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  1. Article: Deep learning-based morphological feature analysis and the prognostic association study in colon adenocarcinoma histopathological images.

    Xiao, Xiao / Wang, Zuoheng / Kong, Yan / Lu, Hui

    Frontiers in oncology

    2023  Volume 13, Page(s) 1081529

    Abstract: Colorectal cancer (CRC) is now the third most common malignancy to cause mortality worldwide, and its prognosis is of great importance. Recent CRC prognostic prediction studies mainly focused on biomarkers, radiometric images, and end-to-end deep ... ...

    Abstract Colorectal cancer (CRC) is now the third most common malignancy to cause mortality worldwide, and its prognosis is of great importance. Recent CRC prognostic prediction studies mainly focused on biomarkers, radiometric images, and end-to-end deep learning methods, while only a few works paid attention to exploring the relationship between the quantitative morphological features of patients' tissue slides and their prognosis. However, existing few works in this area suffered from the drawback of choosing the cells randomly from the whole slides, which contain the non-tumor region that lakes information about prognosis. In addition, the existing works, which tried to demonstrate their biological interpretability using patients' transcriptome data, failed to show the biological meaning closely related to cancer. In this study, we proposed and evaluated a prognostic model using morphological features of cells in the tumor region. The features were first extracted by the software CellProfiler from the tumor region selected by Eff-Unet deep learning model. Features from different regions were then averaged for each patient as their representative, and the Lasso-Cox model was used to select the prognosis-related features. The prognostic prediction model was at last constructed using the selected prognosis-related features and was evaluated through KM estimate and cross-validation. In terms of biological meaning, Gene Ontology (GO) enrichment analysis of the expressed genes that correlated with the prognostically significant features was performed to show the biological interpretability of our model.With the help of tumor segmentation, our model achieved better statistical significance and better biological interpretability compared to the results without tumor segmentation. Statistically, the Kaplan Meier (KM) estimate of our model showed that the model using features in the tumor region has a higher C-index, a lower p-value, and a better performance on cross-validation than the model without tumor segmentation. In addition, revealing the pathway of the immune escape and the spread of the tumor, the model with tumor segmentation demonstrated a biological meaning much more related to cancer immunobiology than the model without tumor segmentation. Our prognostic prediction model using quantitive morphological features from tumor regions was almost as good as the TNM tumor staging system as they had a close C-index, and our model can be combined with the TNM tumor stage system to make a better prognostic prediction. And to the best of our knowledge, the biological mechanisms in our study were the most relevant to the immune mechanism of cancer compared to the previous studies.
    Language English
    Publishing date 2023-02-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2649216-7
    ISSN 2234-943X
    ISSN 2234-943X
    DOI 10.3389/fonc.2023.1081529
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Integrating evolutionary game theory into epigenetic study of embryonic development: Comment on "Epigenetic game theory: How to compute the epigenetic control of maternal-to-zygotic transition" by Qian Wang et al.

    Wang, Zuoheng

    Physics of life reviews

    2017  Volume 20, Page(s) 164–165

    MeSH term(s) Animals ; Biological Evolution ; Embryonic Development ; Game Theory ; Humans ; Zygote
    Language English
    Publishing date 2017
    Publishing country Netherlands
    Document type Journal Article ; Comment
    ZDB-ID 2148883-6
    ISSN 1873-1457 ; 1571-0645
    ISSN (online) 1873-1457
    ISSN 1571-0645
    DOI 10.1016/j.plrev.2017.01.016
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: tRFtarget 2.0: expanding the targetome landscape of transfer RNA-derived fragments.

    Li, Ningshan / Yao, Siqiong / Yu, Guangjun / Lu, Lingeng / Wang, Zuoheng

    Nucleic acids research

    2023  Volume 52, Issue D1, Page(s) D345–D350

    Abstract: tRFtarget 1.0 (http://trftarget.net/) is a platform consolidating both computationally predicted and experimentally validated binding sites between transfer RNA-derived fragments (tRFs) and target genes (or transcripts) across multiple organisms. Here, ... ...

