Michał Koziarski

Learning Decision Trees as Amortized Structure Inference

Mohammed Mahfoud

Ghait Boukachab

Alex Hernandez-Garcia

Stefan Bauer

Nikolay Malkin

Building predictive models for tabular data presents fundamental challenges, notably in scaling consistently, i.e., more resources translati… (voir plus)ng to better performance, and generalizing systematically beyond the training data distribution. Designing decision tree models remains especially challenging given the intractably large search space, and most existing methods rely on greedy heuristics, while deep learning inductive biases expect a temporal or spatial structure not naturally present in tabular data. We propose a hybrid amortized structure inference approach to learn predictive decision tree ensembles given data, formulating decision tree construction as a sequential planning problem. We train a deep reinforcement learning (GFlowNet) policy to solve this problem, yielding a generative model that samples decision trees from the Bayesian posterior. We show that our approach, DT-GFN, outperforms state-of-the-art decision tree and deep learning methods on standard classification benchmarks derived from real-world data, robustness to distribution shifts, and anomaly detection, all while yielding interpretable models with shorter description lengths. Samples from the trained DT-GFN model can be ensembled to construct a random forest, and we further show that the performance of scales consistently in ensemble size, yielding ensembles of predictors that continue to generalize systematically.

2025-03-10

ArXiv (prépublication)

Learning Decision Trees as Amortized Structure Inference

Mohammed Mahfoud

Ghait Boukachab

Alex Hernandez-Garcia

Stefan Bauer

Nikolay Malkin

2025-03-05

ICLR.cc/2025/Workshop/FPI (poster)

Action abstractions for amortized sampling

Oussama Boussif

Lena Nehale Ezzine

Joseph D Viviano

Moksh J. Jain

2025-01-22

ICLR.cc/2025/Conference (poster)

RGFN: Synthesizable Molecular Generation Using GFlowNets

Andrei Rekesh

Dmytro Shevchuk

Almer M. van der Sloot

Cheng-Hao Liu

Mike Tyers

Robert A. Batey

2024-09-25

NeurIPS.cc/2024/Conference (poster)

A high-throughput phenotypic screen combined with an ultra-large-scale deep learning-based virtual screening reveals novel scaffolds of antibacterial compounds

Gabriele Scalia

Steven T. Rutherford

Ziqing Lu

Kerry R. Buchholz

Nicholas Skelton

Kangway Chuang

Nathaniel Diamant

Jan-Christian Hütter

Jerome-Maxim Luescher

Anh Miu

Jeff Blaney

Leo Gendelev

Elizabeth Skippington

Greg Zynda

Nia Dickson

Aviv Regev

Man-Wah Tan

Tommasso Biancalani

The proliferation of multi-drug-resistant bacteria underscores an urgent need for novel antibiotics. Traditional discovery methods face chal… (voir plus)lenges due to limited chemical diversity, high costs, and difficulties in identifying structurally novel compounds. Here, we explore the integration of small molecule high-throughput screening with a deep learning-based virtual screening approach to uncover new antibacterial compounds. Leveraging a diverse library of nearly 2 million small molecules, we conducted comprehensive phenotypic screening against a sensitized Escherichia coli strain that, at a low hit rate, yielded thousands of hits. We trained a deep learning model, GNEprop, to predict antibacterial activity, ensuring robustness through out-of-distribution generalization techniques. Virtual screening of over 1.4 billion compounds identified potential candidates, of which 82 exhibited antibacterial activity, illustrating a 90X improved hit rate over the high-throughput screening experiment GNEprop was trained on. Importantly, a significant portion of these newly identified compounds exhibited high dissimilarity to known antibiotics, indicating promising avenues for further exploration in antibiotic discovery.

2024-09-14

bioRxiv (prépublication)

A high-throughput phenotypic screen combined with an ultra-large-scale deep learning-based virtual screening reveals novel scaffolds of antibacterial compounds

Gabriele Scalia

Steven T. Rutherford

Ziqing Lu

Kerry R. Buchholz

Nicholas Skelton

Kangway Chuang

Nathaniel Diamant

Jan-Christian Hütter

Jerome-Maxim Luescher

Anh Miu

Jeff Blaney

Leo Gendelev

Elizabeth Skippington

Greg Zynda

Nia Dickson

Aviv Regev

Man-Wah Tan

Tommaso Biancalani

2024-09-14

bioRxiv (prépublication)

