Search

Background Bedaquiline is a core drug for the treatment of multidrug-resistant tuberculosis; however, the understanding of resistance mechanisms is poor, which is hampering rapid molecular diagnostics. Some bedaquiline-resistant mutants are also cross-resistant to clofazimine. To decipher bedaquiline and clofazimine resistance determinants, we combined experimental evolution, protein modelling, genome sequencing, and phenotypic data. Methods For this in-vitro and in-silico data analysis, we used a novel in-vitro evolutionary model using subinhibitory drug concentrations to select bedaquiline-resistant and clofazimine-resistant mutants. We determined bedaquiline and clofazimine minimum inhibitory concentrations and did Illumina and PacBio sequencing to characterise selected mutants and establish a mutation catalogue. This catalogue also includes phenotypic and genotypic data of a global collection of more than 14 000 clinical Mycobacterium tuberculosis complex isolates, and publicly available data. We investigated variants implicated in bedaquiline resistance by protein modelling and dynamic simulations. Findings We discerned 265 genomic variants implicated in bedaquiline resistance, with 250 (94%) variants affecting the transcriptional repressor (Rv0678) of the MmpS5–MmpL5 efflux system. We identified 40 new variants in vitro, and a new bedaquiline resistance mechanism caused by a large-scale genomic rearrangement. Additionally, we identified in vitro 15 (7%) of 208 mutations found in clinical bedaquiline-resistant isolates. From our in-vitro work, we detected 14 (16%) of 88 mutations so far identified as being associated with clofazimine resistance and also seen in clinically resistant strains, and catalogued 35 new mutations. Structural modelling of Rv0678 showed four major mechanisms of bedaquiline resistance: impaired DNA binding, reduction in protein stability, disruption of protein dimerisation, and alteration in affinity for its fatty acid ligand. Interpretation Our findings advance the understanding of drug resistance mechanisms in M tuberculosis complex strains. We have established an extended mutation catalogue, comprising variants implicated in resistance and susceptibility to bedaquiline and clofazimine. Our data emphasise that genotypic testing can delineate clinical isolates with borderline phenotypes, which is essential for the design of effective treatments. Funding Leibniz ScienceCampus Evolutionary Medicine of the Lung, Deutsche Forschungsgemeinschaft, Research Training Group 2501 TransEvo, Rhodes Trust, Stanford University Medical Scientist Training Program, National Institute for Health and Care Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Bill & Melinda Gates Foundation, Wellcome Trust, and Marie Skłodowska-Curie Actions.

Healthcare is dynamic as demographics, diseases, and therapeutics constantly evolve. This dynamic nature induces inevitable distribution shifts in populations targeted by clinical AI models, often rendering them ineffective. Incremental learning provides an effective method of adapting deployed clinical models to accommodate these contemporary distribution shifts. However, since incremental learning involves modifying a deployed or in-use model, it can be considered unreliable as any adverse modification due to maliciously compromised or incorrectly labelled data can make the model unsuitable for the targeted application. This paper introduces self-aware stochastic gradient descent (SGD), an incremental deep learning algorithm that utilises a contextual bandit-like sanity check to only allow reliable modifications to a model. The contextual bandit analyses incremental gradient updates to isolate and filter unreliable gradients. This behaviour allows self-aware SGD to balance incremental training and integrity of a deployed model. Experimental evaluations on the Oxford University Hospital datasets highlight that self-aware SGD can provide reliable incremental updates for overcoming distribution shifts in challenging conditions induced by label noise