    Abstract tRFtarget 1.0 (http://trftarget.net/) is a platform consolidating both computationally predicted and experimentally validated binding sites between transfer RNA-derived fragments (tRFs) and target genes (or transcripts) across multiple organisms. Here, we introduce a newly released version of tRFtarget 2.0, in which we integrated 6 additional tRF sources, resulting in a comprehensive collection of 2614 high-quality tRF sequences spanning across 9 species, including 1944 Homo sapiens tRFs and one newly incorporated species Rattus norvegicus. We also expanded target genes by including ribosomal RNAs, long non-coding RNAs, and coding genes >50 kb in length. The predicted binding sites have surged up to approximately 6 billion, a 20.5-fold increase than that in tRFtarget 1.0. The manually curated publications relevant to tRF targets have increased to 400 and the gene-level experimental evidence has risen to 232. tRFtarget 2.0 introduces several new features, including a web-based tool that identifies potential binding sites of tRFs in user's own datasets, integration of standardized tRF IDs, and inclusion of external links to contents within the database. Additionally, we enhanced website framework and user interface. With these improvements, tRFtarget 2.0 is more user-friendly, providing researchers a streamlined and comprehensive platform to accelerate their research progress.
    MeSH term(s) Animals ; Humans ; Rats ; RNA, Transfer/metabolism ; Databases, Nucleic Acid
    Chemical Substances RNA, Transfer (9014-25-9)
    Language English
    Publishing date 2023-10-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkad815
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Transformer with convolution and graph-node co-embedding: An accurate and interpretable vision backbone for predicting gene expressions from local histopathological image.

    Xiao, Xiao / Kong, Yan / Li, Ronghan / Wang, Zuoheng / Lu, Hui

    Medical image analysis

    2023  Volume 91, Page(s) 103040

    Abstract: Inferring gene expressions from histopathological images has long been a fascinating yet challenging task, primarily due to the substantial disparities between the two modality. Existing strategies using local or global features of histological images ... ...

    Abstract Inferring gene expressions from histopathological images has long been a fascinating yet challenging task, primarily due to the substantial disparities between the two modality. Existing strategies using local or global features of histological images are suffering model complexity, GPU consumption, low interpretability, insufficient encoding of local features, and over-smooth prediction of gene expressions among neighboring sites. In this paper, we develop TCGN (Transformer with Convolution and Graph-Node co-embedding method) for gene expression estimation from H&E-stained pathological slide images. TCGN comprises a combination of convolutional layers, transformer encoders, and graph neural networks, and is the first to integrate these blocks in a general and interpretable computer vision backbone. Notably, TCGN uniquely operates with just a single spot image as input for histopathological image analysis, simplifying the process while maintaining interpretability. We validate TCGN on three publicly available spatial transcriptomic datasets. TCGN consistently exhibited the best performance (with median PCC 0.232). TCGN offers superior accuracy while keeping parameters to a minimum (just 86.241 million), and it consumes minimal memory, allowing it to run smoothly even on personal computers. Moreover, TCGN can be extended to handle bulk RNA-seq data while providing the interpretability. Enhancing the accuracy of omics information prediction from pathological images not only establishes a connection between genotype and phenotype, enabling the prediction of costly-to-measure biomarkers from affordable histopathological images, but also lays the groundwork for future multi-modal data modeling. Our results confirm that TCGN is a powerful tool for inferring gene expressions from histopathological images in precision health applications.
    MeSH term(s) Humans ; Image Processing, Computer-Assisted ; Neural Networks, Computer ; Phenotype ; Gene Expression
    Language English
    Publishing date 2023-11-20
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1356436-5
    ISSN 1361-8423 ; 1361-8431 ; 1361-8415
    ISSN (online) 1361-8423 ; 1361-8431
    ISSN 1361-8415
    DOI 10.1016/j.media.2023.103040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Testing gene-environment interactions in the presence of confounders and mismeasured environmental exposures.

    Cheng, Chao / Spiegelman, Donna / Wang, Zuoheng / Wang, Molin

    G3 (Bethesda, Md.)

    2021  Volume 11, Issue 10

    Abstract: Interest in investigating gene-environment (GxE) interactions has rapidly increased over the last decade. Although GxE interactions have been extremely investigated in large studies, few such effects have been identified and replicated, highlighting the ... ...

