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  1. Abstract

    Analysis of single-cell datasets generated from diverse organisms offers unprecedented opportunities to unravel fundamental evolutionary processes of conservation and diversification of cell types. However, interspecies genomic differences limit the joint analysis of cross-species datasets to homologous genes. Here we present SATURN, a deep learning method for learning universal cell embeddings that encodes genes’ biological properties using protein language models. By coupling protein embeddings from language models with RNA expression, SATURN integrates datasets profiled from different species regardless of their genomic similarity. SATURN can detect functionally related genes coexpressed across species, redefining differential expression for cross-species analysis. Applying SATURN to three species whole-organism atlases and frog and zebrafish embryogenesis datasets, we show that SATURN can effectively transfer annotations across species, even when they are evolutionarily remote. We also demonstrate that SATURN can be used to find potentially divergent gene functions between glaucoma-associated genes in humans and four other species.

     
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    Free, publicly-accessible full text available February 16, 2025
  2. Graph Neural Networks (GNNs) are powerful machine learning prediction models on graph-structured data. However, GNNs lack rigorous uncertainty estimates, limiting their reliable deployment in settings where the cost of errors is significant. We propose conformalized GNN (CF-GNN), extending conformal prediction (CP) to graph-based models for guaranteed uncertainty estimates. Given an entity in the graph, CF-GNN produces a prediction set/interval that provably contains the true label with pre-defined coverage probability (e.g. 90%). We establish a permutation invariance condition that enables the validity of CP on graph data and provide an exact characterization of the test-time coverage. Besides valid coverage, it is crucial to reduce the prediction set size/interval length for practical use. We observe a key connection between non-conformity scores and network structures, which motivates us to develop a topology-aware output correction model that learns to update the prediction and produces more efficient prediction sets/intervals. Extensive experiments show that CF-GNN achieves any pre-defined target marginal coverage while significantly reducing the prediction set/interval size by up to 74% over the baselines. It also empirically achieves satisfactory conditional coverage over various raw and network features. 
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    Free, publicly-accessible full text available December 10, 2024
  3. Machine learning models exhibit strong performance on datasets with abundant labeled samples. However, for tabular datasets with extremely high d-dimensional features but limited n samples (i.e. d ≫ n), machine learning models struggle to achieve strong performance due to the risk of overfitting. Here, our key insight is that there is often abundant, auxiliary domain information describing input features which can be structured as a heterogeneous knowledge graph (KG). We propose PLATO, a method that achieves strong performance on tabular data with d ≫ n by using an auxiliary KG describing input features to regularize a multilayer perceptron (MLP). In PLATO, each input feature corresponds to a node in the auxiliary KG. In the MLP’s first layer, each input feature also corresponds to a weight vector. PLATO is based on the inductive bias that two input features corresponding to similar nodes in the auxiliary KG should have similar weight vectors in the MLP’s first layer. PLATO captures this inductive bias by inferring the weight vector for each input feature from its corresponding node in the KG via a trainable message-passing function. Across 6 d ≫ n datasets, PLATO outperforms 13 state-of-the-art baselines by up to 10.19%. 
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    Free, publicly-accessible full text available December 10, 2024
  4. In-context learning is the ability of a pretrained model to adapt to novel and diverse downstream tasks by conditioning on prompt examples, without optimizing any parameters. While large language models have demonstrated this ability, how in-context learning could be performed over graphs is unexplored. In this paper, we develop Pretraining Over Diverse In-Context Graph Systems (PRODIGY), the first pretraining framework that enables in-context learning over graphs. The key idea of our framework is to formulate in-context learning over graphs with a novel prompt graph representation, which connects prompt examples and queries. We then propose a graph neural network architecture over the prompt graph and a corresponding family of in-context pretraining objectives. With PRODIGY, the pre- trained model can directly perform novel downstream classification tasks on unseen graphs via in-context learning. We provide empirical evidence of the effectiveness of our framework by showcasing its strong in-context learning performance on tasks involving citation networks and knowledge graphs. Our approach outperforms the in-context learning accuracy of contrastive pretraining baselines with hard-coded adaptation by 18% on average across all setups. Moreover, it also outperforms standard finetuning with limited data by 33% on average with in-context learning. 
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    Free, publicly-accessible full text available December 10, 2024
  5. Predicting how different interventions will causally affect a specific individual is important in a variety of domains such as personalized medicine, public policy, and online marketing. There are a large number of methods to predict the effect of an existing intervention based on historical data from individuals who received it. However, in many settings it is important to predict the effects of novel interventions (e.g., a newly invented drug), which these methods do not address. Here, we consider zero-shot causal learning: predicting the personalized effects of a novel intervention. We propose CaML, a causal meta-learning framework which formulates the personalized prediction of each intervention’s effect as a task. CaML trains a single meta-model across thousands of tasks, each constructed by sampling an intervention, its recipients, and its nonrecipients. By leveraging both intervention information (e.g., a drug’s attributes) and individual features (e.g., a patient’s history), CaML is able to predict the personalized effects of novel interventions that do not exist at the time of training. Experimental results on real world datasets in large-scale medical claims and cell-line perturbations demonstrate the effectiveness of our approach. Most strikingly, CaML’s zero-shot predictions outperform even strong baselines trained directly on data from the test interventions. 
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    Free, publicly-accessible full text available December 10, 2024
  6. Abstract

