GEESE: Genotype-aware End-to-End Spatio-temporal Embedding for Behavioral Phenotyping
Authors: Yiran Ding, Yuen Gao, Chunqi Qian, Zijun Cui
Organizations: Department of Computer Science and Engineering, Michigan State University, East Lansing, Michigan, USA · Department of Radiology, Michigan State University, East Lansing, Michigan, USA
Abstract
Behavioral phenotyping of genetic animal models currently requires labor-intensive manual feature engineering that limits reproducibility and scalability. We present GEESE, an end-to-end deep learning framework that learns behavioral representations directly from 3D pose dynamics without hand-crafted features. Using a pretrained time series foundation model, we encode movement sequences into a behavioral manifold that supports both behavior classification and genotype prediction. Evaluated across three autism-associated genetic models (CNTNAP2, CHD8, FMR1), our deep learning approach surpasses hand-crafted feature baselines in both tasks, revealing that learned representations capture genotype-specific behavioral signatures. The framework generalizes across genetic backgrounds, and an all-cohort model identifies both genetic background and genotype from movement patterns alone. We further provide HONK, an interactive intelligent tool enabling researchers without programming expertise to perform behavioral phenotyping from pose data through natural language interaction.
Understanding animal behavior at an algorithmic level -- what animals attend to, how they form internal models and plans, and how this maps to action -- remains a central challenge in neuroscience and ethology. Data-driven generative models offer a path toward this understanding. We introduce a framework for training agent-centric autoregressive models of animal behavior from tracked pose, applicable to single animals and to groups in which each agent senses and responds to its conspecifics. Our models input egocentric sensory observations and output egocentric movements, mirroring the biological constraint that animals observe and act on the world from their own reference frame. Social behavior emerges from agents independently sensing and responding to one another. This agent-centric formulation requires managing many parallel representations of the same data, along with ML-specific transformations like discretization. We release a general-purpose library focused on the composable sequences of operations that translate between these representations. We show that trained models capture the distribution of social behavior in groups of courting Drosophila, and our library includes quantitative tools for measuring fit. We demonstrate how the library supports systematic comparison across input and output representations and that it adapts straightforwardly to a new domain.
Predicting complex human traits from genetic data is challenging because different genetic, clinical, and molecular data sources often contain different parts of the signal. Here, we present EFGPP, a reproducible framework for generating, ranking, and combining multiple types of data for genotype-to-phenotype prediction. We applied EFGPP to migraine prediction using UK Biobank data from 733 individuals. The framework combined genotype-derived features, principal components, clinical and metabolomic covariates, and polygenic risk scores generated from migraine and depression GWAS using PLINK, PRSice-2, AnnoPred, and LDAK-GWAS. The best single data type achieved a test AUC of 0.644, while combining multiple data types improved performance to 0.688 using migraine-focused inputs and 0.663 using cross-trait depression-derived inputs. Genetic features alone did not outperform the covariates-only baseline, but genotype-derived features performed better than PRS alone, and depression-derived PRS showed useful predictive signal. Overall, EFGPP provides a practical proof-of-concept framework for prioritising and integrating heterogeneous genetic data sources for complex phenotype prediction.
Deep learning models for neuroimaging have largely been developed for individual tasks, limiting knowledge transfer across applications. Here we introduce GenFAR, a modular deep learning framework that learns general, clinically informed features from brain MRIs. We trained this modular architecture on 49,246 individuals across 11 cohorts, using 17 diverse classification and regression tasks spanning cognition, clinical, diagnosis, demographics, and biomarkers. This yields aggregated, focused feature sets that capture rich, clinically- and biologically-relevant brain representations. We developed a sequential learning approach where tasks progressively build on previously learned representations. Through an analysis of 5,000 task sequences, we identified an optimal sequence length of six tasks and introduced a Donor Score metric to quantify each task's contribution to downstream performance. This analysis revealed five consistently strong donor tasks (Age, AD/MCI, MMSE, Hypertension, Hyperlipidemia) that formed the base of our sequential model. We demonstrated the utility of our learned representation, in various tasks beyond those included in the training set, to serve as the foundation for specialized secondary predictors. We further showed that using the learned feature representation can substantially increase the sample efficiency of secondary deep learning training tasks and models, as well as improve their accuracy.