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Charles W. J. Pugh

dblp:314/7778 · DBLP profile ↗
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1ranked-venue papers
1as first author
1since 2021 · last 2025
—ORCID · none

Domains — the database's venue-derived domains; a paper can count in several

Artificial intelligence and machine learning · 1 · 1 first-author · 1 since 2021

Expertise — from the expertise taxonomy: the topics of the expert's papers under the CCF categories. A weight counts papers with recency: 1 for a paper about the topic, 0.3 when the topic is its context, halved every five years.

Interdisciplinary, comprehensive, and emerging computing
1 paper
Bioinformatics and computational biology · 100%

Topics — the 3 heaviest of 3, each with the papers that count most for it

TopicWeightPapersLastEvidence papers
Bioinformatics and computational biology › sequence analysis
DNA language model
0.912025
From Likelihood to Fitness: Improving Variant Effect Prediction in Protein and Genome Language Models · NeurIPS 2025
Bioinformatics and computational biology › protein sequence analysis › protein sequence representation
protein language model
0.912025
From Likelihood to Fitness: Improving Variant Effect Prediction in Protein and Genome Language Models · NeurIPS 2025
Bioinformatics and computational biology › statistical genetics
variant effect prediction
0.912025
From Likelihood to Fitness: Improving Variant Effect Prediction in Protein and Genome Language Models · NeurIPS 2025

Methods — techniques the papers use, named apart from their topics

ornstein-uhlenbeck model · 0.9likelihood-fitness bridging · 0.9deep mutational scan · 0.9
YearPublicationVenuePosition
2025 From Likelihood to Fitness: Improving Variant Effect Prediction in Protein and Genome Language Models
abstract
Generative models trained on natural sequences are increasingly used to predict the effects of genetic variation, enabling progress in therapeutic design, disease risk prediction, and synthetic biology. In the zero-shot setting, variant impact is estimated by comparing the likelihoods of sequences, under the assumption that likelihood serves as a proxy for fitness. However, this assumption often breaks down in practice: sequence likelihood reflects not only evolutionary fitness constraints, but also phylogenetic structure and sampling biases, especially as model capacity increases. We introduce Likelihood-Fitness Bridging (LFB), a simple and general strategy that improves variant effect prediction by averaging model scores across sequences subject to similar selective pressures. Assuming an Ornstein-Uhlenbeck model of evolution, LFB can be viewed as a way to marginalize the effects of genetic drift, although its benefits appear to extend more broadly. LFB applies to existing protein and genomic language models without requiring retraining, and incurs only modest computational overhead. Evaluated on large-scale deep mutational scans and clinical benchmarks, LFB consistently improves predictive performance across model families and sizes. Notably, it reverses the performance plateau observed in larger protein language models, making the largest models the most accurate when combined with LFB. These results suggest that accounting for phylogenetic and sampling biases is essential to realizing the full potential of large sequence models in variant effect prediction.
Charles W. J. Pugh, Paulina G. Nuñez-Valencia, Mafalda Dias, Jonathan Frazer
NeurIPS1