    Abstract Interest in investigating gene-environment (GxE) interactions has rapidly increased over the last decade. Although GxE interactions have been extremely investigated in large studies, few such effects have been identified and replicated, highlighting the need to develop statistical GxE tests with greater statistical power. The reverse test has been proposed for testing the interaction effect between continuous exposure and genetic variants in relation to a binary disease outcome, which leverages the idea of linear discriminant analysis, significantly increasing statistical power comparing to the standard logistic regression approach. However, this reverse approach did not take into consideration adjustment for confounders. Since GxE interaction studies are inherently nonexperimental, adjusting for potential confounding effects is critical for valid evaluation of GxE interactions. In this study, we extend the reverse test to allow for confounders. The proposed reverse test also allows for exposure measurement errors as typically occurs. Extensive simulation experiments demonstrated that the proposed method not only provides greater statistical power under most simulation scenarios but also provides substantive computational efficiency, which achieves a computation time that is more than sevenfold less than that of the standard logistic regression test. In an illustrative example, we applied the proposed approach to the Veterans Aging Cohort Study (VACS) to search for genetic susceptibility loci modifying the smoking-HIV status association.
    MeSH term(s) Cohort Studies ; Computer Simulation ; Environmental Exposure ; Gene-Environment Interaction ; Humans ; Models, Genetic
    Language English
    Publishing date 2021-08-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2629978-1
    ISSN 2160-1836 ; 2160-1836
    ISSN (online) 2160-1836
    ISSN 2160-1836
    DOI 10.1093/g3journal/jkab236
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  6. Article: Detecting time-varying genetic effects in Alzheimer's disease using a longitudinal GWAS model.

    Zhuang, Xiaowei / Xu, Gang / Amei, Amei / Cordes, Dietmar / Wang, Zuoheng / Oh, Edwin C

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Background: The development and progression of Alzheimer's disease (AD) is a complex process that can change over time, during which genetic influences on phenotypes may also fluctuate. Incorporating longitudinal phenotypes in genome wide association ... ...

    Abstract Background: The development and progression of Alzheimer's disease (AD) is a complex process that can change over time, during which genetic influences on phenotypes may also fluctuate. Incorporating longitudinal phenotypes in genome wide association studies (GWAS) could help unmask genetic loci with time-varying effects. In this study, we incorporated a varying coefficient test in a longitudinal GWAS model to identify single nucleotide polymorphisms (SNPs) that may have time- or age-dependent effects in AD.
    Methods: Genotype data from 1,877 participants in the Alzheimer's Neuroimaging Data Initiative (ADNI) were imputed using the Haplotype Reference Consortium (HRC) panel, resulting in 9,573,130 SNPs. Subjects' longitudinal impairment status at each visit was considered as a binary and clinical phenotype. Participants' composite standardized uptake value ratio (SUVR) derived from each longitudinal amyloid PET scan was considered as a continuous and biological phenotype. The retrospective varying coefficient mixed model association test (RVMMAT) was used in longitudinal GWAS to detect time-varying genetic effects on the impairment status and SUVR measures. Post-hoc analyses were performed on genome-wide significant SNPs, including 1) pathway analyses; 2) age-stratified genotypic comparisons and regression analyses; and 3) replication analyses using data from the National Alzheimer's Coordinating Center (NACC).
    Results: Our model identified 244 genome-wide significant SNPs that revealed time-varying genetic effects on the clinical impairment status in AD; among which, 12 SNPs on chromosome 19 were successfully replicated using data from NACC. Post-hoc age-stratified analyses indicated that for most of these 244 SNPs, the maximum genotypic effect on impairment status occurred between 70 to 80 years old, and then declined with age. Our model further identified 73 genome-wide significant SNPs associated with the temporal variation of amyloid accumulation. For these SNPs, an increasing genotypic effect on PET-SUVR was observed as participants' age increased. Functional pathway analyses on significant SNPs for both phenotypes highlighted the involvement and disruption of immune responses- and neuroinflammation-related pathways in AD.
    Conclusion: We demonstrate that longitudinal GWAS models with time-varying coefficients can boost the statistical power in AD-GWAS. In addition, our analyses uncovered potential time-varying genetic variants on repeated measurements of clinical and biological phenotypes in AD.
    Language English
    Publishing date 2023-10-17
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.10.17.562756
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  7. Article: RETROSPECTIVE VARYING COEFFICIENT ASSOCIATION ANALYSIS OF LONGITUDINAL BINARY TRAITS: APPLICATION TO THE IDENTIFICATION OF GENETIC LOCI ASSOCIATED WITH HYPERTENSION.

    Xu, Gang / Amei, Amei / Wu, Weimiao / Liu, Yunqing / Shen, Linchuan / Oh, Edwin C / Wang, Zuoheng

    The annals of applied statistics

    2024  Volume 18, Issue 1, Page(s) 487–505

    Abstract: Many genetic studies contain rich information on longitudinal phenotypes that require powerful analytical tools for optimal analysis. Genetic analysis of longitudinal data that incorporates temporal variation is important for understanding the genetic ... ...

