Training Flexible Models of Genetic Variant Effects from Functional Annotations using Accelerated Linear Algebra

To understand how genetic variants in human genomes manifest in phenotypes -- traits like height or diseases like asthma -- geneticists have sequenced and measured hundreds of thousands of individuals. Geneticists use this data to build models that predict how a genetic variant impacts phenotype given genomic features of the variant, like DNA accessibility or the presence of nearby DNA-bound proteins. As more data and features become available, one might expect predictive models to improve. Unfortunately, training these models is bottlenecked by the need to solve expensive linear algebra problems because variants in the genome are correlated with nearby variants, requiring inversion of large matrices. Previous methods have therefore been restricted to fitting small models, and fitting simplified summary statistics, rather than the full likelihood of the statistical model. In this paper, we leverage modern fast linear algebra techniques to develop DeepWAS (Deep genome Wide Association Studies), a method to train large and flexible neural network predictive models to optimize likelihood. Notably, we find that larger models only improve performance when using our full likelihood approach; when trained by fitting traditional summary statistics, larger models perform no better than small ones. We find larger models trained on more features make better predictions, potentially improving disease predictions and therapeutic target identification.

Why Masking Diffusion Works: Condition on the Jump Schedule for Improved Discrete Diffusion

Discrete diffusion models, like continuous diffusion models, generate high-quality samples by gradually undoing noise applied to datapoints with a Markov process. Gradual generation in theory comes with many conceptual benefits; for example, inductive biases can be incorporated into the noising Markov process, and access to improved sampling algorithms. In practice, however, the consistently best performing discrete diffusion model is, surprisingly, masking diffusion, which does not denoise gradually. Here we explain the superior performance of masking diffusion by noting that it makes use of a fundamental difference between continuous and discrete Markov processes: discrete Markov processes evolve by discontinuous jumps at a fixed rate and, unlike other discrete diffusion models, masking diffusion builds in the known distribution of jump times and only learns where to jump to. We show that we can similarly bake in the known distribution of jump times into any discrete diffusion model. The resulting models - schedule-conditioned discrete diffusion (SCUD) - generalize classical discrete diffusion and masking diffusion. By applying SCUD to models with noising processes that incorporate inductive biases on images, text, and protein data, we build models that outperform masking.