Biology subjects

Deasy, J. O.

Publications and source records attributed to Deasy, J. O..

27 records · Page 2Linked to original sources

bioRxiv2020

Periodicity Scoring of Time Series Encodes Dynamical Behavior of the Tumor Suppressor p53

In this paper, we analyze the dynamical behavior of the tumor suppressor protein p53, an essential player in the cellular stress response, which prevents a cell from dividing if severe DNA damage is present. When this response system is malfunctioning, e.g. due to mutations in p53, uncontrolled cell proliferation may lead to the development of cancer. Understanding the behavior of p53 is thus crucial to prevent its failing. It has been shown in various experiments that periodicity of the p53 signal is one of the main descriptors of its dynamics, and that its pulsing behavior (regular vs. spontaneous) indicates the level and type of cellular stress. In the present work, we introduce an algorithm to score the local periodicity of a given time series (such as the p53 signal), which we call Detrended Autocorrelation Periodicity Scoring (DAPS). It applies pitch detection (via autocorrelation) on sliding windows of the entire time series to describe the overall periodicity by a distribution of localized pitch scores. We apply DAPS to the p53 time series obtained from single cell experiments and establish a correlation between the periodicity scoring of a cells p53 signal and the number of cell division events. In particular, we show that high periodicity scoring of p53 is correlated to a low number of cell divisions and vice versa. We show similar results with a more computationally intensive state-of-the-art periodicity scoring algorithm based on topology known as Sw1PerS. This correlation has two major implications: It demonstrates that periodicity scoring of the p53 signal is a good descriptor for cellular stress, and it connects the high variability of p53 periodicity observed in cell populations to the variability in the number of cell division events. AMS subject classification92C42, 92C37, 62M10

bioinformatics↗

bioRxiv2019

Library of model implementations for sharing deep-learning image segmentation and outcomes models

An open-source library of implementations for deep-learning based image segmentation and outcomes models is presented in this work. As oncology treatment planning becomes increasingly driven by automation, such a library of model implementations is crucial to (i) validate existing models on datasets collected at different institutions, (ii) automate segmentation, (iii) create ensembles for improving performance and (iv) incorporate validated models in the clinical workflow. The library was developed with Computational Environment for Radiological Research (CERR) software platform. CERR is a natural choice to centralize model implementations due to its comprehensiveness, popularity, and ease of use. CERR provides well-validated feature extraction for radiotherapy dosimetry and radiomics with fine control over the calculation settings. This allows users to select the appropriate feature calculation used in the model derivation. Models for automatic image segmentation are distributed via Singularity containers, with seamless i/o to and from CERR. Singularity containers allow for segmentation models to be deployed with a variety of scientific computing architectures. Deployment of models is driven by JSON configuration file, making it convenient to plug-in models. Models from the library can be called programmatically for batch evaluation. The library includes implementations for popular radiotherapy models outlined in the Quantitative Analysis of Normal Tissue Effects in the Clinic effort and recently published literature. Radiomics models include features from Image Biomarker Standardization features found to be important across multiple sites and image modalities. Deep learning-based image segmentation models include state of the art networks such as Deeplab and other problem-specific architectures. The library is distributed as GNU-copyrighted software at https://www.github.com/cerr/CERR.

bioinformatics↗

bioRxiv2019

Network-based clustering for drug sensitivity prediction in cancer cell lines

The study of large-scale pharmacogenomics provides an unprecedented opportunity to develop computational models that can accurately predict large cohorts of cell lines and drugs. In this work, we present a novel method for predicting drug sensitivity in cancer cell lines which considers both cell line genomic features and drug chemical features. Our network-based approach combines the theory of optimal mass transport (OMT) with machine learning techniques. It starts with unsupervised clustering of both cell line and drug data, followed by the prediction of drug sensitivity in the paired cluster of cell lines and drugs. We show that prior clustering of the heterogenous cell lines and structurally diverse drugs significantly improves the accuracy of the prediction. In addition, it facilities the interpretability of the results and identification of molecular biomarkers which are significant for both clustering of the cell lines and predicting the drug response.

