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Notin, P.

Publications and source records attributed to Notin, P..

2 recordsLinked to original sources

Mixtures of large-scale dynamic functional brain network modes

Accurate temporal modelling of functional brain networks is essential in the quest for understanding how such networks facilitate cognition. Researchers are beginning to adopt time-varying analyses for electrophysiological data that capture highly dynamic processes on the order of milliseconds. Typically, these approaches, such as clustering of functional connectivity profiles and Hidden Markov Modelling (HMM), assume mutual exclusivity of networks over time. Whilst a powerful constraint, this assumption may be compromising the ability of these approaches to describe the data effectively. Here, we propose a new generative model for functional connectivity as a time-varying linear mixture of spatially distributed statistical "modes". The temporal evolution of this mixture is governed by a recurrent neural network, which enables the model to generate data with a rich temporal structure. We use a Bayesian framework known as amortised variational inference to learn model parameters from observed data. We call the approach DyNeMo (for Dynamic Network Modes), and show using simulations it outperforms the HMM when the assumption of mutual exclusivity is violated. In resting-state MEG, DyNeMo reveals a mixture of modes that activate on fast time scales of 100-150 ms, which is similar to state lifetimes found using an HMM. In task MEG data, DyNeMo finds modes with plausible, task-dependent evoked responses without any knowledge of the task timings. Overall, DyNeMo provides decompositions that are an approximate remapping of the HMMs while showing improvements in overall explanatory power. However, the magnitude of the improvements suggests that the HMMs assumption of mutual exclusivity can be reasonable in practice. Nonetheless, DyNeMo provides a flexible framework for implementing and assessing future modelling developments.

neuroscience↗

Large-scale clinical interpretation of genetic variants using evolutionary data and deep learning

Quantifying the pathogenicity of protein variants in human disease-related genes would have a profound impact on clinical decisions, yet the overwhelming majority (over 98%) of these variants still have unknown consequences1-3. In principle, computational methods could support the large-scale interpretation of genetic variants. However, prior methods4-7 have relied on training machine learning models on available clinical labels. Since these labels are sparse, biased, and of variable quality, the resulting models have been considered insufficiently reliable8. By contrast, our approach leverages deep generative models to predict the clinical significance of protein variants without relying on labels. The natural distribution of protein sequences we observe across organisms is the result of billions of evolutionary experiments9,10. By modeling that distribution, we implicitly capture constraints on the protein sequences that maintain fitness. Our model EVE (Evolutionary model of Variant Effect) not only outperforms computational approaches that rely on labelled data, but also performs on par, if not better than, high-throughput assays which are increasingly used as strong evidence for variant classification11-23. After thorough validation on clinical labels, we predict the pathogenicity of 11 million variants across 1,081 disease genes, and assign high-confidence reclassification for 72k Variants of Unknown Significance8. Our work suggests that models of evolutionary information can provide a strong source of independent evidence for variant interpretation and that the approach will be widely useful in research and clinical settings.

genetics↗