Cell Morphology-Guided Small Molecule Generation with GFlowNets

Stephen Zhewen Lu

Ziqing Lu

Ehsan Hajiramezanali

Tommaso Biancalani

Gabriele Scalia

High-content phenotypic screening, including high-content imaging (HCI), has gained popularity in the last few years for its ability to char… (voir plus)acterize novel therapeutics without prior knowledge of the protein target. When combined with deep learning techniques to predict and represent molecular-phenotype interactions, these advancements hold the potential to significantly accelerate and enhance drug discovery applications. This work focuses on the novel task of HCI-guided molecular design. Generative models for molecule design could be guided by HCI data, for example with a supervised model that links molecules to phenotypes of interest as a reward function. However, limited labeled data, combined with the high-dimensional readouts, can make training these methods challenging and impractical. We consider an alternative approach in which we leverage an unsupervised multimodal joint embedding to define a latent similarity as a reward for GFlowNets. The proposed model learns to generate new molecules that could produce phenotypic effects similar to those of the given image target, without relying on pre-annotated phenotypic labels. We demonstrate that the proposed method generates molecules with high morphological and structural similarity to the target, increasing the likelihood of similar biological activity, as confirmed by an independent oracle model.

2024-08-09

ArXiv (prépublication)

Cell Morphology-Guided Small Molecule Generation with GFlowNets

Stephen Zhewen Lu

Ziqing Lu

Ehsan Hajiramezanali

Tommaso Biancalani

Gabriele Scalia

2024-06-16

ICML.cc/2024/Workshop/AI4Science (poster)

RGFN: Synthesizable Molecular Generation Using GFlowNets

Andrei Rekesh

Dmytro Shevchuk

Almer M. van der Sloot

Cheng-Hao Liu

Mike Tyers

Robert A. Batey

Generative models hold great promise for small molecule discovery, significantly increasing the size of search space compared to traditional… (voir plus) in silico screening libraries. However, most existing machine learning methods for small molecule generation suffer from poor synthesizability of candidate compounds, making experimental validation difficult. In this paper we propose Reaction-GFlowNet (RGFN), an extension of the GFlowNet framework that operates directly in the space of chemical reactions, thereby allowing out-of-the-box synthesizability while maintaining comparable quality of generated candidates. We demonstrate that with the proposed set of reactions and building blocks, it is possible to obtain a search space of molecules orders of magnitude larger than existing screening libraries coupled with low cost of synthesis. We also show that the approach scales to very large fragment libraries, further increasing the number of potential molecules. We demonstrate the effectiveness of the proposed approach across a range of oracle models, including pretrained proxy models and GPU-accelerated docking.

2024-06-01

ArXiv (prépublication)

RGFN: Synthesizable Molecular Generation Using GFlowNets

Andrei Rekesh

Dmytro Shevchuk

Almer M. van der Sloot

Cheng-Hao Liu

Mike Tyers

Robert A. Batey

Generative models hold great promise for small molecule discovery, significantly increasing the size of search space compared to traditional… (voir plus) in silico screening libraries. However, most existing machine learning methods for small molecule generation suffer from poor synthesizability of candidate compounds, making experimental validation difficult. In this paper we propose Reaction-GFlowNet (RGFN), an extension of the GFlowNet framework that operates directly in the space of chemical reactions, thereby allowing out-of-the-box synthesizability while maintaining comparable quality of generated candidates. We demonstrate that with the proposed set of reactions and building blocks, it is possible to obtain a search space of molecules orders of magnitude larger than existing screening libraries coupled with low cost of synthesis. We also show that the approach scales to very large fragment libraries, further increasing the number of potential molecules. We demonstrate the effectiveness of the proposed approach across a range of oracle models, including pretrained proxy models and GPU-accelerated docking.

2024-06-01

ArXiv (prépublication)

RGFN: Synthesizable Molecular Generation Using GFlowNets

Andrei Rekesh

Dmytro Shevchuk

Almer M. van der Sloot

Cheng-Hao Liu

Mike Tyers

Robert A. Batey

Generative models hold great promise for small molecule discovery, significantly increasing the size of search space compared to traditional… (voir plus) in silico screening libraries. However, most existing machine learning methods for small molecule generation suffer from poor synthesizability of candidate compounds, making experimental validation difficult. In this paper we propose Reaction-GFlowNet (RGFN), an extension of the GFlowNet framework that operates directly in the space of chemical reactions, thereby allowing out-of-the-box synthesizability while maintaining comparable quality of generated candidates. We demonstrate that with the proposed set of reactions and building blocks, it is possible to obtain a search space of molecules orders of magnitude larger than existing screening libraries coupled with low cost of synthesis. We also show that the approach scales to very large fragment libraries, further increasing the number of potential molecules. We demonstrate the effectiveness of the proposed approach across a range of oracle models, including pretrained proxy models and GPU-accelerated docking.

2024-06-01

ArXiv (prépublication)