bioinformatics↗

bioRxiv2019

Deep learning-based auto-segmentation of swallowing and chewing structures in CT

PurposeDelineating the swallowing and chewing structures in Head and Neck (H&N) CT scans is necessary for radiotherapy treatment (RT) planning to reduce the incidence of radiation-induced dysphagia, trismus, and speech dysfunction. Automating this process would decrease the manual input required and yield reproducible segmentations, but generating accurate segmentations is challenging due to the complex morphology of swallowing and chewing structures and limited soft tissue contrast in CT images. MethodsWe trained deep learning models using 194 H&N CT scans from our institution to segment the masseters (left and right), medial pterygoids (left and right), larynx, and pharyngeal constrictor muscle using DeepLabV3+ with the resnet-101 backbone. Models were trained in a sequential manner to guide the localization of each structure group based on prior segmentations. Additionally, an ensemble of models was developed using contextual information from three different views (axial, coronal, and sagittal), for robustness to occasional failures of the individual models. Output probability maps were averaged, and voxels were assigned labels corresponding to the class with the highest combined probability. ResultsThe median dice similarity coefficients (DSC) computed on a hold-out set of 24 CT scans were 0.87{+/-}0.02 for the masseters, 0.80{+/-}0.03 for the medial pterygoids, 0.81{+/-}0.04 for the larynx, and 0.69{+/-}0.07for the constrictor muscle. The corresponding 95th percentile Hausdorff distances were 0.32{+/-}0.08cm (masseters), 0.42{+/-}0.2cm (medial pterygoids), 0.53{+/-}0.3cm (larynx), and 0.36{+/-}0.15cm (constrictor muscle). Dose-volume histogram (DVH) metrics previously found to correlate with each toxicity were extracted from manual and auto-generated contours and compared between the two sets of contours to assess clinical utility. Differences in DVH metrics were not found to be statistically significant (p>0.05) for any of the structures. Further, inter-observer variability in contouring was studied in 10 CT scans. Automated segmentations were found to agree better with each of the observers as compared to inter-observer agreement, measured in terms of DSC. ConclusionsWe developed deep learning-based auto-segmentation models for swallowing and chewing structures in CT. The resulting segmentations can be included in treatment planning to limit complications following RT for H&N cancer. The segmentation models developed in this work are distributed for research use through the open-source platform CERR, accessible at https://github.com/cerr/CERR.

bioinformatics↗

bioRxiv2019

Anatomically Informed 3D Printed CT phantoms: The First Step of a Pipeline To Identify Robust Quantitative Radiomic Features

PurposeThis study investigates the robustness of quantitative radiomic features derived from computed tomography (CT) images of a novel patient informed 3-D printed phantom, which captures the morphological heterogeneity of tumors and normal tissue observed on CT scans.\n\nMethodsUsing a novel voxel-based multi-material three-dimensional (3D) printer, an anthropomorphic phantom that was modeled after diseased tissue seen on 6 patient CT scans was manufactured. Four patients presented with pancreatic adenocarcinoma tumors (PDAC), 1 with non-small cell lung carcinoma (NSCLC) and 1 with advanced stage hepatic cirrhosis. The 5 tumors were segmented, extracted and then imbedded into CT images of the heterogenous portion of the cirrhotic liver. The composite scan of the implanted tumor within the background cirrhotic liver was then 3D printed. The resultant phantom was scanned sequentially, 30 times with a clinical CT scanner using a reference CT protocol. One hundred and four quantitative radiomic features were then extracted from images of each lesion to determine their repeatability. Repeatability of each radiomic feature was evaluated using the within subject coefficient of variation (wCV, %). A feature with a wCV (%) > 10% was considered as being unrepeatable. A subset of the repeatable features that were also found to be prognostic for lung and pancreatic cancers were then assessed for their percent deviation (pDV, %) from reference values. The reference values were those derived from the repeatability portion of this study. The assessment was conducted by re-scanning the phantom with 11 different clinically relevant sets of scanning parameters. Deviation of radiomic features derived from images of each tumor across all sets of scanning parameters was assessed using the percent deviation relative to the reference values.\n\nResultsTwenty nine of the 104 features presented with wCV (%) > 10%. The lack of repeatability was found to depend on tumor type. The only class of radiomic features with a wCV (%) < 10% were those calculated using the neighboring grey level dependence-based matrices (NGLDM). Notably, skewness, first information correlation, cluster shade, Haralick correlation, autocorrelation, busyness, complexity, high gray level zone emphasis, small area high gray level emphasis, large area low gray level emphasis, large area high gray level emphasis, short run high grey level emphasis, and valley radiomic features had wCV (%) values > 10% for select tumors within the phantom. Two radiomic features prognostic for NSCLC, energy and grey level non-uniformity, had pDVs (%) that exceeded 30% across all scanning techniques. The pDV (%) for the 4 radiomic features prognostic for PDAC tumors depended on tumor type and selected scanning parameter. Application of the lung kernel caused the largest pDVs (%). Scans acquired with the reduced tube current of 100 mA and reconstructed with the bone kernel yielded pDVs (%) within {+/-} 10%.\n\nConclusionWe demonstrated the feasibility with which patient informed 3D printed phantoms can be manufactured directly from lesions seen on CT scans, and demonstrate their potential use for the assessment of robust quantitative radiomic features.

