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Journal articleThomas P, 2019,
Intrinsic and extrinsic noise of gene expression in lineage trees
, Scientific Reports, Vol: 9, ISSN: 2045-2322Cell-to-cell heterogeneity is driven by stochasticity in intracellular reactions and the population dynamics. While these sources are usually studied separately, we develop an agent-based framework that accounts for both factors while tracking every single cell of a growing population. Apart from the common intrinsic variability, the framework also predicts extrinsic noise without the need to introduce fluctuating rate constants. Instead, extrinsic fluctuations are explained by cell cycle fluctuations and differences in cell age. We provide explicit formulas to quantify mean molecule numbers, intrinsic and extrinsic noise statistics in two-colour experiments. We find that these statistics differ significantly depending on the experimental setup used to observe the cells. We illustrate this fact using (i) averages over an isolated cell lineage tracked over many generations as observed in the mother machine, (ii) population snapshots with known cell ages as recorded in time-lapse microscopy, and (iii) snapshots with unknown cell ages as measured from static images or flow cytometry. Applying the method to models of stochastic gene expression and feedback regulation elucidates that isolated lineages, as compared to snapshot data, can significantly overestimate the mean number of molecules, overestimate extrinsic noise but underestimate intrinsic noise and have qualitatively different sensitivities to cell cycle fluctuations.
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Journal articleClarke JM, Warren LR, Arora S, et al., 2018,
Guiding interoperable electronic health records through patient-sharing networks.
, NPJ digital medicine, Vol: 1, Pages: 65-65, ISSN: 2398-6352Effective sharing of clinical information between care providers is a critical component of a safe, efficient health system. National data-sharing systems may be costly, politically contentious and do not reflect local patterns of care delivery. This study examines hospital attendances in England from 2013 to 2015 to identify instances of patient sharing between hospitals. Of 19.6 million patients receiving care from 155 hospital care providers, 130 million presentations were identified. On 14.7 million occasions (12%), patients attended a different hospital to the one they attended on their previous interaction. A network of hospitals was constructed based on the frequency of patient sharing between hospitals which was partitioned using the Louvain algorithm into ten distinct data-sharing communities, improving the continuity of data sharing in such instances from 0 to 65-95%. Locally implemented data-sharing communities of hospitals may achieve effective accessibility of clinical information without a large-scale national interoperable information system.
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Journal articleDawes T, Simoes Monteiro de Marvao A, Shi W, et al., 2018,
Identifying the optimal regional predictor of right ventricular global function: a high resolution 3D cardiac magnetic resonance study
, Anaesthesia, Vol: 74, Pages: 312-320, ISSN: 0003-2409Right ventricular (RV) function has prognostic value in acute, chronic and peri‐operative disease, although the complex RV contractile pattern makes rapid assessment difficult. Several two‐dimensional (2D) regional measures estimate RV function, however the optimal measure is not known. High‐resolution three‐dimensional (3D) cardiac magnetic resonance cine imaging was acquired in 300 healthy volunteers and a computational model of RV motion created. Points where regional function was significantly associated with global function were identified and a 2D, optimised single‐point marker (SPM‐O) of global function developed. This marker was prospectively compared with tricuspid annular plane systolic excursion (TAPSE), septum‐freewall displacement (SFD) and their fractional change (TAPSE‐F, SFD‐F) in a test cohort of 300 patients in the prediction of RV ejection fraction. RV ejection fraction was significantly associated with systolic function in a contiguous 7.3 cm2 patch of the basal RV freewall combining transverse (38%), longitudinal (35%) and circumferential (27%) contraction and coinciding with the four‐chamber view. In the test cohort, all single‐point surrogates correlated with RV ejection fraction (p < 0.010), but correlation (R) was higher for SPM‐O (R = 0.44, p < 0.001) than TAPSE (R = 0.24, p < 0.001) and SFD (R = 0.22, p < 0.001), and non‐significantly higher than TAPSE‐F (R = 0.40, p < 0.001) and SFD‐F (R = 0.43, p < 0.001). SPM‐O explained more of the observed variance in RV ejection fraction (19%) and predicted it more accurately than any other 2D marker (median error 2.8 ml vs 3.6 ml, p < 0.001). We conclude that systolic motion of the basal RV freewall predicts global function more accurately than other 2D estimators. However, no markers summarise 3D contractile patterns, limiting their predictive accuracy.
