David B. Ascher

Magnus H. Strømme, Alex G. C. de Sá, David B. Ascher

Accurate drug response prediction is a critical bottleneck in computational biochemistry, limited by the challenge of modelling the interplay between molecular structure and cellular context. In cancer research, this is acute due to tumour heterogeneity and genomic variability, which hinder the identification of effective therapies. Conventional approaches often fail to capture non-linear relationships between chemical features and biological outcomes across diverse cell lines. To address this, we introduce DPD-Cancer, a deep learning method based on a Graph Attention Transformer (GAT) framework. It is designed for small molecule anti-cancer activity classification and the quantitative prediction of cell-line specific responses, specifically growth inhibition concentration (pGI50). Benchmarked against state-of-the-art methods (pdCSM-cancer, ACLPred, and MLASM), DPD-Cancer demonstrated superior performance, achieving an Area Under ROC Curve (AUC) of up to 0.87 on strictly partitioned NCI60 data and up to 0.98 on ACLPred/MLASM datasets. For pGI50 prediction across 10 cancer types and 73 cell lines, the model achieved Pearson's correlation coefficients of up to 0.72 on independent test sets. These findings confirm that attention-based mechanisms offer significant advantages in extracting meaningful molecular representations, establishing DPD-Cancer as a competitive tool for prioritising drug candidates. Furthermore, DPD-Cancer provides explainability by leveraging the attention mechanism to identify and visualise specific molecular substructures, offering actionable insights for lead optimisation. DPD-Cancer is freely available as a web server at: https://biosig.lab.uq.edu.au/dpd_cancer/.

Alex G. C. de Sá, Daniel Gould, Anna Fedyukova et al.

The intensive care unit (ICU) comprises a complex hospital environment, where decisions made by clinicians have a high level of risk for the patients' lives. A comprehensive care pathway must then be followed to reduce p complications. Uncertain, competing and unplanned aspects within this environment increase the difficulty in uniformly implementing the care pathway. Readmission contributes to this pathway's difficulty, occurring when patients are admitted again to the ICU in a short timeframe, resulting in high mortality rates and high resource utilisation. Several works have tried to predict readmission through patients' medical information. Although they have some level of success while predicting readmission, those works do not properly assess, characterise and understand readmission prediction. This work proposes a standardised and explainable machine learning pipeline to model patient readmission on a multicentric database (i.e., the eICU cohort with 166,355 patients, 200,859 admissions and 6,021 readmissions) while validating it on monocentric (i.e., the MIMIC IV cohort with 382,278 patients, 523,740 admissions and 5,984 readmissions) and multicentric settings. Our machine learning pipeline achieved predictive performance in terms of the area of the receiver operating characteristic curve (AUC) up to 0.7 with a Random Forest classification model, yielding an overall good calibration and consistency on validation sets. From explanations provided by the constructed models, we could also derive a set of insightful conclusions, primarily on variables related to vital signs and blood tests (e.g., albumin, blood urea nitrogen and hemoglobin levels), demographics (e.g., age, and admission height and weight), and ICU-associated variables (e.g., unit type). These insights provide an invaluable source of information during clinicians' decision-making while discharging ICU patients.

Muhammad Muneeb, David B. Ascher

Large language models (LLMs) often lack specialized knowledge for complex bioinformatics applications. We present a reproducible pipeline for fine-tuning LLMs on specialized bioinformatics data, demonstrated through two use cases: PRSGPT, focused on polygenic risk score (PRS) tools, and BioStarsGPT, trained on community forum discussions. The nine-step pipeline integrates diverse data sources, structured preprocessing, prompt-based question-answer (QA) generation (via Google Gemini), natural language inference (NLI) for quality control, semantic deduplication, clustering-based data splitting, and parameter-efficient fine-tuning using LoRA. We fine-tuned three LLMs (LLaMA-3.2-3B, Qwen2.5-7B, Gemma) and benchmarked them on over 14 lexical and semantic metrics. Qwen2.5-7B emerged as the best performer, with BLEU-4 and ROUGE-1 improvements of 82\% and 70\% for PRSGPT and 6\% and 18\% for BioStarsGPT, respectively. The open-source datasets produced include over 28,000 QA pairs for PRSGPT and 154,282 for BioStarsGPT. Human evaluation of PRSGPT yielded 61.9\% accuracy on the PRS tools comparison task, comparable to Google Gemini (61.4\%), but with richer methodological detail and accurate citations. BioStarsGPT demonstrated 59\% conceptual accuracy across 142 curated bioinformatics questions. Our pipeline enables scalable, domain-specific fine-tuning of LLMs. It enables privacy-preserving, locally deployable bioinformatics assistants, explores their practical applications, and addresses the challenges, limitations, and mitigation strategies associated with their development and use.

