Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0051
Brooke L. Fridley, Simon Vandekar, Inna Chervoneva, Julia Wrobel, Siyuan Ma
Immune modulation is considered a hallmark of cancer initiation and progression, with immune cell density being consistently associated with clinical outcomes of individuals with cancer. Multiplex immunofluorescence (mIF) microscopy combined with automated image analysis is a novel and increasingly used technique that allows for the assessment and visualization of the tumor microenvironment (TME). Recently, application of this new technology to tissue microarrays (TMAs) or whole tissue sections from large cancer studies has been used to characterize different cell populations in the TME with enhanced reproducibility and accuracy. Generally, mIF data has been used to examine the presence and abundance of immune cells in the tumor and stroma compartments; however, this aggregate measure assumes uniform patterns of immune cells throughout the TME and overlooks spatial heterogeneity. Recently, the spatial contexture of the TME has been explored with a variety of statistical methods. In this PSB workshop, speakers will present some of the state-of-the-art statistical methods for assessing the TIME from mIF data.
免疫调节被认为是癌症发生和发展的一个标志，免疫细胞密度一直与癌症患者的临床预后相关。多重免疫荧光（mIF）显微镜与自动图像分析相结合，是一种新颖的、应用日益广泛的技术，可对肿瘤微环境（TME）进行评估和可视化。最近，将这项新技术应用于组织微阵列（TMA）或大型癌症研究的整个组织切片已被用来描述肿瘤微环境中不同细胞群的特征，并提高了可重复性和准确性。一般来说，mIF 数据被用来检测肿瘤和基质区免疫细胞的存在和丰度；然而，这种综合测量方法假定整个 TME 中免疫细胞的模式是一致的，而忽略了空间异质性。最近，人们利用各种统计方法对肿瘤组织间质的空间背景进行了探索。在本次 PSB 研讨会上，演讲者将介绍从 mIF 数据中评估 TIME 的一些最新统计方法。
{"title":"Statistical analysis of single-cell protein data.","authors":"Brooke L. Fridley, Simon Vandekar, Inna Chervoneva, Julia Wrobel, Siyuan Ma","doi":"10.1142/9789811286421_0051","DOIUrl":"https://doi.org/10.1142/9789811286421_0051","url":null,"abstract":"Immune modulation is considered a hallmark of cancer initiation and progression, with immune cell density being consistently associated with clinical outcomes of individuals with cancer. Multiplex immunofluorescence (mIF) microscopy combined with automated image analysis is a novel and increasingly used technique that allows for the assessment and visualization of the tumor microenvironment (TME). Recently, application of this new technology to tissue microarrays (TMAs) or whole tissue sections from large cancer studies has been used to characterize different cell populations in the TME with enhanced reproducibility and accuracy. Generally, mIF data has been used to examine the presence and abundance of immune cells in the tumor and stroma compartments; however, this aggregate measure assumes uniform patterns of immune cells throughout the TME and overlooks spatial heterogeneity. Recently, the spatial contexture of the TME has been explored with a variety of statistical methods. In this PSB workshop, speakers will present some of the state-of-the-art statistical methods for assessing the TIME from mIF data.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"82 ","pages":"654-660"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0045
Kathleen M. Cardone, S. Dudek, K. Keat, Yuki Bradford, Zinhle Cindi, Eric S. Daar, Roy Gulick, Sharon A. Riddler, Jeffrey L. Lennox, P. Sinxadi, David W. Haas, Marylyn D. Ritchie
Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global response to the HIV pandemic. Among people living with HIV, there is considerable interindividual variability in absolute CD4 T-cell recovery following initiation of virally suppressive ART. The contribution of host genetics to this variability is not well understood. We explored the contribution of a polygenic score which was derived from large, publicly available summary statistics for absolute lymphocyte count from individuals in the general population (PGSlymph) due to a lack of publicly available summary statistics for CD4 T-cell count. We explored associations with baseline CD4 T-cell count prior to ART initiation (n=4959) and change from baseline to week 48 on ART (n=3274) among treatment-naïve participants in prospective, randomized ART studies of the AIDS Clinical Trials Group. We separately examined an African-ancestry-derived and a European-ancestry-derived PGSlymph, and evaluated their performance across all participants, and also in the African and European ancestral groups separately. Multivariate models that included PGSlymph, baseline plasma HIV-1 RNA, age, sex, and 15 principal components (PCs) of genetic similarity explained ~26-27% of variability in baseline CD4 T-cell count, but PGSlymph accounted for <1% of this variability. Models that also included baseline CD4 T-cell count explained ~7-9% of variability in CD4 T-cell count increase on ART, but PGSlymph accounted for <1% of this variability. In univariate analyses, PGSlymph was not significantly associated with baseline or change in CD4 T-cell count. Among individuals of African ancestry, the African PGSlymph term in the multivariate model was significantly associated with change in CD4 T-cell count while not significant in the univariate model. When applied to lymphocyte count in a general medical biobank population (Penn Medicine BioBank), PGSlymph explained ~6-10% of variability in multivariate models (including age, sex, and PCs) but only ~1% in univariate models. In summary, a lymphocyte count PGS derived from the general population was not consistently associated with CD4 T-cell recovery on ART. Nonetheless, adjusting for clinical covariates is quite important when estimating such polygenic effects.
