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  • 1
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii148-ii148
    Abstract: Glioblastoma is the most common and aggressive adult brain tumor. Clinical histopathologic evaluation is essential for tumor classification, which according to the World Health Organization is associated with prognostic information. Accurate prediction of patient overall survival (OS) from clinical routine baseline histopathology whole slide images (WSI) using advanced computational methods, while considering variations in the staining process, could contribute to clinical decision-making and patient management optimization. METHODS We utilize The Cancer Genome Atlas glioblastoma (TCGA-GBM) collection, comprising multi-institutional hematoxylin and eosin (H & E) stained frozen top-section WSI, genomic, and clinical data from 121 subjects. Data are randomly split into training (80%), validation (10%), and testing (10%) sets, while proportionally keeping the ratio of censored patients. We propose a novel deep learning algorithm to identify survival-discriminative histopathological patterns in a WSI, through feature maps, and quantitatively integrate them with gene expression and clinical data to predict patient OS. The concordance index (C-index) is used to quantify the predictive OS performance. Variations in slide staining are assessed through a novel population-based stain normalization approach, informed of glioblastoma distinct histologic sub-regions and their appearance from 509 H & E stained slides with corresponding anatomical annotations from the Ivy Glioblastoma Atlas Project (IvyGAP). RESULTS C-index was equal to 0.797, 0.713, and 0.703 for the training, validation, and testing data, respectively, prior to stain normalization. Following normalization, staining variations in H & E and ‘E’ gained significant improvements in IvyGAP (pWilcoxon & lt; 0.01) and TCGA-GBM (pWilcoxon & lt; 0.0001) data, respectively. These improvements contributed to further optimizing the C-index to 0.871, 0.777, and 0.780 for the training, validation, and testing data, respectively. CONCLUSIONS Appropriate normalization and integrative deep learning yield accurate OS prediction of glioblastoma patients through H & E slides, generalizable in multi-institutional data, potentially contributing to patient stratification in clinical trials. Our computationally-identified survival-discriminative histopathological patterns can contribute in further understanding glioblastoma.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 2
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii82-ii83
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii82-ii83
    Abstract: Histopathologic evaluation has been an integral part of clinical diagnosis for central nervous system tumors, providing information essential for classification, management, and treatment of the disease. Hematoxylin and eosin (H & E) staining is routinely used in histology, providing detail of tissue morphology, structure, and cellular composition. MOTIVATION: Slide staining is rife with color intensity variations, mainly due to differences in materials and staining protocols among others. These variations introduce inaccuracies in downstream computational analysis and quantification of disease, disabling the generalization of computational models. To overcome these variations, current approaches arbitrarily select a slide within the cohort to normalize all slides of the cohort, leading to non-reproducible results in other cohorts. We develop a population-based whole slide image (WSI) normalization method based on overall region driven stain vectors and color histogram, weighted by corresponding percent contribution to overall slide (PCOS). METHODS: We identified a cohort of 509 H & E stained WSIs with corresponding anatomical annotations from the Ivy Glioblastoma Atlas Project. These WSIs and annotations were reviewed by two neuropathologists for correctly annotated regions. Each region was weighted according to PCOS, WSIs with PCOS & lt; 0.05% were discarded. Then, the optical densities and histograms calculated. Resulting color histogram and optical density was applied to the WSI cohort. Finally, stain intensity variability pre- and post- normalization was compared. RESULTS: Normalizing WSIs based on our approach, results in a significant (p & lt; 0.01, Wilcoxon) improvement in color intensity variation for eight of nine regions tested, with the exception of “Pseudopalisading Cells with no visible Necrosis” (p = 0.8). DISCUSSION: This novel transformative technique is insensitive to artificially staining background density and straightforward to apply. Furthermore, the approach shows promise towards a viable and robust tool for stain normalization in large WSIs cohorts, with the potential towards a stain normalization standard generalizable to other diseases.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2094060-9
