Recent advances in false discovery rate (FDR)-controlled feature selection methods have improved reliability by effectively limiting false positives, making them wellsuited for complex applications. A popular FDR-controlled framework called data splitting uses the "mirror statistics" to select features. However, we find that the unit variance assumption on mirror statistics could potentially limit the feature selection power. To address this, we generalize the mirror statistics in the Gaussian mirror framework and introduce a new approach called "generalized Gaussian mirror" (G2M), which adaptively learns the variance and forms new test statistics. We demonstrate both theoretically and empirically that the proposed test statistics achieve higher power than those of Gaussian mirror and data splitting. Comparisons with other FDR-controlled frameworks on synthetic, semi-synthetic, and real datasets highlight the superior performance of the G2M method in achieving higher power while maintaining FDR control. These findings suggest the potential for the G2M method for practical applications in real-world problems. Code is available at: https://github.com/skyve2012/G2M.

Since itsintroduction inparametric design, knockofftechniques haveevolvedto handle arbitrary data distributions using deep learning-based generative models.

The generated candidates are novel at both the molecular and chemical scaffold levels when compared to the training data.

The advancement of human healthspan and bioengineering relies heavily on predicting the behavior of complex biological systems. While high-throughput multiomics data is becoming increasingly abundant, converting this data into actionable predictive models remains a bottleneck. High-capacity, datadriven simulation systems are critical in this landscape; unlike classical mechanistic models restricted by prior knowledge, these architectures can infer latent interactions directly from observational data, allowing for the simulation of temporal trajectories and the anticipation of downstream intervention effects in personalized medicine and synthetic biology. To address this challenge, we introduce Neural Ordinary Differential Equations (NODEs) as a dynamic framework for learning the complex interplay between the proteome and metabolome. We applied this framework to time-series data derived from engineered Escherichia coli strains, modeling the continuous dynamics of metabolic pathways. The proposed NODE architecture demonstrates superior performance in capturing system dynamics compared to traditional machine learning pipelines. Our results show a greater than 90% improvement in root mean squared error over baselines across both Limonene (up to 94.38% improvement) and Isopentenol (up to 97.65% improvement) pathway datasets. Furthermore, the NODE models demonstrated a 1000x acceleration in inference time, establishing them as a scalable, high-fidelity tool for the next generation of metabolic engineering and biological discovery.

This study systematically compared data-driven and model-based strategies for metabolite quantification in magnetic resonance spectroscopy (MRS), focusing on resilience to out-of-distribution (OoD) effects and the balance between accuracy, robustness, and generalizability. A neural network designed for MRS quantification was trained using three distinct strategies: supervised regression, self-supervised learning, and test-time adaptation. These were compared against model-based fitting tools. Experiments combined large-scale simulated data, designed to probe metabolite concentration extrapolation and signal variability, with 1H single-voxel 7T in-vivo human brain spectra. In simulations, supervised learning achieved high accuracy for spectra similar to those in the training distribution, but showed marked degradation when extrapolated beyond the training distribution. Test-time adaptation proved more resilient to OoD effects, while self-supervised learning achieved intermediate performance. In-vivo experiments showed larger variance across the methods (data-driven and model-based) due to domain shift. Across all strategies, overlapping metabolites and baseline variability remained persistent challenges. While strong performance can be achieved by data-driven methods for MRS metabolite quantification, their reliability is contingent on careful consideration of the training distribution and potential OoD effects. When such conditions in the target distribution cannot be anticipated, test-time adaptation strategies ensure consistency between the quantification, the data, and the model, enabling reliable data-driven MRS pipelines.

In genome-scale constraint-based metabolic models, gene deletion strategies are essential for achieving growth-coupled production, where cell growth and target metabolite synthesis occur simultaneously. Despite the inherently networked nature of genome-scale metabolic models, existing computational approaches rely primarily on sequential data and lack graph representations that capture their complex relationships, as both well-defined graph constructions and learning frameworks capable of exploiting them remain largely unexplored. To address this gap, we present a twofold solution. First, we introduce a systematic pipeline for constructing graph representations from constraint-based metabolic models. Second, we develop a deep learning framework that integrates these graph representations with gene and metabolite sequence data to predict growth-coupled gene deletion strategies. Across three metabolic models of varying scale, our approach consistently outperforms established baselines, achieves improvements of 14.04%, 16.26%, and 13.18% in overall accuracy. The source code and example datasets are available at: https://github.com/MetNetComp/GraphGDel.

Large Language Models (LLMs) have demonstrated remarkable capabilities on general text; however, their proficiency in specialized scientific domains that require deep, interconnected knowledge remains largely uncharacterized. Metabolomics presents unique challenges with its complex biochemical pathways, heterogeneous identifier systems, and fragmented databases. To systematically evaluate LLM capabilities in this domain, we introduce MetaBench, the first benchmark for metabolomics assessment. Curated from authoritative public resources, MetaBench evaluates five capabilities essential for metabolomics research: knowledge, understanding, grounding, reasoning, and research. Our evaluation of 25 open- and closed-source LLMs reveals distinct performance patterns across metabolomics tasks: while models perform well on text generation tasks, cross-database identifier grounding remains challenging even with retrieval augmentation. Model performance also decreases on long-tail metabolites with sparse annotations. With MetaBench, we provide essential infrastructure for developing and evaluating metabolomics AI systems, enabling systematic progress toward reliable computational tools for metabolomics research.

Model-X knockoff has garnered significant attention among various feature selection methods due to its guarantees for controlling the false discovery rate (FDR).

The generated candidates are novel at both the molecular and chemical scaffold levels when compared to the training data.

The analysis of spatial data from biological imaging technology, such as imaging mass spectrometry (IMS) or imaging mass cytometry (IMC), is challenging because of a competitive sampling process which convolves signals from molecules in a single pixel. To address this, we develop a scalable Bayesian framework that leverages natural sparsity in spatial signal patterns to recover relative rates for each molecule across the entire image. Our method relies on the use of a heavy-tailed variant of the graphical lasso prior and a novel hierarchical variational family, enabling efficient inference via automatic differentiation variational inference. Simulation results show that our approach outperforms state-of-the-practice point estimate methodologies in IMS, and has superior posterior coverage than mean-field variational inference techniques. Results on real IMS data demonstrate that our approach better recovers the true anatomical structure of known tissue, removes artifacts, and detects active regions missed by the standard analysis approach.