Malsot, P.; Londschien, M.; Boeva, V.; Raetsch, G.

Motivation: 10x Genomics VisiumHD enables spatial transcriptomics at 2 m x 2 m resolution but exhibits slide-specific, non-periodic striping artifacts due to lane-width variability. These multiplicative row/column effects distort bin total counts and can bias downstream analyses. The state-of-the-art destriping approach is the normalization procedure used as a preprocessing step in bin2cell; it applies sequential high-quantile row- then column-wise normalization, which is asymmetric and can introduce edge effects/macro-stripes and distortions of large-scale total-count structure. Results: We propose a statistical destriping approach that leverages nuclei segmentation from the co-registered H&E image. Assuming transcript abundance is constant within each nucleus, we model bin counts with a negative binomial distribution whose mean is a product of a nucleus-specific concentration and row- and column-specific stripe-factors reflecting lane-width variation. We fit all parameters in a generalized linear modeling framework with cross-validated regularization on stripe-factors and iterative dispersion estimation, and use the fitted parameters to correct the observed counts into a destriped image. On synthetic data with known ground truth, our method improves stripe-factor estimation accuracy and reduces error in corrected counts relative to bin2cell and bin2cell-derived baselines. Across four public VisiumHD slides, it consistently lowers striping intensity while substantially better preserving biological signal present in the large-scale global count structure and avoiding the artifacts introduced by other methods. Availability and Implementation: All source code and links to publicly available data used for this study are available at https://github.com/paolamalsot/destriping-GLM. Contact: [email protected], [email protected] Note: This manuscript extends the version submitted to Intelligent Systems for Molecular Biology (ISMB) 2026 by describing a new optimization algorithm that yields an approximately tenfold speedup. All plots and benchmarks in this manuscript use the updated implementation.