Beyond Cox Models: Assessing the Performance of Machine-Learning Methods in Non-Proportional Hazards and Non-Linear Survival Analysis

Survival analysis often relies on Cox models, assuming both linearity and proportional hazards (PH). This study evaluates machine and deep learning methods that relax these constraints, comparing their performance with penalized Cox models on a benchmark of three synthetic and three real datasets. In total, eight different models were tested, including six non-linear models of which four were also non-PH. Although Cox regression often yielded satisfactory performance, we showed the conditions under which machine and deep learning models can perform better. Indeed, the performance of these methods has often been underestimated due to the improper use of Harrell's concordance index (C-index) instead of more appropriate scores such as Antolini's concordance index, which generalizes C-index in cases where the PH assumption does not hold. In addition, since occasionally high C-index models happen to be badly calibrated, combining Antolini's C-index with Brier's score is useful to assess the overall performance of a survival method. Results on our benchmark data showed that survival prediction should be approached by testing different methods to select the most appropriate one according to sample size, non-linearity and non-PH conditions. To allow an easy reproducibility of these tests on our benchmark data, code and documentation are freely available at https://github.com/compbiomed-unito/survhive.

JanusDDG: A Thermodynamics-Compliant Model for Sequence-Based Protein Stability via Two-Fronts Multi-Head Attention

Understanding how residue variations affect protein stability is crucial for designing functional proteins and deciphering the molecular mechanisms underlying disease-related mutations. Recent advances in protein language models (PLMs) have revolutionized computational protein analysis, enabling, among other things, more accurate predictions of mutational effects. In this work, we introduce JanusDDG, a deep learning framework that leverages PLM-derived embeddings and a bidirectional cross-attention transformer architecture to predict $\Delta \Delta G$ of single and multiple-residue mutations while simultaneously being constrained to respect fundamental thermodynamic properties, such as antisymmetry and transitivity. Unlike conventional self-attention, JanusDDG computes queries (Q) and values (V) as the difference between wild-type and mutant embeddings, while keys (K) alternate between the two. This cross-interleaved attention mechanism enables the model to capture mutation-induced perturbations while preserving essential contextual information. Experimental results show that JanusDDG achieves state-of-the-art performance in predicting $\Delta \Delta G$ from sequence alone, matching or exceeding the accuracy of structure-based methods for both single and multiple mutations.

SurvHive: a package to consistently access multiple survival-analysis packages

Survival analysis, a foundational tool for modeling time-to-event data, has seen growing integration with machine learning (ML) approaches to handle the complexities of censored data and time-varying risks. Despite these advances, leveraging state-of-the-art survival models remains a challenge due to the fragmented nature of existing implementations, which lack standardized interfaces and require extensive preprocessing. We introduce SurvHive, a Python-based framework designed to unify survival analysis methods within a coherent and extensible interface modeled on scikit-learn. SurvHive integrates classical statistical models with cutting-edge deep learning approaches, including transformer-based architectures and parametric survival models. Using a consistent API, SurvHive simplifies model training, evaluation, and optimization, significantly reducing the barrier to entry for ML practitioners exploring survival analysis. The package includes enhanced support for hyper-parameter tuning, time-dependent risk evaluation metrics, and cross-validation strategies tailored to censored data. With its extensibility and focus on usability, SurvHive provides a bridge between survival analysis and the broader ML community, facilitating advancements in time-to-event modeling across domains. The SurvHive code and documentation are available freely at https://github.com/compbiomed-unito/survhive.