Machine-learning-based integrative -'omics analyses reveal immunologic and metabolic dysregulation in environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is a subclinical enteropathy challenging to diagnose due to an overlap of tissue features with other inflammatory enteropathies. EED subjects (n = 52) from Pakistan, controls (n = 25), and a validation EED cohort (n = 30) from Zambia were used to develop a machine-learning-based image analysis classification model. We extracted histologic feature representations from the Pakistan EED model and correlated them to transcriptomics and clinical biomarkers. In-silico metabolic network modeling was used to characterize alterations in metabolic flux between EED and controls and validated using untargeted lipidomics. Genes encoding beta-ureidopropionase, CYP4F3, and epoxide hydrolase 1 correlated to numerous tissue feature representations. Fatty acid and glycerophospholipid metabolism-related reactions showed altered flux. Increased phosphatidylcholine, lysophosphatidylcholine (LPC), and ether-linked LPCs, and decreased ester-linked LPCs were observed in the duodenal lipidome of Pakistan EED subjects, while plasma levels of glycine-conjugated bile acids were significantly increased. Together, these findings elucidate a multi-omic signature of EED.

Identifying metabolic shifts in Crohn's disease using' omics-driven contextualized computational metabolic network models.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. A clear gap in our existing CD diagnostics and current disease management approaches is the lack of highly specific biomarkers that can be used to streamline or personalize disease management. Comprehensive profiling of metabolites holds promise; however, these high-dimensional profiles need to be reduced to have relevance in the context of CD. Machine learning approaches are optimally suited to bridge this gap in knowledge by contextualizing the metabolic alterations in CD using genome-scale metabolic network reconstructions. Our work presents a framework for studying altered metabolic reactions between patients with CD and controls using publicly available transcriptomic data and existing gene-driven metabolic network reconstructions. Additionally, we apply the same methods to patient-derived ileal enteroids to explore the utility of using this experimental in vitro platform for studying CD. Furthermore, we have piloted an untargeted metabolomics approach as a proof-of-concept validation strategy in human ileal mucosal tissue. These findings suggest that in silico metabolic modeling can potentially identify pathways of clinical relevance in CD, paving the way for the future discovery of novel diagnostic biomarkers and therapeutic targets.

Distance from Healthcare Facilities Is Associated with Increased Morbidity of Acute Infection in Pediatric Patients in Matiari, Pakistan.

The relationship between environmental factors and child health is not well understood in rural Pakistan. This study characterized the environmental factors related to the morbidity of acute respiratory infections (ARIs), diarrhea, and growth using geographical information systems (GIS) technology. Anthropometric, address and disease prevalence data were collected through the SEEM (Study of Environmental Enteropathy and Malnutrition) study in Matiari, Pakistan. Publicly available map data were used to compile coordinates of healthcare facilities. A Pearson correlation coefficient (r) was used to calculate the correlation between distance from healthcare facilities and participant growth and morbidity. Other continuous variables influencing these outcomes were analyzed using a random forest regression model. In this study of 416 children, we found that participants living closer to secondary hospitals had a lower prevalence of ARI (r = 0.154, p < 0.010) and diarrhea (r = 0.228, p < 0.001) as well as participants living closer to Maternal Health Centers (MHCs): ARI (r = 0.185, p < 0.002) and diarrhea (r = 0.223, p < 0.001) compared to those living near primary facilities. Our random forest model showed that distance has high variable importance in the context of disease prevalence. Our results indicated that participants closer to more basic healthcare facilities reported a higher prevalence of both diarrhea and ARI than those near more urban facilities, highlighting potential public policy gaps in ameliorating rural health.

Self-Attentive Adversarial Stain Normalization.

Hematoxylin and Eosin (H&E) stained Whole Slide Images (WSIs) are utilized for biopsy visualization-based diagnostic and prognostic assessment of diseases. Variation in the H&E staining process across different lab sites can lead to significant variations in biopsy image appearance. These variations introduce an undesirable bias when the slides are examined by pathologists or used for training deep learning models. Traditionally proposed stain normalization and color augmentation strategies can handle the human level bias. But deep learning models can easily disentangle the linear transformation used in these approaches, resulting in undesirable bias and lack of generalization. To handle these limitations, we propose a Self-Attentive Adversarial Stain Normalization (SAASN) approach for the normalization of multiple stain appearances to a common domain. This unsupervised generative adversarial approach includes self-attention mechanism for synthesizing images with finer detail while preserving the structural consistency of the biopsy features during translation. SAASN demonstrates consistent and superior performance compared to other popular stain normalization techniques on H&E stained duodenal biopsy image data.

Artificial Intelligence-based Analytics for Diagnosis of Small Bowel Enteropathies and Black Box Feature Detection.

OBJECTIVES: Striking histopathological overlap between distinct but related conditions poses a disease diagnostic challenge. There is a major clinical need to develop computational methods enabling clinicians to translate heterogeneous biomedical images into accurate and quantitative diagnostics. This need is particularly salient with small bowel enteropathies; environmental enteropathy (EE) and celiac disease (CD). We built upon our preliminary analysis by developing an artificial intelligence (AI)-based image analysis platform utilizing deep learning convolutional neural networks (CNNs) for these enteropathies. METHODS: Data for the secondary analysis was obtained from three primary studies at different sites. The image analysis platform for EE and CD was developed using CNNs including one with multizoom architecture. Gradient-weighted class activation mappings (Grad-CAMs) were used to visualize the models' decision-making process for classifying each disease. A team of medical experts simultaneously reviewed the stain color normalized images done for bias reduction and Grad-CAMs to confirm structural preservation and biomedical relevance, respectively. RESULTS: Four hundred and sixty-one high-resolution biopsy images from 150 children were acquired. Median age (interquartile range) was 37.5 (19.0-121.5) months with a roughly equal sex distribution; 77 males (51.3%). ResNet50 and shallow CNN demonstrated 98% and 96% case-detection accuracy, respectively, which increased to 98.3% with an ensemble. Grad-CAMs demonstrated models' ability to learn different microscopic morphological features for EE, CD, and controls. CONCLUSIONS: Our AI-based image analysis platform demonstrated high classification accuracy for small bowel enteropathies which was capable of identifying biologically relevant microscopic features and emulating human pathologist decision-making process. Grad-CAMs illuminated the otherwise "black box" of deep learning in medicine, allowing for increased physician confidence in adopting these new technologies in clinical practice.

Artificial Intelligence Applied to Gastrointestinal Diagnostics: A Review.

Artificial intelligence (AI), a discipline encompassed by data science, has seen recent rapid growth in its application to healthcare and beyond, and is now an integral part of daily life. Uses of AI in gastroenterology include the automated detection of disease and differentiation of pathology subtypes and disease severity. Although a majority of AI research in gastroenterology focuses on adult applications, there are a number of pediatric pathologies that could benefit from more research. As new and improved diagnostic tools become available and more information is retrieved from them, AI could provide physicians a method to distill enormous amounts of data into enhanced decision-making and cost saving for children with digestive disorders. This review provides a broad overview of AI and examples of its possible applications in pediatric gastroenterology.