获得安全有效的抗逆转录病毒疗法（ART）是全球应对艾滋病大流行的基石。在艾滋病病毒感染者中，开始接受病毒抑制性抗逆转录病毒疗法后，CD4 T 细胞的绝对恢复能力在个体间存在相当大的差异。宿主遗传学对这一变异性的贡献尚不十分清楚。由于缺乏可公开获得的 CD4 T 细胞计数汇总统计数据，我们对多基因评分的贡献进行了探讨，该评分来自可公开获得的大量普通人群绝对淋巴细胞计数汇总统计数据（PGSlymph）。我们探讨了艾滋病临床试验组（AIDS Clinical Trials Group）前瞻性随机抗逆转录病毒疗法（ART）研究中未接受过治疗的参与者中，抗逆转录病毒疗法开始前的 CD4 T 细胞计数基线（4959 人）和从基线到抗逆转录病毒疗法第 48 周的变化（3274 人）之间的关联。我们分别研究了非洲裔和欧洲裔的 PGSlymph，并评估了它们在所有参与者中的表现，以及在非洲裔和欧洲裔群体中的表现。包括 PGSlymph、基线血浆 HIV-1 RNA、年龄、性别和 15 个遗传相似性主成分 (PCs) 的多变量模型解释了基线 CD4 T 细胞计数变异性的约 26-27%，但 PGSlymph 只占这一变异性的 <1%。还包括基线 CD4 T 细胞计数的模型可解释抗逆转录病毒疗法后 CD4 T 细胞计数增加的约 7-9% 的变异性，但 PGSlymph 在这一变异性中所占比例小于 1%。在单变量分析中，PGSlymph 与 CD4 T 细胞计数的基线或变化无明显关联。在非洲血统的个体中，多变量模型中的非洲 PGSlymph 项与 CD4 T 细胞计数的变化显著相关，而在单变量模型中则不显著。当应用于普通医学生物库人群（宾夕法尼亚医学生物库）的淋巴细胞计数时，PGSlymph 在多变量模型（包括年龄、性别和 PCs）中解释了 ~6-10% 的变异，但在单变量模型中仅解释了 ~1%。总之，来自普通人群的淋巴细胞计数 PGS 与抗逆转录病毒疗法的 CD4 T 细胞恢复并不一致。然而，在估计此类多基因效应时，调整临床协变量是非常重要的。
{"title":"Lymphocyte Count Derived Polygenic Score and Interindividual Variability in CD4 T-cell Recovery in Response to Antiretroviral Therapy","authors":"Kathleen M. Cardone, S. Dudek, K. Keat, Yuki Bradford, Zinhle Cindi, Eric S. Daar, Roy Gulick, Sharon A. Riddler, Jeffrey L. Lennox, P. Sinxadi, David W. Haas, Marylyn D. Ritchie","doi":"10.1142/9789811286421_0045","DOIUrl":"https://doi.org/10.1142/9789811286421_0045","url":null,"abstract":"Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global response to the HIV pandemic. Among people living with HIV, there is considerable interindividual variability in absolute CD4 T-cell recovery following initiation of virally suppressive ART. The contribution of host genetics to this variability is not well understood. We explored the contribution of a polygenic score which was derived from large, publicly available summary statistics for absolute lymphocyte count from individuals in the general population (PGSlymph) due to a lack of publicly available summary statistics for CD4 T-cell count. We explored associations with baseline CD4 T-cell count prior to ART initiation (n=4959) and change from baseline to week 48 on ART (n=3274) among treatment-naïve participants in prospective, randomized ART studies of the AIDS Clinical Trials Group. We separately examined an African-ancestry-derived and a European-ancestry-derived PGSlymph, and evaluated their performance across all participants, and also in the African and European ancestral groups separately. Multivariate models that included PGSlymph, baseline plasma HIV-1 RNA, age, sex, and 15 principal components (PCs) of genetic similarity explained ~26-27% of variability in baseline CD4 T-cell count, but PGSlymph accounted for <1% of this variability. Models that also included baseline CD4 T-cell count explained ~7-9% of variability in CD4 T-cell count increase on ART, but PGSlymph accounted for <1% of this variability. In univariate analyses, PGSlymph was not significantly associated with baseline or change in CD4 T-cell count. Among individuals of African ancestry, the African PGSlymph term in the multivariate model was significantly associated with change in CD4 T-cell count while not significant in the univariate model. When applied to lymphocyte count in a general medical biobank population (Penn Medicine BioBank), PGSlymph explained ~6-10% of variability in multivariate models (including age, sex, and PCs) but only ~1% in univariate models. In summary, a lymphocyte count PGS derived from the general population was not consistently associated with CD4 T-cell recovery on ART. Nonetheless, adjusting for clinical covariates is quite important when estimating such polygenic effects.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"857 ","pages":"594 - 610"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0029
Hannah M. Seagle, J. Hellwege, Brian S. Mautz, Chun Li, Yaomin Xu, Siwei Zhang, Dan M. Roden, Tracy L. McGregor, D. V. Velez Edwards, Todd L. Edwards
Many researchers in genetics and social science incorporate information about race in their work. However, migrations (historical and forced) and social mobility have brought formerly separated populations of humans together, creating younger generations of individuals who have more complex and diverse ancestry and race profiles than older age groups. Here, we sought to better understand how temporal changes in genetic admixture influence levels of heterozygosity and impact health outcomes. We evaluated variation in genetic ancestry over 100 birth years in a cohort of 35,842 individuals with electronic health record (EHR) information in the Southeastern United States. Using the software STRUCTURE, we analyzed 2,678 ancestrally informative markers relative to three ancestral clusters (African, East Asian, and European) and observed rising levels of admixture for all clinically-defined race groups since 1990. Most race groups also exhibited increases in heterozygosity and long-range linkage disequilibrium over time, further supporting the finding of increasing admixture in young individuals in our cohort. These data are consistent with United States Census