RESUMO
OBJECTIVES: A rapid test to diagnose Clostridium difficile infection (CDI) on hospital wards could minimize common but critical diagnostic delay. Field asymmetric ion mobility spectrometry (FAIMS) is a portable mass spectrometry instrument that quickly analyses the chemical composition of gaseous mixtures (e.g., above a stool sample). Can FAIMS accurately distinguish C. difficile-positive from -negative stool samples? METHODS: We analyzed 213 stool samples with FAIMS, of which 71 were C. difficile positive by microbiological analysis. The samples were divided into training, test, and validation samples. We used the training and test samples (n=135) to identify which sample characteristics discriminate between positive and negative samples, and to build machine learning algorithms interpreting these characteristics. The best performing algorithm was then prospectively validated on new, blinded validation samples (n=78). The predicted probability of CDI (as calculated by the algorithm) was compared with the microbiological test results (direct toxin test and culture). RESULTS: Using a Random Forest classification algorithm, FAIMS had a high discriminatory ability on the training and test samples (C-statistic 0.91 (95% confidence interval (CI): 0.86-0.97)). When applied to the blinded validation samples, the C-statistic was 0.86 (0.75-0.97). For samples analyzed ≤7 days of collection (n=76), diagnostic accuracy was even higher (C-statistic: 0.93 (0.85-1.00)). A cutoff value of 0.32 for predicted probability corresponded with a sensitivity of 92.3% (95% CI: 77.4-98.6%) and specificity of 86.0% (78.3-89.3%). For even fresher samples, discriminatory ability further increased. CONCLUSIONS: FAIMS analysis of unprocessed stool samples can differentiate between C. difficile-positive and -negative samples with high diagnostic accuracy.
Assuntos
Algoritmos , Clostridioides difficile/isolamento & purificação , Enterocolite Pseudomembranosa/diagnóstico , Fezes/microbiologia , Análise Espectral/métodos , Infecções por Clostridium/diagnóstico , Enterocolite Pseudomembranosa/microbiologia , Fezes/química , Humanos , Sistemas Automatizados de Assistência Junto ao Leito , Estudos Prospectivos , Projetos de Pesquisa , Sensibilidade e Especificidade , Análise Espectral/instrumentaçãoRESUMO
BACKGROUND: Patient response to chemotherapy for ovarian cancer is extremely heterogeneous and there are currently no tools to aid the prediction of sensitivity or resistance to chemotherapy and allow treatment stratification. Such a tool could greatly improve patient survival by identifying the most appropriate treatment on a patient-specific basis. METHODS: PubMed was searched for studies predicting response or resistance to chemotherapy using gene expression measurements of human tissue in ovarian cancer. RESULTS: 42 studies were identified and both the data collection and modelling methods were compared. The majority of studies utilised fresh-frozen or formalin-fixed paraffin-embedded tissue. Modelling techniques varied, the most popular being Cox proportional hazards regression and hierarchical clustering which were used by 17 and 11 studies respectively. The gene signatures identified by the various studies were not consistent, with very few genes being identified by more than two studies. Patient cohorts were often noted to be heterogeneous with respect to chemotherapy treatment undergone by patients. CONCLUSIONS: A clinically applicable gene signature capable of predicting patient response to chemotherapy has not yet been identified. Research into a predictive, as opposed to prognostic, model could be highly beneficial and aid the identification of the most suitable treatment for patients.
Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Valor Preditivo dos TestesRESUMO
MOTIVATION: The integration of multiple datasets remains a key challenge in systems biology and genomic medicine. Modern high-throughput technologies generate a broad array of different data types, providing distinct-but often complementary-information. We present a Bayesian method for the unsupervised integrative modelling of multiple datasets, which we refer to as MDI (Multiple Dataset Integration). MDI can integrate information from a wide range of different datasets and data types simultaneously (including the ability to model time series data explicitly using Gaussian processes). Each dataset is modelled using a Dirichlet-multinomial allocation (DMA) mixture model, with dependencies between these models captured through parameters that describe the agreement among the datasets. RESULTS: Using a set of six artificially constructed time series datasets, we show that MDI is able to integrate a significant number of datasets simultaneously, and that it successfully captures the underlying structural similarity between the datasets. We also analyse a variety of real Saccharomyces cerevisiae datasets. In the two-dataset case, we show that MDI's performance is comparable with the present state-of-the-art. We then move beyond the capabilities of current approaches and integrate gene expression, chromatin immunoprecipitation-chip and protein-protein interaction data, to identify a set of protein complexes for which genes are co-regulated during the cell cycle. Comparisons to other unsupervised data integration techniques-as well as to non-integrative approaches-demonstrate that MDI is competitive, while also providing information that would be difficult or impossible to extract using other methods.