Alex G. C. de Sá, David B. Ascher

Machine learning (ML) is revolutionising drug discovery by expediting the prediction of small molecule properties essential for developing new drugs. These properties -- including absorption, distribution, metabolism and excretion (ADME)-- are crucial in the early stages of drug development since they provide an understanding of the course of the drug in the organism, i.e., the drug's pharmacokinetics. However, existing methods lack personalisation and rely on manually crafted ML algorithms or pipelines, which can introduce inefficiencies and biases into the process. To address these challenges, we propose a novel evolutionary-based automated ML method (AutoML) specifically designed for predicting small molecule properties, with a particular focus on pharmacokinetics. Leveraging the advantages of grammar-based genetic programming, our AutoML method streamlines the process by automatically selecting algorithms and designing predictive pipelines tailored to the particular characteristics of input molecular data. Results demonstrate AutoML's effectiveness in selecting diverse ML algorithms, resulting in comparable or even improved predictive performances compared to conventional approaches. By offering personalised ML-driven pipelines, our method promises to enhance small molecule research in drug discovery, providing researchers with a valuable tool for accelerating the development of novel therapeutic drugs.

Alex G. C. de Sá, David B. Ascher

Machine learning (ML) has been playing important roles in drug discovery in the past years by providing (pre-)screening tools for prioritising chemical compounds to pass through wet lab experiments. One of the main ML tasks in drug discovery is to build quantitative structure-activity relationship (QSAR) models, associating the molecular structure of chemical compounds with an activity or property. These properties -- including absorption, distribution, metabolism, excretion and toxicity (ADMET) -- are essential to model compound behaviour, activity and interactions in the organism. Although several methods exist, the majority of them do not provide an appropriate model's personalisation, yielding to bias and lack of generalisation to new data since the chemical space usually shifts from application to application. This fact leads to low predictive performance when completely new data is being tested by the model. The area of Automated Machine Learning (AutoML) emerged aiming to solve this issue, outputting tailored ML algorithms to the data at hand. Although an important task, AutoML has not been practically used to assist cheminformatics and computational chemistry researchers often, with just a few works related to the field. To address these challenges, this work introduces Auto-ADMET, an interpretable evolutionary-based AutoML method for chemical ADMET property prediction. Auto-ADMET employs a Grammar-based Genetic Programming (GGP) method with a Bayesian Network Model to achieve comparable or better predictive performance against three alternative methods -- standard GGP method, pkCSM and XGBOOST model -- on 12 benchmark chemical ADMET property prediction datasets. The use of a Bayesian Network model on Auto-ADMET's evolutionary process assisted in both shaping the search procedure and interpreting the causes of its AutoML performance.

Bruna Moreira da Silva, David B. Ascher, Nicholas Geard et al.

Antibodies, a prominent class of approved biologics, play a crucial role in detecting foreign antigens. The effectiveness of antigen neutralisation and elimination hinges upon the strength, sensitivity, and specificity of the paratope-epitope interaction, which demands resource-intensive experimental techniques for characterisation. In recent years, artificial intelligence and machine learning methods have made significant strides, revolutionising the prediction of protein structures and their complexes. The past decade has also witnessed the evolution of computational approaches aiming to support immunotherapy design. This review focuses on the progress of machine learning-based tools and their frameworks in the domain of B-cell immunotherapy design, encompassing linear and conformational epitope prediction, paratope prediction, and antibody design. We mapped the most commonly used data sources, evaluation metrics, and method availability and thoroughly assessed their significance and limitations, discussing the main challenges ahead.

Moi Hoon Yap, Ryo Hachiuma, Azadeh Alavi et al.

There has been a substantial amount of research involving computer methods and technology for the detection and recognition of diabetic foot ulcers (DFUs), but there is a lack of systematic comparisons of state-of-the-art deep learning object detection frameworks applied to this problem. DFUC2020 provided participants with a comprehensive dataset consisting of 2,000 images for training and 2,000 images for testing. This paper summarises the results of DFUC2020 by comparing the deep learning-based algorithms proposed by the winning teams: Faster R-CNN, three variants of Faster R-CNN and an ensemble method; YOLOv3; YOLOv5; EfficientDet; and a new Cascade Attention Network. For each deep learning method, we provide a detailed description of model architecture, parameter settings for training and additional stages including pre-processing, data augmentation and post-processing. We provide a comprehensive evaluation for each method. All the methods required a data augmentation stage to increase the number of images available for training and a post-processing stage to remove false positives. The best performance was obtained from Deformable Convolution, a variant of Faster R-CNN, with a mean average precision (mAP) of 0.6940 and an F1-Score of 0.7434. Finally, we demonstrate that the ensemble method based on different deep learning methods can enhanced the F1-Score but not the mAP.