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Journal articleThomas P, Terradot G, Danos V, et al., 2018,
Sources, propagation and consequences of stochasticity in cellular growth
, Nature Communications, Vol: 9, ISSN: 2041-1723Growth impacts a range of phenotypic responses. Identifying the sources of growth variation and their propagation across the cellular machinery can thus unravel mechanisms that underpin cell decisions. We present a stochastic cell model linking gene expression, metabolism and replication to predict growth dynamics in single bacterial cells. Alongside we provide a theory to analyse stochastic chemical reactions coupled with cell divisions, enabling efficient parameter estimation, sensitivity analysis and hypothesis testing. The cell model recovers population-averaged data on growth-dependence of bacterial physiology and how growth variations in single cells change across conditions. We identify processes responsible for this variation and reconstruct the propagation of initial fluctuations to growth and other processes. Finally, we study drug-nutrient interactions and find that antibiotics can both enhance and suppress growth heterogeneity. Our results provide a predictive framework to integrate heterogeneous data and draw testable predictions with implications for antibiotic tolerance, evolutionary and synthetic biology.
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Journal articleDawes T, Cai J, Quinlan M, et al., 2018,
Fractal analysis of right ventricular trabeculae in pulmonary hypertension
, Radiology, Vol: 288, Pages: 386-395, ISSN: 0033-8419Purpose: To measure right ventricular (RV) trabecular complexity by its fractal dimension (FD) in healthy subjects and patients with pulmonary hypertension (PH) and assess its relationship to hemodynamic and functional parameters, and future cardiovascular events. Materials and methods: This retrospective study used data acquired from May 2004 to October 2013 for 256 patients with newly-diagnosed PH that underwent cardiac magnetic resonance (CMR) imaging, right heart catheterization and six-minute walk distance testing with a median follow-up of 4.0 years. 256 healthy controls underwent CMR only. Biventricular FD, volumes and function were assessed on short-axis cine images. Reproducibility was assessed by intraclass correlation coefficient, correlation between variables was assessed by Pearson’s correlation test, and mortality prediction compared by univariable and multivariable Cox regression analysis. Results: RV-FD reproducibility had an intraclass correlation coefficient of 0.97 (95% confidence interval [CI]: 0.96, 0.98).RV-FD was higher in PH patients than healthy subjects (median 1.310, inter-quartile range [IQR] 1.281-1.341 vs 1.264, 1.242-1.295, P<.001) with the greatest difference near the apex. RV-FD was associated with pulmonary vascular resistance (r=0.30, P<.001). In univariable Cox regression analysis, RV-FD was a significant predictor of death (hazards ratio [HR]: 1.256, CI: 1.011, 1.560, P=.04), but in a multivariable analysis did not predict survival independently of conventional parameters of RV remodeling (HR: 1.179, CI: 0.871, 1.596, P=0.29). Conclusion: Fractal analysis of RV trabecular complexity is a highly reproducible measure of remodeling in PH associated with afterload, although the gain in survival prediction over traditional markers is not significant.
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Journal articleArnaudon A, Holm DD, Sommer S, 2017,
A Geometric Framework for Stochastic Shape Analysis
, Foundations of Computational Mathematics, ISSN: 1615-3375We introduce a stochastic model of diffeomorphisms, whose action on a varietyof data types descends to stochastic evolution of shapes, images and landmarks.The stochasticity is introduced in the vector field which transports the datain the Large Deformation Diffeomorphic Metric Mapping (LDDMM) framework forshape analysis and image registration. The stochasticity thereby models errorsor uncertainties of the flow in following the prescribed deformation velocity.The approach is illustrated in the example of finite dimensional landmarkmanifolds, whose stochastic evolution is studied both via the Fokker-Planckequation and by numerical simulations. We derive two approaches for inferringparameters of the stochastic model from landmark configurations observed atdiscrete time points. The first of the two approaches matches moments of theFokker-Planck equation to sample moments of the data, while the second approachemploys an Expectation-Maximisation based algorithm using a Monte Carlo bridgesampling scheme to optimise the data likelihood. We derive and numerically testthe ability of the two approaches to infer the spatial correlation length ofthe underlying noise.