    Abstract Many genetic studies contain rich information on longitudinal phenotypes that require powerful analytical tools for optimal analysis. Genetic analysis of longitudinal data that incorporates temporal variation is important for understanding the genetic architecture and biological variation of complex diseases. Most of the existing methods assume that the contribution of genetic variants is constant over time and fail to capture the dynamic pattern of disease progression. However, the relative influence of genetic variants on complex traits fluctuates over time. In this study, we propose a retrospective varying coefficient mixed model association test, RVMMAT, to detect time-varying genetic effect on longitudinal binary traits. We model dynamic genetic effect using smoothing splines, estimate model parameters by maximizing a double penalized quasi-likelihood function, design a joint test using a Cauchy combination method, and evaluate statistical significance via a retrospective approach to achieve robustness to model misspecification. Through simulations we illustrated that the retrospective varying-coefficient test was robust to model misspecification under different ascertainment schemes and gained power over the association methods assuming constant genetic effect. We applied RVMMAT to a genome-wide association analysis of longitudinal measure of hypertension in the Multi-Ethnic Study of Atherosclerosis. Pathway analysis identified two important pathways related to G-protein signaling and DNA damage. Our results demonstrated that RVMMAT could detect biologically relevant loci and pathways in a genome scan and provided insight into the genetic architecture of hypertension.
    Language English
    Publishing date 2024-01-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2376910-5
    ISSN 1941-7330 ; 1932-6157
    ISSN (online) 1941-7330
    ISSN 1932-6157
    DOI 10.1214/23-aoas1798
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: tRFtarget: a database for transfer RNA-derived fragment targets.

    Li, Ningshan / Shan, Nayang / Lu, Lingeng / Wang, Zuoheng

    Nucleic acids research

    2020  Volume 49, Issue D1, Page(s) D254–D260

    Abstract: Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs and play important roles in biological and physiological processes. Prediction of tRF target genes and binding sites is crucial in understanding the biological functions of ... ...

    Abstract Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs and play important roles in biological and physiological processes. Prediction of tRF target genes and binding sites is crucial in understanding the biological functions of tRFs in the molecular mechanisms of human diseases. We developed a publicly accessible web-based database, tRFtarget (http://trftarget.net), for tRF target prediction. It contains the computationally predicted interactions between tRFs and mRNA transcripts using the two state-of-the-art prediction tools RNAhybrid and IntaRNA, including location of the binding sites on the target, the binding region, and free energy of the binding stability with graphic illustration. tRFtarget covers 936 tRFs and 135 thousand predicted targets in eight species. It allows researchers to search either target genes by tRF IDs or tRFs by gene symbols/transcript names. We also integrated the manually curated experimental evidence of the predicted interactions into the database. Furthermore, we provided a convenient link to the DAVID® web server to perform downstream functional pathway analysis and gene ontology annotation on the predicted target genes. This database provides useful information for the scientific community to experimentally validate tRF target genes and facilitate the investigation of the molecular functions and mechanisms of tRFs.
    MeSH term(s) Animals ; Base Pairing ; Base Sequence ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Databases, Nucleic Acid ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Gene Ontology ; Humans ; Mice ; Molecular Sequence Annotation ; Nucleic Acid Conformation ; Nucleic Acid Hybridization ; RNA, Messenger/chemistry ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Untranslated/chemistry ; RNA, Small Untranslated/genetics ; RNA, Small Untranslated/metabolism ; RNA, Transfer/chemistry ; RNA, Transfer/genetics ; RNA, Transfer/metabolism ; Rhodobacter sphaeroides/genetics ; Rhodobacter sphaeroides/metabolism ; Schizosaccharomyces/genetics ; Schizosaccharomyces/metabolism ; Thermodynamics ; Xenopus/genetics ; Xenopus/metabolism ; Zebrafish/genetics ; Zebrafish/metabolism
    Chemical Substances RNA, Messenger ; RNA, Small Untranslated ; RNA, Transfer (9014-25-9)
    Language English
    Publishing date 2020-10-09
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 186809-3
    ISSN 1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
    ISSN (online) 1362-4962 ; 1362-4954
    ISSN 0301-5610 ; 0305-1048
    DOI 10.1093/nar/gkaa831
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Discovery and Mediation Analysis of Cross-Phenotype Associations Between Asthma and Body Mass Index in 12q13.2.