Background Our understanding of the global scale of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains incomplete: Routine surveillance data underestimate infection and cannot infer on population immunity; there is a predominance of asymptomatic infections, and uneven access to diagnostics. We meta-analyzed SARS-CoV-2 seroprevalence studies, standardized to those described in the World Health Organization’s Unity protocol (WHO Unity) for general population seroepidemiological studies, to estimate the extent of population infection and seropositivity to the virus 2 years into the pandemic. Methods and findings We conducted a systematic review and meta-analysis, searching MEDLINE, Embase, Web of Science, preprints, and grey literature for SARS-CoV-2 seroprevalence published between January 1, 2020 and May 20, 2022. The review protocol is registered with PROSPERO (CRD42020183634). We included general population cross-sectional and cohort studies meeting an assay quality threshold (90% sensitivity, 97% specificity; exceptions for humanitarian settings). We excluded studies with an unclear or closed population sample frame. Eligible studies—those aligned with the WHO Unity protocol—were extracted and critically appraised in duplicate, with risk of bias evaluated using a modified Joanna Briggs Institute checklist. We meta-analyzed seroprevalence by country and month, pooling to estimate regional and global seroprevalence over time; compared seroprevalence from infection to confirmed cases to estimate underascertainment; meta-analyzed differences in seroprevalence between demographic subgroups such as age and sex; and identified national factors associated with seroprevalence using meta-regression. We identified 513 full texts reporting 965 distinct seroprevalence studies (41% low- and middle-income countries [LMICs]) sampling 5,346,069 participants between January 2020 and April 2022, including 459 low/moderate risk of bias studies with national/subnational scope in further analysis. By September 2021, global SARS-CoV-2 seroprevalence from infection or vaccination was 59.2%, 95% CI [56.1% to 62.2%]. Overall seroprevalence rose steeply in 2021 due to infection in some regions (e.g., 26.6% [24.6 to 28.8] to 86.7% [84.6% to 88.5%] in Africa in December 2021) and vaccination and infection in others (e.g., 9.6% [8.3% to 11.0%] in June 2020 to 95.9% [92.6% to 97.8%] in December 2021, in European high-income countries [HICs]). After the emergence of Omicron in March 2022, infection-induced seroprevalence rose to 47.9% [41.0% to 54.9%] in Europe HIC and 33.7% [31.6% to 36.0%] in Americas HIC. In 2021 Quarter Three (July to September), median seroprevalence to cumulative incidence ratios ranged from around 2:1 in the Americas and Europe HICs to over 100:1 in Africa (LMICs). Children 0 to 9 years and adults 60+ were at lower risk of seropositivity than adults 20 to 29 (p < 0.001 and p = 0.005, respectively). In a multivariable model using prevaccination data, stringent public health and social measures were associated with lower seroprevalence (p = 0.02). The main limitations of our methodology include that some estimates were driven by certain countries or populations being overrepresented. Conclusions In this study, we observed that global seroprevalence has risen considerably over time and with regional variation; however, over one-third of the global population are seronegative to the SARS-CoV-2 virus. Our estimates of infections based on seroprevalence far exceed reported Coronavirus Disease 2019 (COVID-19) cases. Quality and standardized seroprevalence studies are essential to inform COVID-19 response, particularly in resource-limited regions.

Objective To externally evaluate the performance of QRISK3 for predicting 10 year risk of cardiovascular disease (CVD) in the UK Biobank cohort. Methods We used data from the UK Biobank, a large-scale prospective cohort study of 403 370 participants aged 40–69 years recruited between 2006 and 2010 in the UK. We included participants with no previous history of CVD or statin treatment and defined the outcome to be the first occurrence of coronary heart disease, ischaemic stroke or transient ischaemic attack, derived from linked hospital inpatient records and death registrations. Results Our study population included 233 233 women and 170 137 men, with 9295 and 13 028 incident CVD events, respectively. Overall, QRISK3 had moderate discrimination for UK Biobank participants (Harrell’s C-statistic 0.722 in women and 0.697 in men) and discrimination declined by age (

Existing heterogeneous treatment effects learners, also known as conditional average treatment effects (CATE) learners, lack a general mechanism for end-to-end inter-treatment information sharing, and data have to be split among potential outcome functions to train CATE learners which can lead to biased estimates with limited observational datasets. To address this issue, we propose a novel deep learning-based framework to train CATE learners that facilitates dynamic end-to-end information sharing among treatment groups. The framework is based on \textit{soft weight sharing} of \textit{hypernetworks}, which offers advantages such as parameter efficiency, faster training, and improved results. The proposed framework complements existing CATE learners and introduces a new class of uncertainty-aware CATE learners that we refer to as \textit{HyperCATE}. We develop HyperCATE versions of commonly used CATE learners and evaluate them on IHDP, ACIC-2016, and Twins benchmarks. Our experimental results show that the proposed framework improves the CATE estimation error via counterfactual inference, with increasing effectiveness for smaller datasets., (under review)

Machine learning is becoming increasingly prominent in healthcare. Although its benefits are clear, growing attention is being given to how these tools may exacerbate existing biases and disparities. In this study, we introduce an adversarial training framework that is capable of mitigating biases that may have been acquired through data collection. We demonstrate this proposed framework on the real-world task of rapidly predicting COVID-19, and focus on mitigating site-specific (hospital) and demographic (ethnicity) biases. Using the statistical definition of equalized odds, we show that adversarial training improves outcome fairness, while still achieving clinically-effective screening performances (negative predictive values >0.98). We compare our method to previous benchmarks, and perform prospective and external validation across four independent hospital cohorts. Our method can be generalized to any outcomes, models, and definitions of fairness.

