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Forecasting the change in the distribution of viral variants is crucial for therapeutic design and disease surveillance. This task poses significant modeling challenges due to the sharp differences in virus distributions across sub-populations (e.g., countries) and their dynamic interactions. Existing machine learning approaches that model the variant distribution as a whole are incapable of making location-specific predictions and ignore transmissions that shape the viral landscape. In this paper, we propose a sub-population specific protein evolution model, which predicts the time-resolved distributions of viral proteins in different locations. The algorithm explicitly models the transmission rates between sub-populations and learns their interdependence from data. The change in protein distributions across all sub-populations is defined through a linear ordinary differential equation (ODE) parametrized by transmission rates. Solving this ODE yields the likelihood of a given protein occurring in particular sub-populations. Multi-year evaluation on both SARS-CoV-2 and influenza A/H3N2 demonstrates that our model outperforms baselines in accurately predicting distributions of viral proteins across continents and countries. We also find that the transmission rates learned from data are consistent with the transmission pathways discovered by retrospective phylogenetic analysis.

Perturbation experiments allow biologists to discover causal relationships between variables of interest, but the sparsity and high dimensionality of these data pose significant challenges for causal structure learning algorithms. Biological knowledge graphs can bootstrap the inference of causal structures in these situations, but since they compile vastly diverse information, they can bias predictions towards well-studied systems. Alternatively, amortized causal structure learning algorithms encode inductive biases through data simulation and train supervised models to recapitulate these synthetic graphs. However, realistically simulating biology is arguably even harder than understanding a specific system. In this work, we take inspiration from both strategies and propose an amortized algorithm for refining domain knowledge, based on data observations. On real and synthetic datasets, we show that our approach outperforms baselines in recovering ground truth causal graphs and identifying errors in the prior knowledge with limited interventional data.

Rationally identifying variables responsible for changes to a biological system can enable myriad applications in disease understanding and cell engineering. From a causality perspective, we are given two datasets generated by the same causal model, one observational (control) and one interventional (perturbed). The goal is to isolate the subset of measured variables (e.g. genes) that were the targets of the intervention, i.e. those whose conditional independencies have changed. Knowing the causal graph would limit the search space, allowing us to efficiently pinpoint these variables. However, current algorithms that infer causal graphs in the presence of unknown intervention targets scale poorly to the hundreds or thousands of variables in biological data, as they must jointly search the combinatorial spaces of graphs and consistent intervention targets. In this work, we propose a causality-inspired approach for predicting perturbation targets that decouples the two search steps. First, we use an amortized causal discovery model to separately infer causal graphs from the observational and interventional datasets. Then, we learn to map these paired graphs to the sets of variables that were intervened upon, in a supervised learning framework. This approach consistently outperforms baselines for perturbation modeling on seven single-cell transcriptomics datasets, each with thousands of measured variables. We also demonstrate significant improvements over six causal discovery algorithms in predicting intervention targets across a variety of tractable, synthetic datasets.

Proteolysis targeting chimeras (PROTACs) are small molecules that trigger the breakdown of traditionally ``undruggable'' proteins by binding simultaneously to their targets and degradation-associated proteins. A key challenge in their rational design is understanding their structural basis of activity. Due to the lack of crystal structures (18 in the PDB), existing PROTAC docking methods have been forced to simplify the problem into a distance-constrained protein-protein docking task. To address the data issue, we develop a novel pseudo-data generation scheme that requires only binary protein-protein complexes. This new dataset enables PROflow, an iterative refinement model for PROTAC-induced structure prediction that models the full PROTAC flexibility during constrained protein-protein docking. PROflow outperforms the state-of-the-art across docking metrics and runtime. Its inference speed enables the large-scale screening of PROTAC designs, and computed properties of predicted structures achieve statistically significant correlations with published degradation activities., Comment: Published at the GEM workshop, ICLR 2024

Causal discovery, the task of inferring causal structure from data, promises to accelerate scientific research, inform policy making, and more. However, causal discovery algorithms over larger sets of variables tend to be brittle against misspecification or when data are limited. To mitigate these challenges, we train a supervised model that learns to predict a larger causal graph from the outputs of classical causal discovery algorithms run over subsets of variables, along with other statistical hints like inverse covariance. Our approach is enabled by the observation that typical errors in the outputs of classical methods remain comparable across datasets. Theoretically, we show that this model is well-specified, in the sense that it can recover a causal graph consistent with graphs over subsets. Empirically, we train the model to be robust to erroneous estimates using diverse synthetic data. Experiments on real and synthetic data demonstrate that this model maintains high accuracy in the face of misspecification or distribution shift, and can be adapted at low cost to different discovery algorithms or choice of statistics., Comment: Preprint. Under review

