Large scale field-phenotyping approaches have the potential to solve important questions about the relationship of plant genotype to plant phenotype. Computational approaches to measuring the phenotype (the observable plant features) are required to address the problem at a large scale, but machine learning approaches to extract phenotypes from sensor data have been hampered by limited access to (a) sufficiently large, organized multi-sensor datasets, (b) field trials that have a large scale and significant number of genotypes, (c) full genetic sequencing of those phenotypes, and (d) datasets sufficiently organized so that algorithm centered researchers can directly address the real biological problems. To address this, we present SGxP, a novel benchmark dataset from a large-scale field trial consisting of the complete genotype of over 300 sorghum varieties, and time sequences of imagery from several field plots growing each variety, taken with RGB and laser 3D scanner imaging. To lower the barrier to entry and facilitate further developments, we provide a set of well organized, multi-sensor imagery and corresponding genomic data. We implement baseline deep learning based phenotyping approaches to create baseline results for individual sensors and multi-sensor fusion for detecting genetic mutations with known impacts. We also provide and support an open-ended challenge by identifying thousands of genetic mutations whose phenotypic impacts are currently unknown. A web interface for machine learning researchers and practitioners to share approaches, visualizations and hypotheses supports engagement with plant biologists to further the understanding of the sorghum genotype x phenotype relationship. The full dataset, leaderboard (including baseline results) and discussion forums can be found at http://sorghumsnpbenchmark.com.

Neural Information Processing Systems http://nips.cc/

Training from scratch, as a substitute, demands more epochs to converge and brings no computation saving.

Machine learning models increasingly map biological sequence-fitness landscapes to predict mutational effects. Effective evaluation of these models requires benchmarks curated from empirical data. Despite their impressive scales, existing benchmarks lack topographical information regarding the underlying fitness landscapes, which hampers interpretation and comparison of model performance beyond averaged scores. Here, we introduce GraphFLA, a Python framework that constructs and analyzes fitness landscapes from mutagensis data in diverse modalities (e.g., DNA, RNA, protein, and beyond) with up to millions of mutants. GraphFLA calculates 20 biologically relevant features that characterize 4 fundamental aspects of landscape topography. By applying GraphFLA to over 5,300 landscapes from ProteinGym, RNAGym, and CIS-BP, we demonstrate its utility in interpreting and comparing the performance of dozens of fitness prediction models, highlighting factors influencing model accuracy and respective advantages of different models. In addition, we release 155 combinatorially complete empirical fitness landscapes, encompassing over 2.2 million sequences across various modalities. All the codes and datasets are available at https://github.com/COLA-Laboratory/GraphFLA.

We extend biologically-informed neural networks (BINNs) for genomic prediction (GP) and selection (GS) in crops by integrating thousands of single-nucleotide polymorphisms (SNPs) with multi-omics measurements and prior biological knowledge. Traditional genotype-to-phenotype (G2P) models depend heavily on direct mappings that achieve only modest accuracy, forcing breeders to conduct large, costly field trials to maintain or marginally improve genetic gain. Models that incorporate intermediate molecular phenotypes such as gene expression can achieve higher predictive fit, but they remain impractical for GS since such data are unavailable at deployment or design time. BINNs overcome this limitation by encoding pathway-level inductive biases and leveraging multi-omics data only during training, while using genotype data alone during inference. Applied to maize gene-expression and multi-environment field-trial data, BINN improves rank-correlation accuracy by up to 56% within and across subpopulations under sparse-data conditions and nonlinearly identifies genes that GWAS/TWAS fail to uncover. With complete domain knowledge for a synthetic metabolomics benchmark, BINN reduces prediction error by 75% relative to conventional neural nets and correctly identifies the most important nonlinear pathway. Importantly, both cases show highly sensitive BINN latent variables correlate with the experimental quantities they represent, despite not being trained on them. This suggests BINNs learn biologically-relevant representations, nonlinear or linear, from genotype to phenotype. Together, BINNs establish a framework that leverages intermediate domain information to improve genomic prediction accuracy and reveal nonlinear biological relationships that can guide genomic selection, candidate gene selection, pathway enrichment, and gene-editing prioritization.