biophysics↗

bioRxiv2019

Hierarchical Network Exploration using Gaussian MixtureModels

We present a framework based on optimal mass transport to construct, for a given network, a reduction hierarchy which can be used for interactive data exploration and community detection. Given a network and a set of numerical data samples for each node, we calculate a new computationally-efficient comparison metric between Gaussian Mixture Models, the Gaussian Mixture Transport distance, to determine a series of merge simplifications of the network. If only a network is given, numerical samples are synthesized from the network topology. The method has its basis in the local connection structure of the network, as well as the joint distribution of the data associated with neighboring nodes.\n\nThe analysis is benchmarked on networks with known community structures. We also analyze gene regulatory networks, including the PANTHER curated database and networks inferred from the GTEx lung and breast tissue RNA profiles. Gene Ontology annotations from the EBI GOA database are ranked and superimposed to explain the salient gene modules. We find that several gene modules related to highly specific biological processes are well-coordinated in such tissues. We also find that 18 of the 50 genes of the PAM50 breast-tumor prognostic signature appear among the highly coordinated genes in a single gene module, in both the breast and lung samples. Moreover these 18 are precisely the subset of the PAM50 recently identified as the basal-like markers.

bioinformatics↗

bioRxiv2019

Optimal Mass Transport Kinetic Modeling for Head and Neck DCE-MRI: Initial Analysis

Current state-of-the-art models for estimating the pharmacokinetic parameters do not account for intervoxel movement of the contrast agent (CA). We introduce an optimal mass transport (OMT) formulation that naturally handles intervoxel CA movement and distinguishes between advective and diffusive flows. Ten patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in the study between June 2014 and October 2015 and under-went DCE MRI imaging prior to beginning treatment. The CA tissue concentration information was taken as the input in the data-driven OMT model. The OMT approach was tested on HNSCC DCE data that provides quantitative information for forward flux ({Phi}F) and backward flux ({Phi}B). OMT-derived {Phi}F was compared with the volume transfer constant for CA, Ktrans, derived from the Extended Tofts Model (ETM). The OMT-derived flows showed a consistent jump in the CA diffusive behavior across the images in accordance with the known CA dynamics. The mean forward flux was 0.0082 {+/-} 0.0091 (min-1) whereas the mean advective component was 0.0052{+/-}0.0086 (min-1) in the HNSCC patients. The diffusive percentages in forward and backward flux ranged from 8.67-18.76% and 12.76-30.36%, respectively. The OMT model accounts for intervoxel CA movement and results show that the forward flux ({Phi}F) is comparable with the ETM-derived Ktrans. This is a novel data-driven study based on optimal mass transport principles applied to patient DCE imaging to analyze CA flow in HNSCC.

systems biology↗

bioRxiv2019

Computed Tomography Measures of Inter-site tumor Heterogeneity for Classifying Outcomes in High-Grade Serous Ovarian Carcinoma: a Retrospective Study