Background: Bedaquiline is a core drug for the treatment of multidrug-resistant tuberculosis; however, the understanding of resistance mechanisms is poor, which is hampering rapid molecular diagnostics. Some bedaquiline-resistant mutants are also cross-resistant to clofazimine. To decipher bedaquiline and clofazimine resistance determinants, we combined experimental evolution, protein modelling, genome sequencing, and phenotypic data. Methods: For this in-vitro and in-silico data analysis, we used a novel in-vitro evolutionary model using subinhibitory drug concentrations to select bedaquiline-resistant and clofazimine-resistant mutants. We determined bedaquiline and clofazimine minimum inhibitory concentrations and did Illumina and PacBio sequencing to characterise selected mutants and establish a mutation catalogue. This catalogue also includes phenotypic and genotypic data of a global collection of more than 14 000 clinical Mycobacterium tuberculosis complex isolates, and publicly available data. We investigated variants implicated in bedaquiline resistance by protein modelling and dynamic simulations. Findings: We discerned 265 genomic variants implicated in bedaquiline resistance, with 250 (94%) variants affecting the transcriptional repressor (Rv0678) of the MmpS5–MmpL5 efflux system. We identified 40 new variants in vitro, and a new bedaquiline resistance mechanism caused by a large-scale genomic rearrangement. Additionally, we identified in vitro 15 (7%) of 208 mutations found in clinical bedaquiline-resistant isolates. From our in-vitro work, we detected 14 (16%) of 88 mutations so far identified as being associated with clofazimine resistance and also seen in clinically resistant strains, and catalogued 35 new mutations. Structural modelling of Rv0678 showed four major mechanisms of bedaquiline resistance: impaired DNA binding, reduction in protein stability, disruption of protein dimerisation, and alteration in affinity for its fatty acid ligand. Interpretation: Our findings advance the understanding of drug resistance mechanisms in M tuberculosis complex strains. We have established an extended mutation catalogue, comprising variants implicated in resistance and susceptibility to bedaquiline and clofazimine. Our data emphasise that genotypic testing can delineate clinical isolates with borderline phenotypes, which is essential for the design of effective treatments. Funding: Leibniz ScienceCampus Evolutionary Medicine of the Lung, Deutsche Forschungsgemeinschaft, Research Training Group 2501 TransEvo, Rhodes Trust, Stanford University Medical Scientist Training Program, National Institute for Health and Care Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Bill & Melinda Gates Foundation, Wellcome Trust, and Marie Skłodowska-Curie Actions.

Irregular time-series (ITS) are prevalent in the electronic health records (EHR) as the data is recorded in EHR system as per the clinical guidelines/requirements but not for research and also depends on the patient health status. ITS present challenges in training of machine learning algorithms, which are mostly built on assumption of coherent fixed dimensional feature space. In this paper, we propose a computationally efficient variant of the transformer based on the idea of cross-attention, called Perceiver, for time-series in healthcare. We further develop continuous patient state attention models, using the Perceiver and the transformer to deal with ITS in EHR. The continuous patient state models utilise neural ordinary differential equations to learn the patient health dynamics, i.e., patient health trajectory from the observed irregular time-steps, which enables them to sample any number of time-steps at any time. The performance of the proposed models is evaluated on in-hospital-mortality prediction task on Physionet-2012 challenge and MIMIC-III datasets. The Perceiver model significantly outperforms the baselines and reduces the computational complexity, as compared with the transformer model, without significant loss of performance. The carefully designed experiments to study irregularity in healthcare also show that the continuous patient state models outperform the baselines. The code is publicly released and verified athttps://codeocean.com/capsule/4587224.