information from broader geographic areas and highlight the changing demography of the population. This increased diversity challenges classic approaches to studies of genotype-phenotype relationships which motivated us to explore the relationship between heterozygosity and disease diagnosis. Using a phenome-wide association study approach, we explored the relationship between admixture and disease risk and found that increased admixture resulted in protective associations with female reproductive disorders and increased risk for diseases with links to autoimmune dysfunction. These data suggest that tendencies in the United States population are increasing ancestral complexity over time. Further, these observations imply that, because both prevalence and severity of many diseases vary by race groups, complexity of ancestral origins influences health and disparities.
{"title":"Evidence of recent and ongoing admixture in the U.S. and influences on health and disparities.","authors":"Hannah M. Seagle, J. Hellwege, Brian S. Mautz, Chun Li, Yaomin Xu, Siwei Zhang, Dan M. Roden, Tracy L. McGregor, D. V. Velez Edwards, Todd L. Edwards","doi":"10.1142/9789811286421_0029","DOIUrl":"https://doi.org/10.1142/9789811286421_0029","url":null,"abstract":"Many researchers in genetics and social science incorporate information about race in their work. However, migrations (historical and forced) and social mobility have brought formerly separated populations of humans together, creating younger generations of individuals who have more complex and diverse ancestry and race profiles than older age groups. Here, we sought to better understand how temporal changes in genetic admixture influence levels of heterozygosity and impact health outcomes. We evaluated variation in genetic ancestry over 100 birth years in a cohort of 35,842 individuals with electronic health record (EHR) information in the Southeastern United States. Using the software STRUCTURE, we analyzed 2,678 ancestrally informative markers relative to three ancestral clusters (African, East Asian, and European) and observed rising levels of admixture for all clinically-defined race groups since 1990. Most race groups also exhibited increases in heterozygosity and long-range linkage disequilibrium over time, further supporting the finding of increasing admixture in young individuals in our cohort. These data are consistent with United States Census information from broader geographic areas and highlight the changing demography of the population. This increased diversity challenges classic approaches to studies of genotype-phenotype relationships which motivated us to explore the relationship between heterozygosity and disease diagnosis. Using a phenome-wide association study approach, we explored the relationship between admixture and disease risk and found that increased admixture resulted in protective associations with female reproductive disorders and increased risk for diseases with links to autoimmune dysfunction. These data suggest that tendencies in the United States population are increasing ancestral complexity over time. Further, these observations imply that, because both prevalence and severity of many diseases vary by race groups, complexity of ancestral origins influences health and disparities.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"137 ","pages":"374-388"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0035
Jiarong Song, Josh Lamstein, Vivek Gopal Ramaswamy, Michelle Webb, Gabriel Zada, Steven Finkbeiner, David W. Craig
Spatial transcriptomics (ST) represents a pivotal advancement in biomedical research, enabling the transcriptional profiling of cells within their morphological context and providing a pivotal tool for understanding spatial heterogeneity in cancer tissues. However, current analytical approaches, akin to single-cell analysis, largely depend on gene expression, underutilizing the rich morphological information inherent in the tissue. We present a novel method integrating spatial transcriptomics and histopathological image data to better capture biologically meaningful patterns in patient data, focusing on aggressive cancer types such as glioblastoma and triple-negative breast cancer. We used a ResNet-based deep learning model to extract key morphological features from high-resolution whole-slide histology images. Spot-level PCA-reduced vectors of both the ResNet-50 analysis of the histological image and the spatial gene expression data were used in Louvain clustering to enable image-aware feature discovery. Assessment of features from image-aware clustering successfully pinpointed key biological features identified by manual histopathology, such as for regions of fibrosis and necrosis, as well as improved edge definition in EGFR-rich areas. Importantly, our combinatorial approach revealed crucial characteristics seen in histopathology that gene-expression-only analysis had missed.Supplemental Material: https://github.com/davcraig75/song_psb2014/blob/main/SupplementaryData.pdf.