    Salinas, Yasmmyn D / Wang, Zuoheng / DeWan, Andrew T

    American journal of epidemiology

    2020  Volume 190, Issue 1, Page(s) 85–94

    Abstract: Twin studies suggest that shared genetics contributes to the comorbidity of asthma and obesity, but candidate-gene studies provide limited evidence of pleiotropy. We conducted genome-wide association analyses of asthma and body mass index (BMI; weight ( ... ...

    Abstract Twin studies suggest that shared genetics contributes to the comorbidity of asthma and obesity, but candidate-gene studies provide limited evidence of pleiotropy. We conducted genome-wide association analyses of asthma and body mass index (BMI; weight (kg)/height (m)2)) among 305,945 White British subjects recruited into the UK Biobank in 2006-2010. We searched for overlapping signals and conducted mediation analyses on genome-wide-significant cross-phenotype associations, assessing moderation by sex and age at asthma diagnosis, and adjusting for confounders of the asthma-BMI relationship. We identified a genome-wide-significant cross-phenotype association at rs705708 (asthma odds ratio = 1.05, 95% confidence interval: 1.03, 1.07; P = 7.20 × 10-9; and BMI β = -0.065, 95% confidence interval: -0.087, -0.042; P = 1.30 × 10-8). rs705708 resides on 12q13.2, which harbors 9 other asthma- and BMI-associated variants (all P < 5 × 10-5 for asthma; all but one P < 5 × 10-5 for BMI). Follow-up analyses of rs705708 show that most of the BMI association occurred independently of asthma, with consistent magnitude between men and women and persons with and without asthma, irrespective of age at diagnosis; the asthma association was stronger for childhood versus adult asthma; and both associations remained after confounder adjustment. This suggests that 12q13.2 displays pleiotropy for asthma and BMI. Upon further characterization, 12q13.2 might provide a target for interventions that simultaneously prevent or treat asthma and obesity.
    MeSH term(s) Adult ; Age Factors ; Aged ; Asthma/complications ; Asthma/genetics ; Body Mass Index ; Female ; Genome-Wide Association Study ; Humans ; Male ; Mediation Analysis ; Middle Aged ; Obesity/complications ; Obesity/genetics ; Phenotype ; Prospective Studies ; Sex Factors ; United Kingdom/epidemiology
    Language English
    Publishing date 2020-07-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2937-3
    ISSN 1476-6256 ; 0002-9262
    ISSN (online) 1476-6256
    ISSN 0002-9262
    DOI 10.1093/aje/kwaa144
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Direct assessment of multiple testing correction in case-control association studies with related individuals.

    Wang, Zuoheng

    Genetic epidemiology

    2011  Volume 35, Issue 1, Page(s) 70–79

    Abstract: Genome-wide association studies typically test large numbers of genetic variants in association with trait values. It is well known that linkage disequilibrium (LD) between nearby markers tends to introduce correlation among association tests. Failure to ...

    Abstract Genome-wide association studies typically test large numbers of genetic variants in association with trait values. It is well known that linkage disequilibrium (LD) between nearby markers tends to introduce correlation among association tests. Failure to properly adjust for multiple comparisons can lead to false-positive results or missing true-positive signals. The Bonferroni correction is generally conservative in the presence of LD. The permutation procedure, although has been widely employed to adjust for correlated tests, is not applicable when related individuals are included in case-control samples. With related individuals, the dependence among relatives' genotypes can also contribute to the correlation between tests. We present a new method P(norm) to correct for multiple hypothesis testing in case-control association studies in which some individuals are related. The adjustment with P(norm) simultaneously accounts for two sources of correlations of the test statistics: (1) LD among genetic markers (2) dependence among genotypes across related individuals. Using simulated data based on the International HapMap Project, we demonstrate that it has better control of type I error and is more powerful than some of the recently developed methods. We apply the method to a genome-wide association study of alcoholism in the GAW 14 COGA data set and detect genome-wide significant association.
    MeSH term(s) Alcoholism/genetics ; Case-Control Studies ; Computer Simulation ; Data Interpretation, Statistical ; Genetic Variation ; Genome-Wide Association Study ; Genotype ; Humans ; Linkage Disequilibrium ; Mathematical Computing ; Pedigree
    Language English
    Publishing date 2011-01
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 605785-8
    ISSN 1098-2272 ; 0741-0395
    ISSN (online) 1098-2272
    ISSN 0741-0395
    DOI 10.1002/gepi.20555
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