Most video-and-language representation learning approaches employ contrastive learning, e.g., CLIP, to project the video and text features into a common latent space according to the semantic similarities of text-video pairs. However, such learned shared latent spaces are not often optimal, and the modality gap between visual and textual representation can not be fully eliminated. In this paper, we propose Expectation-Maximization Contrastive Learning (EMCL) to learn compact video-and-language representations. Specifically, we use the Expectation-Maximization algorithm to find a compact set of bases for the latent space, where the features could be concisely represented as the linear combinations of these bases. Such feature decomposition of video-and-language representations reduces the rank of the latent space, resulting in increased representing power for the semantics. Extensive experiments on three benchmark text-video retrieval datasets prove that our EMCL can learn more discriminative video-and-language representations than previous methods, and significantly outperform previous state-of-the-art methods across all metrics. More encouragingly, the proposed method can be applied to boost the performance of existing approaches either as a jointly training layer or an out-of-the-box inference module with no extra training, making it easy to be incorporated into any existing methods., Accepted to NeurIPS 2022

Observational studies have recently received significant attention from the machine learning community due to the increasingly available non-experimental observational data and the limitations of the experimental studies, such as considerable cost, impracticality, small and less representative sample sizes, etc. In observational studies, de-confounding is a fundamental problem of individualised treatment effects (ITE) estimation. This paper proposes disentangled representations with adversarial training to selectively balance the confounders in the binary treatment setting for the ITE estimation. The adversarial training of treatment policy selectively encourages treatment-agnostic balanced representations for the confounders and helps to estimate the ITE in the observational studies via counterfactual inference. Empirical results on synthetic and real-world datasets, with varying degrees of confounding, prove that our proposed approach improves the state-of-the-art methods in achieving lower error in the ITE estimation., accepted to AISTATS 2023

The emergence of drug-resistant tuberculosis is a major global public health concern that threatens the ability to control the disease. Whole-genome sequencing as a tool to rapidly diagnose resistant infections can transform patient treatment and clinical practice. While resistance mechanisms are well understood for some drugs, there are likely many mechanisms yet to be uncovered, particularly for new and repurposed drugs. We sequenced 10,228 Mycobacterium tuberculosis (MTB) isolates worldwide and determined the minimum inhibitory concentration (MIC) on a grid of 2-fold concentration dilutions for 13 antimicrobials using quantitative microtiter plate assays. We performed oligopeptide- and oligonucleotide-based genome-wide association studies using linear mixed models to discover resistance-conferring mechanisms not currently catalogued. Use of MIC over binary resistance phenotypes increased sample heritability for the new and repurposed drugs by 26% to 37%, increasing our ability to detect novel associations. For all drugs, we discovered uncatalogued variants associated with MIC, including in the Rv1218c promoter binding site of the transcriptional repressor Rv1219c (isoniazid), upstream of the vapBC20 operon that cleaves 23S rRNA (linezolid) and in the region encoding an α-helix lining the active site of Cyp142 (clofazimine, all p < 10−7.7). We observed that artefactual signals of cross-resistance could be unravelled based on the relative effect size on MIC. Our study demonstrates the ability of very large-scale studies to substantially improve our knowledge of genetic variants associated with antimicrobial resistance in M. tuberculosis.

Contains fulltext : 251202.pdf (Publisher’s version ) (Open Access) A growing number of artificial intelligence (AI)-based clinical decision support systems are showing promising performance in preclinical, in silico, evaluation, but few have yet demonstrated real benefit to patient care. Early stage clinical evaluation is important to assess an AI system’s actual clinical performance at small scale, ensure its safety, evaluate the human factors surrounding its use, and pave the way to further large scale trials. However, the reporting of these early studies remains inadequate. The present statement provides a multistakeholder, consensus-based reporting guideline for the Developmental and Exploratory Clinical Investigations of DEcision support systems driven by Artificial Intelligence (DECIDE-AI). We conducted a two round, modified Delphi process to collect and analyse expert opinion on the reporting of early clinical evaluation of AI systems. Experts were recruited from 20 predefined stakeholder categories. The final composition and wording of the guideline was determined at a virtual consensus meeting. The checklist and the Explanation & Elaboration (E&E) sections were refined based on feedback from a qualitative evaluation process. 123 experts participated in the first round of Delphi, 138 in the second, 16 in the consensus meeting, and 16 in the qualitative evaluation. The DECIDE-AI reporting guideline comprises 17 AI specific reporting items (made of 28 subitems) and 10 generic reporting items, with an E&E paragraph provided for each. Through consultation and consensus with a range of stakeholders, we have developed a guideline comprising key items that should be reported in early stage clinical studies of AI-based decision support systems in healthcare. By providing an actionable checklist of minimal reporting items, the DECIDE-AI guideline will facilitate the appraisal of these studies and replicability of their findings.