{"title":"Enhancing Spatial Transcriptomics Analysis by Integrating Image-Aware Deep Learning Methods.","authors":"Jiarong Song, Josh Lamstein, Vivek Gopal Ramaswamy, Michelle Webb, Gabriel Zada, Steven Finkbeiner, David W. Craig","doi":"10.1142/9789811286421_0035","DOIUrl":"https://doi.org/10.1142/9789811286421_0035","url":null,"abstract":"Spatial transcriptomics (ST) represents a pivotal advancement in biomedical research, enabling the transcriptional profiling of cells within their morphological context and providing a pivotal tool for understanding spatial heterogeneity in cancer tissues. However, current analytical approaches, akin to single-cell analysis, largely depend on gene expression, underutilizing the rich morphological information inherent in the tissue. We present a novel method integrating spatial transcriptomics and histopathological image data to better capture biologically meaningful patterns in patient data, focusing on aggressive cancer types such as glioblastoma and triple-negative breast cancer. We used a ResNet-based deep learning model to extract key morphological features from high-resolution whole-slide histology images. Spot-level PCA-reduced vectors of both the ResNet-50 analysis of the histological image and the spatial gene expression data were used in Louvain clustering to enable image-aware feature discovery. Assessment of features from image-aware clustering successfully pinpointed key biological features identified by manual histopathology, such as for regions of fibrosis and necrosis, as well as improved edge definition in EGFR-rich areas. Importantly, our combinatorial approach revealed crucial characteristics seen in histopathology that gene-expression-only analysis had missed.Supplemental Material: https://github.com/davcraig75/song_psb2014/blob/main/SupplementaryData.pdf.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"49 21","pages":"450-463"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0021
Ayush Jain, Marie Charpignon, Irene Y. Chen, Anthony Philippakis, Ahmed Alaa
The drug development pipeline for a new compound can last 10-20 years and cost over $10 billion. Drug repurposing offers a more time- and cost-effective alternative. Computational approaches based on network graph representations, comprising a mixture of disease nodes and their interactions, have recently yielded new drug repurposing hypotheses, including suitable candidates for COVID-19. However, these interactomes remain aggregate by design and often lack disease specificity. This dilution of information may affect the relevance of drug node embeddings to a particular disease, the resulting drug-disease and drug-drug similarity scores, and therefore our ability to identify new targets or drug synergies. To address this problem, we propose constructing and learning disease-specific hypergraphs in which hyperedges encode biological pathways of various lengths. We use a modified node2vec algorithm to generate pathway embeddings. We evaluate our hypergraph's ability to find repurposing targets for an incurable but prevalent disease, Alzheimer's disease (AD), and compare our ranked-ordered recommendations to those derived from a state-of-the-art knowledge graph, the multiscale interactome. Using our method, we successfully identified 7 promising repurposing candidates for AD that were ranked as unlikely repurposing targets by the multiscale interactome but for which the existing literature provides supporting evidence. Additionally, our drug repositioning suggestions are accompanied by explanations, eliciting plausible biological pathways. In the future, we plan on scaling our proposed method to 800+ diseases, combining single-disease hypergraphs into multi-disease hypergraphs to account for subpopulations with risk factors or encode a given patient's comorbidities to formulate personalized repurposing recommendations.Supplementary materials and code: https://github.com/ayujain04/psb_supplement.
