Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing最新文献

{"title":"Combined kinome inhibition states are predictive of cancer cell line sensitivity to kinase inhibitor combination therapies.","authors":"Chinmaya U. Joisa, Kevin A Chen, Samantha Beville, T. Stuhlmiller, Matthew E. Berginski, Denis O Okumu, B. Golitz, M. East, Gary L Johnson, Shawn M Gomez","doi":"10.1142/9789811286421_0022","DOIUrl":"https://doi.org/10.1142/9789811286421_0022","url":null,"abstract":"Protein kinases are a primary focus in targeted therapy development for cancer, owing to their role as regulators in nearly all areas of cell life. Recent strategies targeting the kinome with combination therapies have shown promise, such as trametinib and dabrafenib in advanced melanoma, but empirical design for less characterized pathways remains a challenge. Computational combination screening is an attractive alternative, allowing in-silico filtering prior to experimental testing of drastically fewer leads, increasing efficiency and effectiveness of drug development pipelines. In this work, we generated combined kinome inhibition states of 40,000 kinase inhibitor combinations from kinobeads-based kinome profiling across 64 doses. We then integrated these with transcriptomics from CCLE to build machine learning models with elastic-net feature selection to predict cell line sensitivity across nine cancer types, with accuracy R2 ∼ 0.75-0.9. We then validated the model by using a PDX-derived TNBC cell line and saw good global accuracy (R2 ∼ 0.7) as well as high accuracy in predicting synergy using four popular metrics (R2 ∼ 0.9). Additionally, the model was able to predict a highly synergistic combination of trametinib and omipalisib for TNBC treatment, which incidentally was recently in phase I clinical trials. Our choice of tree-based models for greater interpretability allowed interrogation of highly predictive kinases in each cancer type, such as the MAPK, CDK, and STK kinases. Overall, these results suggest that kinome inhibition states of kinase inhibitor combinations are strongly predictive of cell line responses and have great potential for integration into computational drug screening pipelines. This approach may facilitate the identification of effective kinase inhibitor combinations and accelerate the development of novel cancer therapies, ultimately improving patient outcomes.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"46 21","pages":"276-290"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176269","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}

{"title":"FedBrain: Federated Training of Graph Neural Networks for Connectome-based Brain Imaging Analysis.","authors":"Yi Yang, Han Xie, Hejie Cui, †. CarlYang","doi":"10.1142/9789811286421_0017","DOIUrl":"https://doi.org/10.1142/9789811286421_0017","url":null,"abstract":"Recent advancements in neuroimaging techniques have sparked a growing interest in understanding the complex interactions between anatomical regions of interest (ROIs), forming into brain networks that play a crucial role in various clinical tasks, such as neural pattern discovery and disorder diagnosis. In recent years, graph neural networks (GNNs) have emerged as powerful tools for analyzing network data. However, due to the complexity of data acquisition and regulatory restrictions, brain network studies remain limited in scale and are often confined to local institutions. These limitations greatly challenge GNN models to capture useful neural circuitry patterns and deliver robust downstream performance. As a distributed machine learning paradigm, federated learning (FL) provides a promising solution in addressing resource limitation and privacy concerns, by enabling collaborative learning across local institutions (i.e., clients) without data sharing. While the data heterogeneity issues have been extensively studied in recent FL literature, cross-institutional brain network analysis presents unique data heterogeneity challenges, that is, the inconsistent ROI parcellation systems and varying predictive neural circuitry patterns across local neuroimaging studies. To this end, we propose FedBrain, a GNN-based personalized FL framework that takes into account the unique properties of brain network data. Specifically, we present a federated atlas mapping mechanism to overcome the feature and structure heterogeneity of brain networks arising from different ROI atlas systems, and a clustering approach guided by clinical prior knowledge to address varying predictive neural circuitry patterns regarding different patient groups, neuroimaging modalities and clinical outcomes. Compared to existing FL strategies, our approach demonstrates superior and more consistent performance, showcasing its strong potential and generalizability in cross-institutional connectome-based brain imaging analysis. The implementation is available here.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"370 ","pages":"214-225"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176559","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}

