# Predicting gene essentiality and drug response from perturbation screens in preclinical cancer models with LEAP: Layered Ensemble of Autoencoders and Predictors

arXiv: https://arxiv.org/abs/2502.15646 · HTML: https://mlsanity.com/paper/2502.15646/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 4 of its 47 references that are in the map.
- First posted on arXiv 21 Feb 2025.

## Builds on (most cited first, 4 of 4)

- [Simple and Scalable Predictive Uncertainty Estimation using Deep Ensembles](https://mlsanity.com/paper/1612.01474/) (2016)
- [Deep Ensembles: A Loss Landscape Perspective](https://mlsanity.com/paper/1912.02757/) (2019)
- [Deep Ensembles Work, But Are They Necessary?](https://mlsanity.com/paper/2202.06985/) (2022)
- [Ensemble Transfer Learning for the Prediction of Anti-Cancer Drug Response](https://mlsanity.com/paper/2005.09572/) (2020)

## Abstract (arXiv)

High-throughput preclinical perturbation screens, where the effects of genetic, chemical, or environmental perturbations are systematically tested on disease models, hold significant promise for machine learning-enhanced drug discovery due to their scale and causal nature. Predictive models trained on such datasets can be used to (i) infer perturbation response for previously untested disease models, and (ii) characterise the biological context that affects perturbation response. Existing predictive models suffer from limited reproducibility, generalisability and interpretability. To address these issues, we introduce a framework of Layered Ensemble of Autoencoders and Predictors (LEAP), a general and flexible ensemble strategy to aggregate predictions from multiple regressors trained using diverse gene expression representation models. LEAP consistently improves prediction performances in unscreened cell lines across modelling strategies. In particular, LEAP applied to perturbation-specific LASSO regressors (PS-LASSO) provides a favorable balance between near state-of-the-art performance and low computation time. We also propose an interpretability approach combining model distillation and stability selection to identify important biological pathways for perturbation response prediction in LEAP. Our models have the potential to accelerate the drug discovery pipeline by guiding the prioritisation of preclinical experiments and providing insights into the biological mechanisms involved in perturbation response. The code and datasets used in this work are publicly available.