{"title":"Generating new drug repurposing hypotheses using disease-specific hypergraphs.","authors":"Ayush Jain, Marie Charpignon, Irene Y. Chen, Anthony Philippakis, Ahmed Alaa","doi":"10.1142/9789811286421_0021","DOIUrl":"https://doi.org/10.1142/9789811286421_0021","url":null,"abstract":"The drug development pipeline for a new compound can last 10-20 years and cost over $10 billion. Drug repurposing offers a more time- and cost-effective alternative. Computational approaches based on network graph representations, comprising a mixture of disease nodes and their interactions, have recently yielded new drug repurposing hypotheses, including suitable candidates for COVID-19. However, these interactomes remain aggregate by design and often lack disease specificity. This dilution of information may affect the relevance of drug node embeddings to a particular disease, the resulting drug-disease and drug-drug similarity scores, and therefore our ability to identify new targets or drug synergies. To address this problem, we propose constructing and learning disease-specific hypergraphs in which hyperedges encode biological pathways of various lengths. We use a modified node2vec algorithm to generate pathway embeddings. We evaluate our hypergraph's ability to find repurposing targets for an incurable but prevalent disease, Alzheimer's disease (AD), and compare our ranked-ordered recommendations to those derived from a state-of-the-art knowledge graph, the multiscale interactome. Using our method, we successfully identified 7 promising repurposing candidates for AD that were ranked as unlikely repurposing targets by the multiscale interactome but for which the existing literature provides supporting evidence. Additionally, our drug repositioning suggestions are accompanied by explanations, eliciting plausible biological pathways. In the future, we plan on scaling our proposed method to 800+ diseases, combining single-disease hypergraphs into multi-disease hypergraphs to account for subpopulations with risk factors or encode a given patient's comorbidities to formulate personalized repurposing recommendations.Supplementary materials and code: https://github.com/ayujain04/psb_supplement.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"53 19","pages":"261-275"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0037
Gokul Srinivasan, Matthew Davis, M. LeBoeuf, Michael Y Fatemi, Zarif L. Azher, Yunrui Lu, Alos Diallo, Marietta Saldías Montivero, Fred W. Kolling, Laurent Perrard, L. Salas, B. Christensen, Thomas J Palys, M. Karagas, Scott M. Palisoul, G. Tsongalis, L. Vaickus, Sarah Preum, Joshua J. Levy
The advent of spatial transcriptomics technologies has heralded a renaissance in research to advance our understanding of the spatial cellular and transcriptional heterogeneity within tissues. Spatial transcriptomics allows investigation of the interplay between cells, molecular pathways, and the surrounding tissue architecture and can help elucidate developmental trajectories, disease pathogenesis, and various niches in the tumor microenvironment. Photoaging is the histological and molecular skin damage resulting from chronic/acute sun exposure and is a major risk factor for skin cancer. Spatial transcriptomics technologies hold promise for improving the reliability of evaluating photoaging and developing new therapeutics. Challenges to current methods include limited focus on dermal elastosis variations and reliance on self-reported measures, which can introduce subjectivity and inconsistency. Spatial transcriptomics offers an opportunity to assess photoaging objectively and reproducibly in studies of carcinogenesis and discern the effectiveness of therapies that intervene in photoaging and preventing cancer. Evaluation of distinct histological architectures using highly-multiplexed spatial technologies can identify specific cell lineages that have been understudied due to their location beyond the depth of UV penetration. However, the cost and interpatient variability using state-of-the-art assays such as the 10x Genomics Spatial Transcriptomics assays limits the scope and scale of large-scale molecular epidemiologic studies. Here, we investigate the inference of spatial transcriptomics information from routine hematoxylin and eosin-stained (H&E) tissue slides. We employed the Visium CytAssist spatial transcriptomics assay to analyze over 18,000 genes at a 50-micron resolution for four patients from a cohort of 261 skin specimens collected adjacent to surgical resection sites for basal cell and squamous cell keratinocyte tumors. The spatial transcriptomics data was co-registered with 40x resolution whole slide imaging (WSI) information. We developed machine learning models that achieved a macro-averaged median AUC and F1 score of 0.80 and 0.61 and Spearman coefficient of 0.60 in inferring transcriptomic profiles across the slides, and accurately captured biological pathways across various tissue architectures.