{"title":"APPLICATION OF QUANTILE DISCRETIZATION AND BAYESIAN NETWORK ANALYSIS TO PUBLICLY AVAILABLE CYSTIC FIBROSIS DATA SETS.","authors":"Kiyoshi Ferreira Fukutani, Thomas H. Hampton, Carly A. Bobak, Todd A. MacKenzie, Bruce A. Stanton","doi":"10.1142/9789811286421_0041","DOIUrl":"https://doi.org/10.1142/9789811286421_0041","url":null,"abstract":"The availability of multiple publicly-available datasets studying the same phenomenon has the promise of accelerating scientific discovery. Meta-analysis can address issues of reproducibility and often increase power. The promise of meta-analysis is especially germane to rarer diseases like cystic fibrosis (CF), which affects roughly 100,000 people worldwide. A recent search of the National Institute of Health's Gene Expression Omnibus revealed 1.3 million data sets related to cancer compared to about 2,000 related to CF. These studies are highly diverse, involving different tissues, animal models, treatments, and clinical covariates. In our search for gene expression studies of primary human airway epithelial cells, we identified three studies with compatible methodologies and sufficient metadata: GSE139078, Sala Study, and PRJEB9292. Even so, experimental designs were not identical, and we identified significant batch effects that would have complicated functional analysis. Here we present quantile discretization and Bayesian network construction using the Hill climb method as a powerful tool to overcome experimental differences and reveal biologically relevant responses to the CF genotype itself, exposure to virus, bacteria, and drugs used to treat CF. Functional patterns revealed by cluster Profiler included interferon signaling, interferon gamma signaling, interleukins 4 and 13 signaling, interleukin 6 signaling, interleukin 21 signaling, and inactivation of CSF3/G-CSF signaling pathways showing significant alterations. These pathways were consistently associated with higher gene expression in CF epithelial cells compared to non-CF cells, suggesting that targeting these pathways could improve clinical outcomes. The success of quantile discretization and Bayesian network analysis in the context of CF suggests that these approaches might be applicable to other contexts where exactly comparable data sets are hard to find.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"161 ","pages":"534-548"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176596","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}

{"title":"Impact of Measurement Noise on Genetic Association Studies of Cardiac Function.","authors":"Milos Vukadinovic, Gauri Renjith, Victoria Yuan, Alan Kwan, Susan C. Cheng, Debiao Li, Shoa L. Clarke, David Ouyang","doi":"10.1142/9789811286421_0011","DOIUrl":"https://doi.org/10.1142/9789811286421_0011","url":null,"abstract":"Recent research has effectively used quantitative traits from imaging to boost the capabilities of genome-wide association studies (GWAS), providing further understanding of disease biology and various traits. However, it's important to note that phenotyping inherently carries measurement error and noise that could influence subsequent genetic analyses. The study focused on left ventricular ejection fraction (LVEF), a vital yet potentially inaccurate quantitative measurement, to investigate how imprecision in phenotype measurement affects genetic studies. Several methods of acquiring LVEF, along with simulating measurement noise, were assessed for their effects on ensuing genetic analyses. The results showed that by introducing just 7.9% of measurement noise, all genetic associations in an LVEF GWAS with almost forty thousand individuals could be eliminated. Moreover, a 1% increase in mean absolute error (MAE) in LVEF had an effect equivalent to a 10% reduction in the sample size of the cohort on the power of GWAS. Therefore, enhancing the accuracy of phenotyping is crucial to maximize the effectiveness of genome-wide association studies.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"45 46","pages":"134-147"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176290","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}

{"title":"Session Introduction: Drug-repurposing and discovery in the era of \"big\" real-world data: how the incorporation of observational data, genetics, and other -omic technologies can move us forward.","authors":"Megan M. Shuey, J. Hellwege, Nikhil Khankari, Marijana Vujkovic, Todd L. Edwards","doi":"10.1142/9789811286421_0018","DOIUrl":"https://doi.org/10.1142/9789811286421_0018","url":null,"abstract":"This PSB 2024 session discusses the many broad biological, computational, and statistical approaches currently being used for therapeutic drug target identification and repurposing of existing treatments. Drug repurposing efforts have the potential to dramatically improve the treatment landscape by more rapidly identifying drug targets and alternative strategies for untreated or poorly managed diseases. The overarching theme for this session is the use and integration of real-world data to identify drug-disease pairs with potential therapeutic use. These drug-disease pairs may be identified through genomic, proteomic, biomarkers, protein interaction analyses, electronic health records, and chemical profiling. Taken together, this session combines novel applications of methods and innovative modeling strategies with diverse real-world data to suggest new pharmaceutical treatments for human diseases.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"36 11","pages":"226-231"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176551","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}

{"title":"Practical Approaches to Enhancing Fairness, Social Responsibility and the Inclusion of Diverse Viewpoints in Biomedicine.","authors":"D. Martschenko, Nicole Martinez-Martin, Meghan Halley","doi":"10.1142/9789811286421_0049","DOIUrl":"https://doi.org/10.1142/9789811286421_0049","url":null,"abstract":"The following sections are included:Workshop DescriptionLearning ObjectivesPresenter InformationAbout the Workshop OrganizersPresentationsSpeaker Presentations.","PeriodicalId":34954,"journal":{"name":"Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing","volume":"151 ","pages":"645-649"},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139176615","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}

{"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}

{"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}

{"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}

{"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}