Maxwell W. Libbrecht

M. Sadegh Saberian, Kathleen P. Moriarty, Andrea D. Olmstead et al.

Drug repurposing can accelerate the identification of effective compounds for clinical use against SARS-CoV-2, with the advantage of pre-existing clinical safety data and an established supply chain. RNA viruses such as SARS-CoV-2 manipulate cellular pathways and induce reorganization of subcellular structures to support their life cycle. These morphological changes can be quantified using bioimaging techniques. In this work, we developed DEEMD: a computational pipeline using deep neural network models within a multiple instance learning framework, to identify putative treatments effective against SARS-CoV-2 based on morphological analysis of the publicly available RxRx19a dataset. This dataset consists of fluorescence microscopy images of SARS-CoV-2 non-infected cells and infected cells, with and without drug treatment. DEEMD first extracts discriminative morphological features to generate cell morphological profiles from the non-infected and infected cells. These morphological profiles are then used in a statistical model to estimate the applied treatment efficacy on infected cells based on similarities to non-infected cells. DEEMD is capable of localizing infected cells via weak supervision without any expensive pixel-level annotations. DEEMD identifies known SARS-CoV-2 inhibitors, such as Remdesivir and Aloxistatin, supporting the validity of our approach. DEEMD can be explored for use on other emerging viruses and datasets to rapidly identify candidate antiviral treatments in the future}. Our implementation is available online at https://www.github.com/Sadegh-Saberian/DEEMD

Behrooz Azarkhalili, Maxwell Libbrecht

This paper introduces Generalized Attention Flow (GAF), a novel feature attribution method for Transformer-based models to address the limitations of current approaches. By extending Attention Flow and replacing attention weights with the generalized Information Tensor, GAF integrates attention weights, their gradients, the maximum flow problem, and the barrier method to enhance the performance of feature attributions. The proposed method exhibits key theoretical properties and mitigates the shortcomings of prior techniques that rely solely on simple aggregation of attention weights. Our comprehensive benchmarking on sequence classification tasks demonstrates that a specific variant of GAF consistently outperforms state-of-the-art feature attribution methods in most evaluation settings, providing a more reliable interpretation of Transformer model outputs.

Maxwell W Libbrecht, Rachel CW Chan, Michael M Hoffman

Segmentation and genome annotation (SAGA) algorithms are widely used to understand genome activity and gene regulation. These algorithms take as input epigenomic datasets, such as chromatin immunoprecipitation-sequencing (ChIP-seq) measurements of histone modifications or transcription factor binding. They partition the genome and assign a label to each segment such that positions with the same label exhibit similar patterns of input data. SAGA algorithms discover categories of activity such as promoters, enhancers, or parts of genes without prior knowledge of known genomic elements. In this sense, they generally act in an unsupervised fashion like clustering algorithms, but with the additional simultaneous function of segmenting the genome. Here, we review the common methodological framework that underlies these methods, review variants of and improvements upon this basic framework, catalogue existing large-scale reference annotations, and discuss the outlook for future work.