The healthcare industry generates troves of unlabelled physiological data. This data can be exploited via contrastive learning, a self-supervised pre-training method that encourages representations of instances to be similar to one another. We propose a family of contrastive learning methods, CLOCS, that encourages representations across space, time, \textit{and} patients to be similar to one another. We show that CLOCS consistently outperforms the state-of-the-art methods, BYOL and SimCLR, when performing a linear evaluation of, and fine-tuning on, downstream tasks. We also show that CLOCS achieves strong generalization performance with only 25\% of labelled training data. Furthermore, our training procedure naturally generates patient-specific representations that can be used to quantify patient-similarity., Accepted to ICML 2021

Sepsis is associated with high mortality—particularly in low–middle income countries (LMICs). Critical care management of sepsis is challenging in LMICs due to the lack of care providers and the high cost of bedside monitors. Recent advances in wearable sensor technology and machine learning (ML) models in healthcare promise to deliver new ways of digital monitoring integrated with automated decision systems to reduce the mortality risk in sepsis. In this study, firstly, we aim to assess the feasibility of using wearable sensors instead of traditional bedside monitors in the sepsis care management of hospital admitted patients, and secondly, to introduce automated prediction models for the mortality prediction of sepsis patients. To this end, we continuously monitored 50 sepsis patients for nearly 24 h after their admission to the Hospital for Tropical Diseases in Vietnam. We then compared the performance and interpretability of state-of-the-art ML models for the task of mortality prediction of sepsis using the heart rate variability (HRV) signal from wearable sensors and vital signs from bedside monitors. Our results show that all ML models trained on wearable data outperformed ML models trained on data gathered from the bedside monitors for the task of mortality prediction with the highest performance (area under the precision recall curve = 0.83) achieved using time-varying features of HRV and recurrent neural networks. Our results demonstrate that the integration of automated ML prediction models with wearable technology is well suited for helping clinicians who manage sepsis patients in LMICs to reduce the mortality risk of sepsis.

Non-invasive foetal electrocardiography (NI-FECG) has become an important prenatal monitoring method in the hospital. However, due to its susceptibility to non-stationary noise sources and lack of robust extraction methods, the capture of high-quality NI-FECG remains a challenge. Recording waveforms of sufficient quality for clinical use typically requires human visual inspection of each recording. A Signal Quality Index (SQI) can help to automate this task but, contrary to adult ECG, work on SQIs for NI-FECG is sparse. In this paper, a multi-channel signal quality classifier for NI-FECG waveforms is presented. The model can be used during the capture of NI-FECG to assist technicians to record high-quality waveforms, which is currently a labour-intensive task. A Convolutional Neural Network (CNN) is trained to distinguish between NI-FECG segments of high and low quality. NI-FECG recordings with one maternal channel and three abdominal channels were collected from 100 subjects during a routine hospital screening (102.6amp;nbsp;min of data). The model achieves an average 10-fold cross-validated AUC of 0.95amp;nbsp;±amp;nbsp;0.02. The results show that the model can reliably assess the FECG signal quality on our dataset. The proposed model can improve the automated capture and analysis of NI-FECG as well as reduce technician labour time.

In this work, we study robust deep learning against abnormal training data from the perspective of example weighting built in empirical loss functions, i.e., gradient magnitude with respect to logits, an angle that is not thoroughly studied so far. Consequently, we have two key findings: (1) Mean Absolute Error (MAE) Does Not Treat Examples Equally. We present new observations and insightful analysis about MAE, which is theoretically proved to be noise-robust. First, we reveal its underfitting problem in practice. Second, we analyse that MAE's noise-robustness is from emphasising on uncertain examples instead of treating training samples equally, as claimed in prior work. (2) The Variance of Gradient Magnitude Matters. We propose an effective and simple solution to enhance MAE's fitting ability while preserving its noise-robustness. Without changing MAE's overall weighting scheme, i.e., what examples get higher weights, we simply change its weighting variance non-linearly so that the impact ratio between two examples are adjusted. Our solution is termed Improved MAE (IMAE). We prove IMAE's effectiveness using extensive experiments: image classification under clean labels, synthetic label noise, and real-world unknown noise., ICLR 2023, RTML Workshop paper. For the source code, based on the requests for academic research and kindness to cite our work, we will release and maintain it in https://github.com/XinshaoAmosWang/DeepCriticalLearning

