Spatial transcriptomics enables the contextualization of gene expression with spatial organization, advancing our understanding of development, disease, and tissue architecture. However, existing analysis pipelines require multiple tools to explore spatial domains, and few methods can jointly analyse spatial data from annotation-free and annotation-guided perspectives with high interpretability. We therefore propose the Spatial Topic Model (SpaTM), a topic-modelling framework capable of annotation-guided and annotation-free analysis of spatial transcriptomes. SpaTM can learn gene programs that represent histology-based annotations while also inferring spatial domains with an annotation-free approach if manual annotations are limited or noisy. In benchmarking experiments, SpaTM achieves competitive performance at spatial label prediction and clustering when compared with existing state-of-the-art methods. We demonstrate SpaTM's interpretability by using topic mixtures to capture transcriptional programs in dorsolateral prefrontal cortex and ductal carcinoma samples and show how its intuitive framework facilitates the integration of spatial transcriptomics tasks. Finally, we showcase how SpaTM can extend the analysis of large-scale snRNA-seq atlases in human brains with Major Depressive Disorder. Overall, SpaTM provides a unified and interpretable analysis framework for spatial transcriptomics, enabling competitive performance in multiple tasks while inferring biologically informed gene programs.

MOTIVATION: Colocalization analysis is commonly used to assess whether two or more traits share the same genetic signals identified in genome-wide association studies (GWAS), and is important for prioritizing targets for functional follow-up of GWAS results. Existing colocalization methods can have suboptimal performance when there are multiple causal variants in one genomic locus. RESULTS: We propose SharePro to extend the COLOC framework for colocalization analysis. SharePro integrates linkage disequilibrium (LD) modeling and colocalization assessment by grouping correlated variants into effect groups. With an efficient variational inference algorithm, posterior colocalization probabilities can be accurately estimated. In simulation studies, SharePro demonstrated increased power with a well-controlled false positive rate at a low computational cost. Compared to existing methods, SharePro provided stronger and more consistent colocalization evidence for known lipid-lowering drug target proteins and their corresponding lipid traits. Through an additional challenging case of the colocalization analysis of the circulating abundance of R-spondin 3 GWAS and estimated bone mineral density GWAS, we demonstrated the utility of SharePro in identifying biologically plausible colocalized signals. AVAILABILITY AND IMPLEMENTATION: SharePro for colocalization analysis is written in Python and openly available at https://github.com/zhwm/SharePro_coloc.

BACKGROUND: DNA microarrays are popular tools for measuring gene expression of biological samples. This ever increasing popularity is ensuring that a large number of microarray studies are conducted, many of which with data publicly available for mining by other investigators. Under most circumstances, validation of differential expression of genes is performed on a gene to gene basis. Thus, it is not possible to generalize validation results to the remaining majority of non-validated genes or to evaluate the overall quality of these studies. RESULTS: We present an approach for the global validation of DNA microarray experiments that will allow researchers to evaluate the general quality of their experiment and to extrapolate validation results of a subset of genes to the remaining non-validated genes. We illustrate why the popular strategy of selecting only the most differentially expressed genes for validation generally fails as a global validation strategy and propose random-stratified sampling as a better gene selection method. We also illustrate shortcomings of often-used validation indices such as overlap of significant effects and the correlation coefficient and recommend the concordance correlation coefficient (CCC) as an alternative. CONCLUSION: We provide recommendations that will enhance validity checks of microarray experiments while minimizing the need to run a large number of labour-intensive individual validation assays.