popular benchmark datasets, evaluation metrics and open-source implementations to clearly illustrate various experimental settings. Last but not least, we discuss the practical applications of deep clustering and suggest challenging topics deserving further investigations as future directions.

Causal Inference from Small High-dimensional Datasets

Many methods have been proposed to estimate treatment effects with observational data. Often, the choice of the method considers the application's characteristics, such as type of treatment and outcome, confounding effect, and the complexity of the data. These methods implicitly assume that the sample size is large enough to train such models, especially the neural network-based estimators. What if this is not the case? In this work, we propose Causal-Batle, a methodology to estimate treatment effects in small high-dimensional datasets in the presence of another high-dimensional dataset in the same feature space. We adopt an approach that brings transfer learning techniques into causal inference. Our experiments show that such an approach helps to bring stability to neural network-based methods and improve the treatment effect estimates in small high-dimensional datasets.