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  • 3
    In: Diabetes, American Diabetes Association, Vol. 72, No. Supplement_1 ( 2023-06-20)
    Abstract: Type 2 diabetes (T2D) mellitus is a complex polygenic disease. Multiple genome-wide association studies (GWAS) have identified hundreds of T2D-related genetic variants, the vast majority of which are non-coding. Pinpointing the actual causal variants and their target gene transcripts has been challenging. Building on recent advances in CRISPR technology and protocols that allow differentiation into functional pancreatic beta cells, we created isogenic hPSCs encompassing knockout (KO) mutations in 20 GWAS-identified T2D risk genes, and systematically examined their roles in beta cell differentiation, insulin production, glucose response, and apoptosis. As a result, loss of TCF7L2, HNF4A, TLE4, TGFB1, GIPR and COBLL1 severely impaired the differentiation capacities of hPSCs into functional beta cells and over half of the 20 T2D genes shared implications in beta cell dysfunctions including decreased insulin content, impaired insulin secretion and high susceptibility to lipotoxicity. Next, we sorted beta cells from each KO and performed RNA-seq and ATAC-seq assays. An integrative analysis revealed KO of HNF4A, HNF1A, ABCC8, KCNJ11, TLE4 and WDR13 resulted in extensive transcriptomic and epigenetic changes in the beta cells. We identify that KO of HNF4A results in dramatic expressional changes of dozens of known T2D effector genes and additional ones critical to beta cell functions and biology. An analysis of T2D GWAS credible set of SNPs using ATAC-seq and RNA-seq coupled with functional assays, helped us to nominate a single likely T2D causal SNP (rs7132908) at FAIM2 locus. Finally, a correlation analysis of gene expression levels and insulin content across KO lines identified 1,867 differential genes including PCSK1N that likely serves as a hub gene by mediating insulin production in beta cells. This study thus offers a powerful strategy to interrogate shared molecular pathways among multiple risk genes for diabetes. Disclosure D.Xue: None. J.Vandana: None. A.Chong: None. F.S.Collins: None. S.Chen: Consultant; Vesalius Therapeutics, Stock/Shareholder; Oncobeat Theraputics. N.Narisu: None. T.Yan: None. M.Zhang: None. C.Grenko: None. X.Tang: None. J.Zhu: None. L.L.Bonnycastle: None. M.Erdos: None. Funding American Diabetes Association (9-22-PDFPM-06 to D.X.)
    Type of Medium: Online Resource
    ISSN: 0012-1797
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2023
    detail.hit.zdb_id: 1501252-9
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  • 4
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 7 ( 2023-02-14)
    Abstract: Genetic studies have identified ≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans- acting genetic components and mapping cis -acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans -acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Institute of Electrical and Electronics Engineers (IEEE) ; 2022
    In:  IEEE Open Journal of Engineering in Medicine and Biology Vol. 3 ( 2022), p. 218-226
    In: IEEE Open Journal of Engineering in Medicine and Biology, Institute of Electrical and Electronics Engineers (IEEE), Vol. 3 ( 2022), p. 218-226
    Type of Medium: Online Resource
    ISSN: 2644-1276
    Language: Unknown
    Publisher: Institute of Electrical and Electronics Engineers (IEEE)
    Publication Date: 2022
    detail.hit.zdb_id: 3012072-X
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  • 6
    In: Communications Engineering, Springer Science and Business Media LLC, Vol. 2, No. 1 ( 2023-05-16)
    Abstract: Deep Learning (DL) has the potential to optimize machine learning in both the scientific and clinical communities. However, greater expertise is required to develop DL algorithms, and the variability of implementations hinders their reproducibility, translation, and deployment. Here we present the community-driven Generally Nuanced Deep Learning Framework (GaNDLF), with the goal of lowering these barriers. GaNDLF makes the mechanism of DL development, training, and inference more stable, reproducible, interpretable, and scalable, without requiring an extensive technical background. GaNDLF aims to provide an end-to-end solution for all DL-related tasks in computational precision medicine. We demonstrate the ability of GaNDLF to analyze both radiology and histology images, with built-in support for k -fold cross-validation, data augmentation, multiple modalities and output classes. Our quantitative performance evaluation on numerous use cases, anatomies, and computational tasks supports GaNDLF as a robust application framework for deployment in clinical workflows.
    Type of Medium: Online Resource
    ISSN: 2731-3395
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 3121995-0
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