Linking histology and molecular state across human tissues

Histological imaging and molecular profiling of human tissues both offer information-rich characterizations of biological structure and function. Each of these modalities has been used to characterize the organization and dysregulation of a variety of tissues and cell types. While large-scale studies of each modality in isolation have been conducted, it remains largely unknown the extent to which these two views of a tissue relate to one another. Understanding how cellular states are encoded in cellular morphology would increase the utility and interpretability of imaging data; conversely, understanding the state of the cells within histology images would give deeper insights into the types and states of cells that constitute these tissue samples. To this end, we jointly analyzed 13, 360 human tissue samples with paired bulk gene expression profiles and histology images across 935 donors from the Genotype and Tissue Expression (GTEx) Consortium v8 study. This analysis reveals relationships among gene expression and cellular morphology through shared sources of expression and morphological heterogeneity both within and between tissue types. We describe shared sources of variation including cell-type heterogeneity, sample ischemic time, and donor health and demographics. We find specific correlated effects in both morphology and transcription linked to specific donor characteristics, such as their use of mechanical ventilation. This paired understanding adds value to each data modality on their own by enabling a more precise characterization of the alternative modality in the absence of those data.