    A long-standing expectation is that large, dense and cosmopolitan areas support socioeconomic mixing and exposure among diverse individuals1–6. Assessing this hypothesis has been difficult because previous measures of socioeconomic mixing have relied on static residential housing data rather than real-life exposures among people at work, in places of leisure and in home neighbourhoods7,8. Here we develop a measure of exposure segregation that captures the socioeconomic diversity of these everyday encounters. Using mobile phone mobility data to represent 1.6 billion real-world exposures among 9.6 million people in the United States, we measure exposure segregation across 382 metropolitan statistical areas (MSAs) and 2,829 counties. We find that exposure segregation is 67% higher in the ten largest MSAs than in small MSAs with fewer than 100,000 residents. This means that, contrary to expectations, residents of large cosmopolitan areas have less exposure to a socioeconomically diverse range of individuals. Second, we find that the increased socioeconomic segregation in large cities arises because they offer a greater choice of differentiated spaces targeted to specific socioeconomic groups. Third, we find that this segregation-increasing effect is countered when a city’s hubs (such as shopping centres) are positioned to bridge diverse neighbourhoods and therefore attract people of all socioeconomic statuses. Our findings challenge a long-standing conjecture in human geography and highlight how urban design can both prevent and facilitate encounters among diverse individuals.

     
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    Free, publicly-accessible full text available December 21, 2024
  7. Learning to predict properties of a large graph is challenging because each prediction requires the knowledge of an entire graph, while the amount of memory available during training is bounded. Here we propose Graph Segment Training (GST), a general framework that utilizes a divide-and-conquer approach to allow learning large graph property prediction with a constant memory footprint. GST first divides a large graph into segments and then backpropagates through only a few segments sampled per training iteration. We refine the GST paradigm by introducing a historical embedding table to efficiently obtain embeddings for segments not sampled for backpropagation. To mitigate the staleness of historical embeddings, we design two novel techniques. First, we finetune the prediction head to fix the input distribution shift. Second, we introduce Stale Embedding Dropout to drop some stale embeddings during training to reduce bias. We evaluate our complete method GST+EFD (with all the techniques together) on two large graph property prediction benchmarks: MalNet and TpuGraphs. Our experiments show that GST+EFD is both memory-efficient and fast, while offering a slight boost on test accuracy over a typical full graph training regime. 
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    Free, publicly-accessible full text available December 10, 2024
  8. Visual question answering (VQA) requires systems to perform concept-level reasoning by unifying unstructured (e.g., the context in question and answer; “QA context”) and structured (e.g., knowledge graph for the QA context and scene; “concept graph”) multimodal knowledge. Existing works typically combine a scene graph and a concept graph of the scene by connecting corresponding visual nodes and concept nodes, then incorporate the QA context representation to perform question answering. However, these methods only perform a unidirectional fusion from unstructured knowledge to structured knowledge, limiting their potential to capture joint reasoning over the heterogeneous modalities of knowledge. To perform more expressive reasoning, we propose VQA-GNN, a new VQA model that performs bidirectional fusion between unstructured and structured multimodal knowledge to obtain unified knowledge representations. Specifically, we inter-connect the scene graph and the concept graph through a super node that represents the QA context, and introduce a new multimodal GNN technique to perform inter-modal message passing for reasoning that mitigates representational gaps between modalities. On two challenging VQA tasks (VCR and GQA), our method outperforms strong baseline VQA methods by 3.2% on VCR (Q-AR) and 4.6% on GQA, suggesting its strength in performing concept-level reasoning. Ablation studies further demonstrate the efficacy of the bidirectional fusion and multimodal GNN method in unifying unstructured and structured multimodal knowledge. 
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    Free, publicly-accessible full text available October 4, 2024
  9. We present the Temporal Graph Benchmark (TGB), a collection of challenging and diverse benchmark datasets for realistic, reproducible, and robust evaluation of machine learning models on temporal graphs. TGB datasets are of large scale, spanning years in duration, incorporate both node and edge-level prediction tasks and cover a diverse set of domains including social, trade, transaction, and transportation networks. For both tasks, we design evaluation protocols based on realistic use-cases. We extensively benchmark each dataset and find that the performance of common models can vary drastically across datasets. In addition, on dynamic node property prediction tasks, we show that simple methods often achieve superior performance compared to existing temporal graph models. We believe that these findings open up opportunities for future research on temporal graphs. Finally, TGB provides an automated machine learning pipeline for reproducible and accessible temporal graph research, including data loading, experiment setup and performance evaluation. TGB will be maintained and updated on a regular basis and welcomes community feedback. TGB datasets, data loaders, example codes, evaluation setup, and leaderboards are publicly available at https://tgb.complexdatalab.com/. 
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    Free, publicly-accessible full text available December 10, 2024
  10. Abstract

    Understanding cellular responses to genetic perturbation is central to numerous biomedical applications, from identifying genetic interactions involved in cancer to developing methods for regenerative medicine. However, the combinatorial explosion in the number of possible multigene perturbations severely limits experimental interrogation. Here, we present graph-enhanced gene activation and repression simulator (GEARS), a method that integrates deep learning with a knowledge graph of gene–gene relationships to predict transcriptional responses to both single and multigene perturbations using single-cell RNA-sequencing data from perturbational screens. GEARS is able to predict outcomes of perturbing combinations consisting of genes that were never experimentally perturbed. GEARS exhibited 40% higher precision than existing approaches in predicting four distinct genetic interaction subtypes in a combinatorial perturbation screen and identified the strongest interactions twice as well as prior approaches. Overall, GEARS can predict phenotypically distinct effects of multigene perturbations and thus guide the design of perturbational experiments.

     
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    Free, publicly-accessible full text available August 17, 2024