Motivation Resistance co-occurrence within first-line anti-tuberculosis (TB) drugs is a common phenomenon. Existing methods based on genetic data analysis of Mycobacterium tuberculosis (MTB) have been able to predict resistance of MTB to individual drugs, but have not considered the resistance co-occurrence and cannot capture latent structure of genomic data that corresponds to lineages. Results We used a large cohort of TB patients from 16 countries across six continents where whole-genome sequences for each isolate and associated phenotype to anti-TB drugs were obtained using drug susceptibility testing recommended by the World Health Organization. We then proposed an end-to-end multi-task model with deep denoising auto-encoder (DeepAMR) for multiple drug classification and developed DeepAMR_cluster, a clustering variant based on DeepAMR, for learning clusters in latent space of the data. The results showed that DeepAMR outperformed baseline model and four machine learning models with mean AUROC from 94.4% to 98.7% for predicting resistance to four first-line drugs [i.e. isoniazid (INH), ethambutol (EMB), rifampicin (RIF), pyrazinamide (PZA)], multi-drug resistant TB (MDR-TB) and pan-susceptible TB (PANS-TB: MTB that is susceptible to all four first-line anti-TB drugs). In the case of INH, EMB, PZA and MDR-TB, DeepAMR achieved its best mean sensitivity of 94.3%, 91.5%, 87.3% and 96.3%, respectively. While in the case of RIF and PANS-TB, it generated 94.2% and 92.2% sensitivity, which were lower than baseline model by 0.7% and 1.9%, respectively. t-SNE visualization shows that DeepAMR_cluster captures lineage-related clusters in the latent space. Availability and implementation The details of source code are provided at http://www.robots.ox.ac.uk/∼davidc/code.php.

11 págs, 4 figuras y fórmulas matemáticas. Material suplementario en: http://dx.doi.org/10.1093/molbev/msaa069, The dN/dS ratio provides evidence of adaptation or functional constraint in protein-coding genes by quantifying the relative excess or deficit of amino acid-replacing versus silent nucleotide variation. Inexpensive sequencing promises a better understanding of parameters, such as dN/dS, but analyzing very large data sets poses a major statistical challenge. Here, I introduce genomegaMap for estimating within-species genome-wide variation in dN/dS, and I apply it to 3,979 genes across 10,209 tuberculosis genomes to characterize the selection pressures shaping this global pathogen. GenomegaMap is a phylogeny-free method that addresses two major problems with existing approaches: 1) It is fast no matter how large the sample size and 2) it is robust to recombination, which causes phylogenetic methods to report artefactual signals of adaptation. GenomegaMap uses population genetics theory to approximate the distribution of allele frequencies under general, parent-dependent mutation models. Coalescent simulations show that substitution parameters are well estimated even when genomegaMap's simplifying assumption of independence among sites is violated. I demonstrate the ability of genomegaMap to detect genuine signatures of selection at antimicrobial resistance-conferring substitutions in Mycobacterium tuberculosis and describe a novel signature of selection in the cold-shock DEAD-box protein A gene deaD/csdA. The genomegaMap approach helps accelerate the exploitation of big data for gaining new insights into evolution within species., D.J.W. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (grant no. 101237/Z/13/B) and is a Big Data Institute Robertson Fellow. The CRyPTIC Consortium was supported by grants from the Bill and Melinda Gates Foundation (OPP1133541) and a Wellcome Trust/Newton Fund-MRC Collaborative Award (200205/Z/15/Z). F.A.D. was supported by the Imperial Biomedical Research Centre

© 2018 The Author(s) Novelty detection is a particular example of pattern recognition identifying patterns that departure from some model of “normal behaviour”. The classification of point patterns is considered that are defined as sets of N observations of a multivariate random variable X and where the value N follows a discrete stochastic distribution. The use of point process models is introduced that allow us to describe the length N as well as the geometrical configuration in data space of such patterns. It is shown that such infinite dimensional study can be translated into a one-dimensional study that is analytically tractable for a multivariate Gaussian distribution. Moreover, for other multivariate distributions, an analytic approximation is obtained, by the use of extreme value theory, to model point patterns that occur in low-density regions as defined by X. The proposed models are demonstrated on synthetic and real-world data sets. ispartof: Computational Statistics & Data Analysis vol:125 pages:86-103 status: published