The competitive and cooperative forces of natural selection have driven the evolution of intelligence for millions of years, culminating in nature's vast biodiversity and the complexity of human minds. Inspired by this process, we propose a novel multi-agent reinforcement learning framework where each agent is assigned a genotype and where reward functions are modelled after the concept of inclusive fitness. An agent's genetic material may be shared with other agents, and our inclusive reward function naturally accounts for this. We study the resulting social dynamics in two types of network games with prisoner's dilemmas and find that our results align with well-established principles from biology, such as Hamilton's rule. Furthermore, we outline how this framework can extend to more open-ended environments with spatial and temporal structure, finite resources, and evolving populations. We hypothesize the emergence of an arms race of strategies, where each new strategy is a gradual improvement over earlier adaptations of other agents, effectively producing a multi-agent autocurriculum analogous to biological evolution. In contrast to the binary team-based structures prevalent in earlier research, our gene-based reward structure introduces a spectrum of cooperation ranging from full adversity to full cooperativeness based on genetic similarity, enabling unique non team-based social dynamics. For example, one agent having a mutual cooperative relationship with two other agents, while the two other agents behave adversarially towards each other. We argue that incorporating inclusive fitness in agents provides a foundation for the emergence of more strategically advanced and socially intelligent agents.

Neural Information Processing Systems http://nips.cc/

Variations in complex traits are influenced by multiple genetic variants, environmental risk factors, and their interactions. Though substantial progress has been made in identifying single genetic variants associated with complex traits, detecting the gene-gene and gene-environment interactions remains a great challenge. When a large number of genetic variants and environmental risk factors are involved, searching for interactions is limited to pair-wise interactions due to the exponentially increased feature space and computational intensity. Alternatively, recursive partitioning approaches, such as random forests, have gained popularity in high-dimensional genetic association studies. In this article, we propose a U-Statistic-based random forest approach, referred to as Forest U-Test, for genetic association studies with quantitative traits. Through simulation studies, we showed that the Forest U-Test outperformed existing methods. The proposed method was also applied to study Cannabis Dependence CD, using three independent datasets from the Study of Addiction: Genetics and Environment. A significant joint association was detected with an empirical p-value less than 0.001. The finding was also replicated in two independent datasets with p-values of 5.93e-19 and 4.70e-17, respectively.

While progress has been made in identifying common genetic variants associated with human diseases, for most of common complex diseases, the identified genetic variants only account for a small proportion of heritability. Challenges remain in finding additional unknown genetic variants predisposing to complex diseases. With the advance in next-generation sequencing technologies, sequencing studies have become commonplace in genetic research. The ongoing exome-sequencing and whole-genome-sequencing studies generate a massive amount of sequencing variants and allow researchers to comprehensively investigate their role in human diseases. The discovery of new disease-associated variants can be enhanced by utilizing powerful and computationally efficient statistical methods. In this paper, we propose a functional analysis of variance (FANOVA) method for testing an association of sequence variants in a genomic region with a qualitative trait. The FANOVA has a number of advantages: (1) it tests for a joint effect of gene variants, including both common and rare; (2) it fully utilizes linkage disequilibrium and genetic position information; and (3) allows for either protective or risk-increasing causal variants. Through simulations, we show that FANOVA outperform two popularly used methods - SKAT and a previously proposed method based on functional linear models (FLM), - especially if a sample size of a study is small and/or sequence variants have low to moderate effects. We conduct an empirical study by applying three methods (FANOVA, SKAT and FLM) to sequencing data from Dallas Heart Study. While SKAT and FLM respectively detected ANGPTL 4 and ANGPTL 3 associated with obesity, FANOVA was able to identify both genes associated with obesity.

Isocitrate DeHydrogenase (IDH) mutation status is a crucial biomarker for glioma prognosis. However, current prediction methods are limited by the low availability and noise of functional MRI. Structural and morphological connectomes offer a non-invasive alternative, yet existing approaches often ignore the brain's hierarchical organisation and multiscale interactions. To address this, we propose Hi-SMGNN, a hierarchical framework that integrates structural and morphological connectomes from regional to modular levels. It features a multimodal interaction module with a Siamese network and cross-modal attention, a multiscale feature fusion mechanism for reducing redundancy, and a personalised modular partitioning strategy to enhance individual specificity and interpretability. Experiments on the UCSF-PDGM dataset demonstrate that Hi-SMGNN outperforms baseline and state-of-the-art models, showing improved robustness and effectiveness in IDH mutation prediction.