{"title":"Potential to Enhance Large Scale Molecular Assessments of Skin Photoaging through Virtual Inference of Spatial Transcriptomics from Routine Staining.","authors":"Gokul Srinivasan, Matthew Davis, M. LeBoeuf, Michael Y Fatemi, Zarif L. Azher, Yunrui Lu, Alos Diallo, Marietta Saldías Montivero, Fred W. Kolling, Laurent Perrard, L. Salas, B. Christensen, Thomas J Palys, M. Karagas, Scott M. Palisoul, G. Tsongalis, L. Vaickus, Sarah Preum, Joshua J. Levy","doi":"10.1142/9789811286421_0037","DOIUrl":"https://doi.org/10.1142/9789811286421_0037","url":null,"abstract":"The advent of spatial transcriptomics technologies has heralded a renaissance in research to advance our understanding of the spatial cellular and transcriptional heterogeneity within tissues. Spatial transcriptomics allows investigation of the interplay between cells, molecular pathways, and the surrounding tissue architecture and can help elucidate developmental trajectories, disease pathogenesis, and various niches in the tumor microenvironment. Photoaging is the histological and molecular skin damage resulting from chronic/acute sun exposure and is a major risk factor for skin cancer. Spatial transcriptomics technologies hold promise for improving the reliability of evaluating photoaging and developing new therapeutics. Challenges to current methods include limited focus on dermal elastosis variations and reliance on self-reported measures, which can introduce subjectivity and inconsistency. Spatial transcriptomics offers an opportunity to assess photoaging objectively and reproducibly in studies of carcinogenesis and discern the effectiveness of therapies that intervene in photoaging and preventing cancer. Evaluation of distinct histological architectures using highly-multiplexed spatial technologies can identify specific cell lineages that have been understudied due to their location beyond the depth of UV penetration. However, the cost and interpatient variability using state-of-the-art assays such as the 10x Genomics Spatial Transcriptomics assays limits the scope and scale of large-scale molecular epidemiologic studies. Here, we investigate the inference of spatial transcriptomics information from routine hematoxylin and eosin-stained (H&E) tissue slides. We employed the Visium CytAssist spatial transcriptomics assay to analyze over 18,000 genes at a 50-micron resolution for four patients from a cohort of 261 skin specimens collected adjacent to surgical resection sites for basal cell and squamous cell keratinocyte tumors. The spatial transcriptomics data was co-registered with 40x resolution whole slide imaging (WSI) information. We developed machine learning models that achieved a macro-averaged median AUC and F1 score of 0.80 and 0.61 and Spearman coefficient of 0.60 in inferring transcriptomic profiles across the slides, and accurately captured biological pathways across various tissue architectures.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"37 18","pages":"477-491"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0034
Yana Bromberg, Hannah Carter, Steven E. Brenner
Precision medicine, also often referred to as personalized medicine, targets the development of treatments and preventative measures specific to the individual's genomic signatures, lifestyle, and environmental conditions. The series of Precision Medicine sessions in PSB has continuously highlighted the advances in this field. Our 2024 collection of manuscripts showcases algorithmic advances that integrate data from distinct modalities and introduce innovative approaches to extract new, medically relevant information from existing data. These evolving technology and analytical methods promise to bring closer the goals of precision medicine to improve health and increase lifespan.
{"title":"Session Introduction: Precision Medicine: Innovative methods for advanced understanding of molecular underpinnings of disease.","authors":"Yana Bromberg, Hannah Carter, Steven E. Brenner","doi":"10.1142/9789811286421_0034","DOIUrl":"https://doi.org/10.1142/9789811286421_0034","url":null,"abstract":"Precision medicine, also often referred to as personalized medicine, targets the development of treatments and preventative measures specific to the individual's genomic signatures, lifestyle, and environmental conditions. The series of Precision Medicine sessions in PSB has continuously highlighted the advances in this field. Our 2024 collection of manuscripts showcases algorithmic advances that integrate data from distinct modalities and introduce innovative approaches to extract new, medically relevant information from existing data. These evolving technology and analytical methods promise to bring closer the goals of precision medicine to improve health and increase lifespan.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"27 11","pages":"446-449"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0001
S. Fouladvand, Emma Pierson, Ivana Jankovic, David Ouyang, Jonathan H. Chen, Roxana Daneshjou
Artificial Intelligence (AI) models are substantially enhancing the capability to analyze complex and multi-dimensional datasets. Generative AI and deep learning models have demonstrated significant advancements in extracting knowledge from unstructured text, imaging as well as structured and tabular data. This recent breakthrough in AI has inspired research in medicine, leading to the development of numerous tools for creating clinical decision support systems, monitoring tools, image interpretation, and triaging capabilities. Nevertheless, comprehensive research is imperative to evaluate the potential impact and implications of AI systems in healthcare. At the 2024 Pacific Symposium on Biocomputing (PSB) session entitled "Artificial Intelligence in Clinical Medicine: Generative and Interactive Systems at the Human-Machine Interface", we spotlight research that develops and applies AI algorithms to solve real-world problems in healthcare.