AbstractO_ST_ABSBackgroundC_ST_ABSHigh grade serous ovarian carcinoma shows marked intra-tumoral heterogeneity which is associated with decreased survival and resistance to platinum-based chemotherapy. Pre-treatment quantification of spatial tumor heterogeneity by multiple tissue sampling is not clinically feasible. Using standard-of-care CT imaging to non-invasively quantify heterogeneity could have high clinical utility and would be highly cost-effective. Texture analysis measures local variations in computed tomography (CT) image intensity. Haralick texture methods are typically used to capture the heterogeneity of entire lesions; however, this neglects the possible presence of texture habitats within the lesion, and the differences between metastatic sites. The primary aim of this study was to develop texture analysis of intra-site and inter-site spatial heterogeneity from standard-of-care CT images and to correlate these measures with clinical and genomic features in patients with HGSOC. Methods and findingsWe analyzed the data from a retrospective cohort of 84 patients with HGSOC consisting of 46 patients from Memorial Sloan Kettering Cancer Center (MSKCC) and 38 non-MSKCC cases selected from The Cancer Imaging Archive (TCIA). Inclusion criteria consisted of FIGO stage II-IV HGSOC, attempted primary cytoreductive surgery, intravenous contrast-enhanced CT of abdomen and pelvis performed prior to surgery and availability of molecular tumor data analysed as per the Cancer Genome Atlas (TCGA) Research Network ovarian cancer project. Manual segmentation and image analysis was performed on 463 metastatic tumor sites from 84 patients. In the MSKCC cohort the median number of tumor sites was 7 (interquartile range 5-9) and 4 (interquartile range 3-4) in the TCIA patients. Sub-regions were produced within each tumor site by grouping voxels with similar Haralick texture using the Kernel K-means method. We derived statistical measures of intra- and inter-site tumor heterogeneity (IISTH) including cluster sites entropy (cSE), cluster sites standard deviation (cluDev) and cluster sites dissimilarity (cluDiss) from sub-regions identified within and between individual tumor sites. Unsupervised clustering was used to group patient IISTH measures into low, medium, high, and ultra-high heterogeneity clusters from each cohort. The IISTH measure cluDiss was an independent predictor of progression-free survival (PFS) in multivariable analysis in both datasets (MSKCC hazard ratio [HR] 1.04, 95% CI 1.01-1.06, P = 0.002; TCIA HR 1.05, 95% CI 1.00-1.10, P = 0.049). Low and medium IISTH clusters were associated with longer PFS in multivariable analysis (MSKCC HR 2.94, 90% CI 1.29-6.70, P = 0.009, TCIA HR 5.94, 95% CI 1.05-33.6, P = 0.044). IISTH measures were robust to differences in the CT imaging systems. Average Haralick textures contrast (TCIA HR 1.08, 95% CI 1.01-1.10, P = 0.019) and homogeneity (TCIA HR 1.09, 95% CI 1.02-1.16, P = 0.008) were associated with PFS in mutivariate analysis only in the TCIA dataset. All other average Haralick textures and total tumor volume were not associated with PFS in either dataset. ConclusionsTexture measures of intra- and inter-site tumor heterogeneity from standard of care CT images are correlated with shorter PFS in HGSOC patients. These quantitative methods are independent of the CT imaging system and can thus be applied in clinical practice. The methodology proposed here enables the non-invasive quantification of intra-tumoral heterogeneity and disease stratification for future experimental medicine studies and clinical trials, particularly in cases where total tumour volume and averaged textures have low predictive power. Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LITumor heterogeneity is a feature of many solid malignancies including ovarian cancer. C_LIO_LIRecent genomic research suggests that intra-site tumor heterogeneity (heterogeneity within a single tumor site) and inter-site tumor heterogeneity (heterogeneity between different metastatic sites in the same patient) correlate with clinical outcome in HGSOC. C_LI What did the researchers do and find?O_LIWe developed quantitative and non-invasive image-analysis based measures for predicting outcome in HGSOC patients by combining image-based information from within and between multiple tumor sites. C_LIO_LIUsing datasets from two sources, we demonstrate that these image-based tumor heterogeneity measures predict progression free survival in patients with HGSOC. C_LI What do these findings mean?O_LINon-invasive measures of CT image heterogeneity may predict outcomes in HGSOC patients. C_LIO_LIWider application of these CT image heterogeneity measures could prove useful for stratifying patients to different therapies given that total tumour volume and averaged textures have low predictive power. C_LI

bioinformatics↗

bioRxiv2018

Topological Data Analysis of PAM50 and 21-Gene Breast Cancer Assays

We introduce a classification of breast tumors into 7 classes which are more clearly defined by interpretable mRNA signatures along the PAM50 gene set than the 5 traditional PAM50 intrinsic subtypes. Each intrinsic subtype is partially concordant with one of our classes, and the 2 additional classes correspond to division of the classes concordant with the Luminal B and the Normal intrinsic subtypes along expression of the Her2 gene group. Our Normal class shows similarity with the myoepithelial mammary cell phenotype, including TP63 expression (specificity: 80.8% and sensitivity: 82.8%), and exhibits the best overall survival (89.6% at 5 years). Though Luminal A tumors are traditionally considered the least aggressive, our analysis shows that only the Luminal A tumors which are now classified as myoepithelial have this phenotype, while tumors in our luminal class (concordant with Luminal A) may be more aggressive than previously thought. We also find that patients with Basal tumors surviving to 48 months exhibit favorable survival rates when certain markers for B-lymphocytes are present and poor survival rates when they are absent, which is consistent with recent findings.

cancer biology↗