Intra-tumoral heterogeneity and cell-state plasticity are key drivers for the therapeutic resistance of glioblastoma. Here, we investigate the association between spatial cellular organization and glioblastoma prognosis. Leveraging single-cell RNA-seq and spatial transcriptomics data, we develop a deep learning model to predict transcriptional subtypes of glioblastoma cells from histology images. Employing this model, we phenotypically analyze 40 million tissue spots from 410 patients and identify consistent associations between tumor architecture and prognosis across two independent cohorts. Patients with poor prognosis exhibit higher proportions of tumor cells expressing a hypoxia-induced transcriptional program. Furthermore, a clustering pattern of astrocyte-like tumor cells is associated with worse prognosis, while dispersion and connection of the astrocytes with other transcriptional subtypes correlate with decreased risk. To validate these results, we develop a separate deep learning model that utilizes histology images to predict prognosis. Applying this model to spatial transcriptomics data reveal survival-associated regional gene expression programs. Overall, our study presents a scalable approach to unravel the transcriptional heterogeneity of glioblastoma and establishes a critical connection between spatial cellular architecture and clinical outcomes.

Undetected infection and delayed isolation of infected individuals are key factors driving the monkeypox virus (now termed mpox virus or MPXV) outbreak. To enable earlier detection of MPXV infection, we developed an image-based deep convolutional neural network (named MPXV-CNN) for the identification of the characteristic skin lesions caused by MPXV. We assembled a dataset of 139,198 skin lesion images, split into training/validation and testing cohorts, comprising non-MPXV images (n = 138,522) from eight dermatological repositories and MPXV images (n = 676) from the scientific literature, news articles, social media and a prospective cohort of the Stanford University Medical Center (n = 63 images from 12 patients, all male). In the validation and testing cohorts, the sensitivity of the MPXV-CNN was 0.83 and 0.91, the specificity was 0.965 and 0.898 and the area under the curve was 0.967 and 0.966, respectively. In the prospective cohort, the sensitivity was 0.89. The classification performance of the MPXV-CNN was robust across various skin tones and body regions. To facilitate the usage of the algorithm, we developed a web-based app by which the MPXV-CNN can be accessed for patient guidance. The capability of the MPXV-CNN for identifying MPXV lesions has the potential to aid in MPXV outbreak mitigation.

Background The introduction of deep learning in both imaging and genomics has significantly advanced the analysis of biomedical data. For complex diseases such as cancer, different data modalities may reveal different disease characteristics, and the integration of imaging with genomic data has the potential to unravel additional information than when using these data sources in isolation. Here, we propose a DL framework that combines these two modalities with the aim to predict brain tumor prognosis. Methods Using two separate glioma cohorts of 783 adults and 305 pediatric patients we developed a DL framework that can fuse histopathology images with gene expression profiles. Three strategies for data fusion were implemented and compared: early, late, and joint fusion. Additional validation of the adult glioma models was done on an independent cohort of 97 adult patients. Results Here we show that the developed multimodal data models achieve better prediction results compared to the single data models, but also lead to the identification of more relevant biological pathways. When testing our adult models on a third brain tumor dataset, we show our multimodal framework is able to generalize and performs better on new data from different cohorts. Leveraging the concept of transfer learning, we demonstrate how our pediatric multimodal models can be used to predict prognosis for two more rare (less available samples) pediatric brain tumors. Conclusions Our study illustrates that a multimodal data fusion approach can be successfully implemented and customized to model clinical outcome of adult and pediatric brain tumors.

DNA methylation (DNAme) is a major epigenetic factor influencing gene expression with alterations leading to cancer, immunological, and cardiovascular diseases. Recent technological advances enable genome-wide quantification of DNAme in large human cohorts. So far, existing methods have not been evaluated to identify differential DNAme present in large and heterogeneous patient cohorts. We developed an end-to-end analytical framework named "EpiMix" for population-level analysis of DNAme and gene expression. Compared to existing methods, EpiMix showed higher sensitivity in detecting abnormal DNAme that was present in only small patient subsets. We extended the model-based analyses of EpiMix to cis-regulatory elements within protein-coding genes, distal enhancers, and genes encoding microRNAs and lncRNAs. Using cell-type specific data from two separate studies, we discovered novel epigenetic mechanisms underlying childhood food allergy and survival-associated, methylation-driven non-coding RNAs in non-small cell lung cancer.

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