Synthesizing high-quality 3D face models from natural language descriptions is very valuable for many applications, including avatar creation, virtual reality, and telepresence. However, little research ever tapped into this task. We argue the major obstacle lies in 1) the lack of high-quality 3D face data with descriptive text annotation, and 2) the complex mapping relationship between descriptive language space and shape/appearance space. To solve these problems, we build Describe3D dataset, the first large-scale dataset with fine-grained text descriptions for text-to-3D face generation task. Then we propose a two-stage framework to first generate a 3D face that matches the concrete descriptions, then optimize the parameters in the 3D shape and texture space with abstract description to refine the 3D face model. Extensive experimental results show that our method can produce a faithful 3D face that conforms to the input descriptions with higher accuracy and quality than previous methods. The code and Describe3D dataset are released at https://github.com/zhuhao-nju/describe3d ., Comment: Accepted to CVPR 2023

Understanding how proteins structurally interact is crucial to modern biology, with applications in drug discovery and protein design. Recent machine learning methods have formulated protein-small molecule docking as a generative problem with significant performance boosts over both traditional and deep learning baselines. In this work, we propose a similar approach for rigid protein-protein docking: DiffDock-PP is a diffusion generative model that learns to translate and rotate unbound protein structures into their bound conformations. We achieve state-of-the-art performance on DIPS with a median C-RMSD of 4.85, outperforming all considered baselines. Additionally, DiffDock-PP is faster than all search-based methods and generates reliable confidence estimates for its predictions. Our code is publicly available at $\texttt{https://github.com/ketatam/DiffDock-PP}$, Comment: ICLR Machine Learning for Drug Discovery (MLDD) Workshop 2023

We propose a robust and accurate non-parametric method for single-view 3D face reconstruction (SVFR). While tremendous efforts have been devoted to parametric SVFR, a visible gap still lies between the result 3D shape and the ground truth. We believe there are two major obstacles: 1) the representation of the parametric model is limited to a certain face database; 2) 2D images and 3D shapes in the fitted datasets are distinctly misaligned. To resolve these issues, a large-scale pseudo 2D\&3D dataset is created by first rendering the detailed 3D faces, then swapping the face in the wild images with the rendered face. These pseudo 2D&3D pairs are created from publicly available datasets which eliminate the gaps between 2D and 3D data while covering diverse appearances, poses, scenes, and illumination. We further propose a non-parametric scheme to learn a well-generalized SVFR model from the created dataset, and the proposed hierarchical signed distance function turns out to be effective in predicting middle-scale and small-scale 3D facial geometry. Our model outperforms previous methods on FaceScape-wild/lab and MICC benchmarks and is well generalized to various appearances, poses, expressions, and in-the-wild environments. The code is released at http://github.com/zhuhao-nju/rafare ., Comment: Accepted to AAAI 2023 (Oral)

In this paper, we present a large-scale detailed 3D face dataset, FaceScape, and the corresponding benchmark to evaluate single-view facial 3D reconstruction. By training on FaceScape data, a novel algorithm is proposed to predict elaborate riggable 3D face models from a single image input. FaceScape dataset releases $16,940$ textured 3D faces, captured from $847$ subjects and each with $20$ specific expressions. The 3D models contain the pore-level facial geometry that is also processed to be topologically uniform. These fine 3D facial models can be represented as a 3D morphable model for coarse shapes and displacement maps for detailed geometry. Taking advantage of the large-scale and high-accuracy dataset, a novel algorithm is further proposed to learn the expression-specific dynamic details using a deep neural network. The learned relationship serves as the foundation of our 3D face prediction system from a single image input. Different from most previous methods, our predicted 3D models are riggable with highly detailed geometry under different expressions. We also use FaceScape data to generate the in-the-wild and in-the-lab benchmark to evaluate recent methods of single-view face reconstruction. The accuracy is reported and analyzed on the dimensions of camera pose and focal length, which provides a faithful and comprehensive evaluation and reveals new challenges. The unprecedented dataset, benchmark, and code have been released at https://github.com/zhuhao-nju/facescape., Comment: Accepted to T-PAMI 2023; Extension of FaceScape(CVPR 2020); Code & data are available at https://github.com/zhuhao-nju/facescape

In this paper, we explore meta-learning for few-shot text classification. Meta-learning has shown strong performance in computer vision, where low-level patterns are transferable across learning tasks. However, directly applying this approach to text is challenging--lexical features highly informative for one task may be insignificant for another. Thus, rather than learning solely from words, our model also leverages their distributional signatures, which encode pertinent word occurrence patterns. Our model is trained within a meta-learning framework to map these signatures into attention scores, which are then used to weight the lexical representations of words. We demonstrate that our model consistently outperforms prototypical networks learned on lexical knowledge (Snell et al., 2017) in both few-shot text classification and relation classification by a significant margin across six benchmark datasets (20.0% on average in 1-shot classification)., Comment: ICLR 2020