{"title":"Session Introduction: Artificial Intelligence in Clinical Medicine: Generative and Interactive Systems at the Human-Machine Interface.","authors":"S. Fouladvand, Emma Pierson, Ivana Jankovic, David Ouyang, Jonathan H. Chen, Roxana Daneshjou","doi":"10.1142/9789811286421_0001","DOIUrl":"https://doi.org/10.1142/9789811286421_0001","url":null,"abstract":"Artificial Intelligence (AI) models are substantially enhancing the capability to analyze complex and multi-dimensional datasets. Generative AI and deep learning models have demonstrated significant advancements in extracting knowledge from unstructured text, imaging as well as structured and tabular data. This recent breakthrough in AI has inspired research in medicine, leading to the development of numerous tools for creating clinical decision support systems, monitoring tools, image interpretation, and triaging capabilities. Nevertheless, comprehensive research is imperative to evaluate the potential impact and implications of AI systems in healthcare. At the 2024 Pacific Symposium on Biocomputing (PSB) session entitled \"Artificial Intelligence in Clinical Medicine: Generative and Interactive Systems at the Human-Machine Interface\", we spotlight research that develops and applies AI algorithms to solve real-world problems in healthcare.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"29 4","pages":"1-7"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0039
Nicolae Sapoval, Marko Tanevski, T. Treangen
The microbes present in the human gastrointestinal tract are regularly linked to human health and disease outcomes. Thanks to technological and methodological advances in recent years, metagenomic sequencing data, and computational methods designed to analyze metagenomic data, have contributed to improved understanding of the link between the human gut microbiome and disease. However, while numerous methods have been recently developed to extract quantitative and qualitative results from host-associated microbiome data, improved computational tools are still needed to track microbiome dynamics with short-read sequencing data. Previously we have proposed KOMB as a de novo tool for identifying copy number variations in metagenomes for characterizing microbial genome dynamics in response to perturbations. In this work, we present KombOver (KO), which includes four key contributions with respect to our previous work: (i) it scales to large microbiome study cohorts, (ii) it includes both k-core and K-truss based analysis, (iii) we provide the foundation of a theoretical understanding of the relation between various graph-based metagenome representations, and (iv) we provide an improved user experience with easier-to-run code and more descriptive outputs/results. To highlight the aforementioned benefits, we applied KO to nearly 1000 human microbiome samples, requiring less than 10 minutes and 10 GB RAM per sample to process these data. Furthermore, we highlight how graph-based approaches such as k-core and K-truss can be informative for pinpointing microbial community dynamics within a myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) cohort. KO is open source and available for download/use at: https://github.com/treangenlab/komb
人类胃肠道中的微生物经常与人类健康和疾病结果联系在一起。近年来，由于技术和方法上的进步，元基因组测序数据和用于分析元基因组数据的计算方法有助于人们更好地了解人类肠道微生物组与疾病之间的联系。然而，尽管最近已开发出许多方法来从宿主相关微生物组数据中提取定量和定性结果，但仍需要改进计算工具来利用短线程测序数据跟踪微生物组动态。在此之前，我们已经提出了 KOMB 作为一种全新的工具，用于识别元基因组中的拷贝数变异，以描述微生物基因组对扰动的动态响应。在这项工作中，我们提出了 KombOver (KO)，它与我们之前的工作相比有四个主要贡献：(i) 它可扩展到大型微生物组研究队列；(ii) 它包括基于 K 核和 K 桁架的分析；(iii) 我们为理解各种基于图的元基因组表示之间的关系提供了理论基础；(iv) 我们提供了更好的用户体验，代码更易于运行，输出/结果更具描述性。为了突出上述优势，我们将 KO 应用于近 1000 个人类微生物组样本，每个样本只需不到 10 分钟和 10 GB 内存就能处理这些数据。此外，我们还强调了基于图的方法（如 K-core 和 K-truss）如何为确定肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）队列中的微生物群落动态提供信息。KO 是开放源代码，可在以下网站下载/使用： https://github.com/treangenlab/komb
{"title":"KombOver: Efficient k-core and K-truss based characterization of perturbations within the human gut microbiome","authors":"Nicolae Sapoval, Marko Tanevski, T. Treangen","doi":"10.1142/9789811286421_0039","DOIUrl":"https://doi.org/10.1142/9789811286421_0039","url":null,"abstract":"The microbes present in the human gastrointestinal tract are regularly linked to human health and disease outcomes. Thanks to technological and methodological advances in recent years, metagenomic sequencing data, and computational methods designed to analyze metagenomic data, have contributed to improved understanding of the link between the human gut microbiome and disease. However, while numerous methods have been recently developed to extract quantitative and qualitative results from host-associated microbiome data, improved computational tools are still needed to track microbiome dynamics with short-read sequencing data. Previously we have proposed KOMB as a de novo tool for identifying copy number variations in metagenomes for characterizing microbial