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Conference paperAltuncu MT, Mayer E, Yaliraki SN, et al., 2018,
From Text to Topics in Healthcare Records: An Unsupervised Graph Partitioning Methodology
, 2018 KDD Conference Proceedings - MLMH: Machine Learning for Medicine and HealthcareElectronic Healthcare Records contain large volumes of unstructured data,including extensive free text. Yet this source of detailed information oftenremains under-used because of a lack of methodologies to extract interpretablecontent in a timely manner. Here we apply network-theoretical tools to analysefree text in Hospital Patient Incident reports from the National HealthService, to find clusters of documents with similar content in an unsupervisedmanner at different levels of resolution. We combine deep neural networkparagraph vector text-embedding with multiscale Markov Stability communitydetection applied to a sparsified similarity graph of document vectors, andshowcase the approach on incident reports from Imperial College Healthcare NHSTrust, London. The multiscale community structure reveals different levels ofmeaning in the topics of the dataset, as shown by descriptive terms extractedfrom the clusters of records. We also compare a posteriori against hand-codedcategories assigned by healthcare personnel, and show that our approachoutperforms LDA-based models. Our content clusters exhibit good correspondencewith two levels of hand-coded categories, yet they also provide further medicaldetail in certain areas and reveal complementary descriptors of incidentsbeyond the external classification taxonomy.
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Journal articleArnaudon A, Holm D, Sommer S, 2018,
String methods for stochastic image and shape matching
, Journal of Mathematical Imaging and Vision, Vol: 60, Pages: 953-967, ISSN: 0924-9907Matching of images and analysis of shape differences is traditionally pursued by energy minimization of paths of deformations acting to match the shape objects. In the large deformation diffeomorphic metric mapping (LDDMM) framework, iterative gradient descents on the matching functional lead to matching algorithms informally known as Beg algorithms. When stochasticity is introduced to model stochastic variability of shapes and to provide more realistic models of observed shape data, the corresponding matching problem can be solved with a stochastic Beg algorithm, similar to the finite-temperature string method used in rare event sampling. In this paper, we apply a stochastic model compatible with the geometry of the LDDMM framework to obtain a stochastic model of images and we derive the stochastic version of the Beg algorithm which we compare with the string method and an expectation-maximization optimization of posterior likelihoods. The algorithm and its use for statistical inference is tested on stochastic LDDMM landmarks and images.
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Journal articleLiu D, Mannan AA, Han Y, et al., 2018,
Dynamic metabolic control: towards precision engineering of metabolism
, Journal of Industrial Microbiology and Biotechnology, Vol: 45, Pages: 535-543, ISSN: 1367-5435Advances in metabolic engineering have led to the synthesis of a wide variety of valuable chemicals in microorganisms. The key to commercializing these processes is the improvement of titer, productivity, yield, and robustness. Traditional approaches to enhancing production use the “push–pull-block” strategy that modulates enzyme expression under static control. However, strains are often optimized for specific laboratory set-up and are sensitive to environmental fluctuations. Exposure to sub-optimal growth conditions during large-scale fermentation often reduces their production capacity. Moreover, static control of engineered pathways may imbalance cofactors or cause the accumulation of toxic intermediates, which imposes burden on the host and results in decreased production. To overcome these problems, the last decade has witnessed the emergence of a new technology that uses synthetic regulation to control heterologous pathways dynamically, in ways akin to regulatory networks found in nature. Here, we review natural metabolic control strategies and recent developments in how they inspire the engineering of dynamically regulated pathways. We further discuss the challenges of designing and engineering dynamic control and highlight how model-based design can provide a powerful formalism to engineer dynamic control circuits, which together with the tools of synthetic biology, can work to enhance microbial production.
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Conference paperAltuncu T, Yaliraki SN, Barahona M, 2018,
Content-driven, unsupervised clustering of news articles through multiscale graph partitioning
, KDD 2018 - Workshop on Data Science Journalism and Media (DSJM)The explosion in the amount of news and journalistic content being generatedacross the globe, coupled with extended and instantaneous access to informationthrough online media, makes it difficult and time-consuming to monitor newsdevelopments and opinion formation in real time. There is an increasing needfor tools that can pre-process, analyse and classify raw text to extractinterpretable content; specifically, identifying topics and content-drivengroupings of articles. We present here such a methodology that brings togetherpowerful vector embeddings from Natural Language Processing with tools fromGraph Theory that exploit diffusive dynamics on graphs to reveal naturalpartitions across scales. Our framework uses a recent deep neural network textanalysis methodology (Doc2vec) to represent text in vector form and thenapplies a multi-scale community detection method (Markov Stability) topartition a similarity graph of document vectors. The method allows us toobtain clusters of documents with similar content, at different levels ofresolution, in an unsupervised manner. We showcase our approach with theanalysis of a corpus of 9,000 news articles published by Vox Media over oneyear. Our results show consistent groupings of documents according to contentwithout a priori assumptions about the number or type of clusters to be found.The multilevel clustering reveals a quasi-hierarchy of topics and subtopicswith increased intelligibility and improved topic coherence as compared toexternal taxonomy services and standard topic detection methods.
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