Gaussian process regression (GPR) provides a means to generate flexible personalised models of timeseries of patient vital signs. These models can perform useful clinical inference in ways that population-based models cannot. A challenge for the use of personalised models is that they must be amenable to a wide range of parameterisations, to accommodate the plausible physiology of any patient in the population. Additionally, optimal performance is typically achieved when models are regularised in light of knowledge of the physiology of the individual patient. In this paper, we describe a method to build GP models with varying complexity (via covariance kernels) and regularisation (via fixed priors over hyperparameters) on a patient-specific level, for the purpose of robust vitalsign forecasting. To this end, our results present evidence in support of two main hypotheses: (i) the use of patientspecific models can out-perform population-based models for useful clinical tasks, such as vital-sign forecasting; and (ii) the optimal values of (hyper)parameters of these models are best determined by sophisticated methods of optimisation, due to high correlation between dimensions of the search space. The resulting models are sufficiently robust to inform clinicians of a patient’s vital-sign trajectory, and warn of imminent deterioration.

Healthcare information, and to some extent patient management, is progressing toward a wireless digital future. This change is driven partly by a desire to improve the current state of medicine using new technologies, partly by supply-and-demand economics, and partly by the utility of wireless devices. Wired technology can be cumbersome for patient monitoring and can restrict the behavior of the monitored patients, introducing bias or artifacts. However, wireless technologies, while mitigating some of these issues, have introduced new problems such as data dropout and “information overload” for the clinical team. This review provides an overview of current wireless technology used for patient monitoring and disease management. We identify some of the major related issues and describe some existing and possible solutions. In particular, we discuss the rapidly evolving fields of telemedicine and mHealth in the context of increasingly resource-constrained healthcare systems.

The presence of respiratory information within the electrocardiogram (ECG) signal is a well-documented phenomenon. We present a Gaussian process framework for the estimation of respiratory rate from the different sources of modulation in a single-lead ECG. We propose a periodic covariance function to model the frequency- and amplitude-modulation time series derived from the ECG, where the hyperparameters of the process are used to derive the respiratory rate. The approach is evaluated using data taken from 40 healthy subjects each with 2 hours of monitoring, containing ECG and respiration waveforms. Results indicate that the accuracy of our proposed method is comparable with that of existing methods, but with the advantages of a principled probabilistic approach, including the direct quantification of the uncertainty in the estimation. © 2013 IEEE.

Assessment of physiological instability preceding adverse events on hospital wards has been previously investigated through clinical early warning score (EWS) systems. Such systems often rely on routinely collected vital-sign data, such as the National Early Warning Score system that is currently deployed across the United Kingdom. In this thesis, we propose improved and generalisable risk assessment algorithms, that can continuously alert for deterioration preceding the composite outcome of unplanned intensive care unit admission, cardiac arrest, and mortality. We develop and validate three statistical and machine learning models using large-scale datasets from two independent centres: Oxford University Hospitals and Portsmouth NHS Hospitals within the HAVEN database. The retrieved datasets include patient demographics, vital signs, laboratory tests, and data of the occurrence of any adverse events. The first model is the Age- and Sex- specific Early Warning Score (ASEWS), which was derived from statistical distributions of vital signs. The work suggests that accounting for age-related vital-sign changes can more accurately detect deterioration in younger patients (16-45 years old). We also propose the Deep Early Warning Score (DEWS), which consists of an end-to-end attention-based deep learning architecture that processes vital-sign time-series data. The vital-sign data is initially modelled using Gaussian Process Regression. The results suggest that deep learning improves the detection of clinical outcomes by recognising complex patterns in the data. The final model is the information Fusion in a multi-modal Early Warning System (iFEWS), which incorporates additional information about the patient, such as results of laboratory tests or the first diagnosis assigned at admission. In this framework, representation learning and continued learning within a multi-modal system improved the performance of detecting deterioration. All of our proposed models achieved a better performance than the state-of-the-art clinical EWS systems across two independent testing sets. Given their high performance, clinical utility, and illustrated interpretability, our models can be easily deployed in clinical settings to supplement existing EWS systems since they use the same data streams.