genome dynamics in response to perturbations. In this work, we present KombOver (KO), which includes four key contributions with respect to our previous work: (i) it scales to large microbiome study cohorts, (ii) it includes both k-core and K-truss based analysis, (iii) we provide the foundation of a theoretical understanding of the relation between various graph-based metagenome representations, and (iv) we provide an improved user experience with easier-to-run code and more descriptive outputs/results. To highlight the aforementioned benefits, we applied KO to nearly 1000 human microbiome samples, requiring less than 10 minutes and 10 GB RAM per sample to process these data. Furthermore, we highlight how graph-based approaches such as k-core and K-truss can be informative for pinpointing microbial community dynamics within a myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) cohort. KO is open source and available for download/use at: https://github.com/treangenlab/komb","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"28 4","pages":"506 - 520"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-17DOI: 10.1142/9789811286421_0020
Rachel A. Hoffing, A. Deaton, Aaron M. Holleman, Lynne Krohn, Philip J. LoGerfo, Mollie E. Plekan, Sebastian Akle Serrano, P. Nioi, Lucas D. Ward
A single gene can produce multiple transcripts with distinct molecular functions. Rare-variant association tests often aggregate all coding variants across individual genes, without accounting for the variants' presence or consequence in resulting transcript isoforms. To evaluate the utility of transcript-aware variant sets, rare predicted loss-of-function (pLOF) variants were aggregated for 17,035 protein-coding genes using 55,558 distinct transcript-specific variant sets. These sets were tested for their association with 728 circulating proteins and 188 quantitative phenotypes across 406,921 individuals in the UK Biobank. The transcript-specific approach resulted in larger estimated effects of pLOF variants decreasing serum cis-protein levels compared to the gene-based approach (pbinom ≤ 2x10-16). Additionally, 251 quantitative trait associations were identified as being significant using the transcript-specific approach but not the gene-based approach, including PCSK5 transcript ENST00000376752 and standing height (transcript-specific statistic, P = 1.3x10-16, effect = 0.7 SD decrease; gene-based statistic, P = 0.02, effect = 0.05 SD decrease) and LDLR transcript ENST00000252444 and apolipoprotein B (transcript-specific statistic, P = 5.7x10-20, effect = 1.0 SD increase; gene-based statistic, P = 3.0x10-4, effect = 0.2 SD increase). This approach demonstrates the importance of considering the effect of pLOFs on specific transcript isoforms when performing rare-variant association studies.
{"title":"Transcript-aware analysis of rare predicted loss-of-function variants in the UK Biobank elucidate new isoform-trait associations.","authors":"Rachel A. Hoffing, A. Deaton, Aaron M. Holleman, Lynne Krohn, Philip J. LoGerfo, Mollie E. Plekan, Sebastian Akle Serrano, P. Nioi, Lucas D. Ward","doi":"10.1142/9789811286421_0020","DOIUrl":"https://doi.org/10.1142/9789811286421_0020","url":null,"abstract":"A single gene can produce multiple transcripts with distinct molecular functions. Rare-variant association tests often aggregate all coding variants across individual genes, without accounting for the variants' presence or consequence in resulting transcript isoforms. To evaluate the utility of transcript-aware variant sets, rare predicted loss-of-function (pLOF) variants were aggregated for 17,035 protein-coding genes using 55,558 distinct transcript-specific variant sets. These sets were tested for their association with 728 circulating proteins and 188 quantitative phenotypes across 406,921 individuals in the UK Biobank. The transcript-specific approach resulted in larger estimated effects of pLOF variants decreasing serum cis-protein levels compared to the gene-based approach (pbinom ≤ 2x10-16). Additionally, 251 quantitative trait associations were identified as being significant using the transcript-specific approach but not the gene-based approach, including PCSK5 transcript ENST00000376752 and standing height (transcript-specific statistic, P = 1.3x10-16, effect = 0.7 SD decrease; gene-based statistic, P = 0.02, effect = 0.05 SD decrease) and LDLR transcript ENST00000252444 and apolipoprotein B (transcript-specific statistic, P = 5.7x10-20, effect = 1.0 SD increase; gene-based statistic, P = 3.0x10-4, effect = 0.2 SD increase). This approach demonstrates the importance of considering the effect of pLOFs on specific transcript isoforms when performing rare-variant association studies.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"760 ","pages":"247-260"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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