Assuntos
Genômica/métodos , Modelos Estatísticos , Teorema de Bayes , Imunoprecipitação da Cromatina , Análise por Conglomerados , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Distribuição Normal , Análise de Sequência com Séries de Oligonucleotídeos , Mapeamento de Interação de Proteínas , Saccharomyces cerevisiae/genética , Biologia de SistemasRESUMO
Different data types can offer complementary perspectives on the same biological phenomenon. In cancer studies, for example, data on copy number alterations indicate losses and amplifications of genomic regions in tumours, while transcriptomic data point to the impact of genomic and environmental events on the internal wiring of the cell. Fusing different data provides a more comprehensive model of the cancer cell than that offered by any single type. However, biological signals in different patients exhibit diverse degrees of concordance due to cancer heterogeneity and inherent noise in the measurements. This is a particularly important issue in cancer subtype discovery, where personalised strategies to guide therapy are of vital importance. We present a nonparametric Bayesian model for discovering prognostic cancer subtypes by integrating gene expression and copy number variation data. Our model is constructed from a hierarchy of Dirichlet Processes and addresses three key challenges in data fusion: (i) To separate concordant from discordant signals, (ii) to select informative features, (iii) to estimate the number of disease subtypes. Concordance of signals is assessed individually for each patient, giving us an additional level of insight into the underlying disease structure. We exemplify the power of our model in prostate cancer and breast cancer and show that it outperforms competing methods. In the prostate cancer data, we identify an entirely new subtype with extremely poor survival outcome and show how other analyses fail to detect it. In the breast cancer data, we find subtypes with superior prognostic value by using the concordant results. These discoveries were crucially dependent on our model's ability to distinguish concordant and discordant signals within each patient sample, and would otherwise have been missed. We therefore demonstrate the importance of taking a patient-specific approach, using highly-flexible nonparametric Bayesian methods.
Assuntos
Teorema de Bayes , Neoplasias da Mama/mortalidade , Modelos Biológicos , Modelos Estatísticos , Neoplasias da Próstata/mortalidade , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Variações do Número de Cópias de DNA/genética , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Masculino , Prognóstico , Neoplasias da Próstata/classificação , Neoplasias da Próstata/genética , Transdução de Sinais , Estatísticas não Paramétricas , Análise de SobrevidaRESUMO
OBJECTIVES: To develop and validate tests to assess the risk of any cancer for patients referred to the NHS Urgent Suspected Cancer (2-week wait, 2WW) clinical pathways. SETTING: Primary and secondary care, one participating regional centre. PARTICIPANTS: Retrospective analysis of data from 371 799 consecutive 2WW referrals in the Leeds region from 2011 to 2019. The development cohort was composed of 224 669 consecutive patients with an urgent suspected cancer referral in Leeds between January 2011 and December 2016. The diagnostic algorithms developed were then externally validated on a similar consecutive sample of 147 130 patients (between January 2017 and December 2019). All such patients over the age of 18 with a minimum set of blood counts and biochemistry measurements available were included in the cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: sensitivity, specificity, negative predictive value, positive predictive value, Receiver Operating Characteristic (ROC) curve Area Under Curve (AUC), calibration curves RESULTS: We present results for two clinical use-cases. In use-case 1, the algorithms identify 20% of patients who do not have cancer and may not need an urgent 2WW referral. In use-case 2, they identify 90% of cancer cases with a high probability of cancer that could be prioritised for review. CONCLUSIONS: Combining a panel of widely available blood markers produces effective blood tests for cancer for NHS 2WW patients. The tests are affordable, and can be deployed rapidly to any NHS pathology laboratory with no additional hardware requirements.
Assuntos
Aprendizado de Máquina , Neoplasias , Adulto , Algoritmos , Humanos , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Atenção Primária à Saúde , Encaminhamento e Consulta , Estudos RetrospectivosRESUMO
BACKGROUND: Post-genomic molecular biology has resulted in an explosion of data, providing measurements for large numbers of genes, proteins and metabolites. Time series experiments have become increasingly common, necessitating the development of novel analysis tools that capture the resulting data structure. Outlier measurements at one or more time points present a significant challenge, while potentially valuable replicate information is often ignored by existing techniques. RESULTS: We present a generative model-based Bayesian hierarchical clustering algorithm for microarray time series that employs Gaussian process regression to capture the structure of the data. By using a mixture model likelihood, our method permits a small proportion of the data to be modelled as outlier measurements, and adopts an empirical Bayes approach which uses replicate observations to inform a prior distribution of the noise variance. The method automatically learns the optimum number of clusters and can incorporate non-uniformly sampled time points. Using a wide variety of experimental data sets, we show that our algorithm consistently yields higher quality and more biologically meaningful clusters than current state-of-the-art methodologies. We highlight the importance of modelling outlier values by demonstrating that noisy genes can be grouped with other genes of similar biological function. We demonstrate the importance of including replicate information, which we find enables the discrimination of additional distinct expression profiles. CONCLUSIONS: By incorporating outlier measurements and replicate values, this clustering algorithm for time series microarray data provides a step towards a better treatment of the noise inherent in measurements from high-throughput genomic technologies. Timeseries BHC is available as part of the R package 'BHC' (version 1.5), which is available for download from Bioconductor (version 2.9 and above) via http://www.bioconductor.org/packages/release/bioc/html/BHC.html?pagewanted=all.
Assuntos
Teorema de Bayes , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Algoritmos , Análise por Conglomerados , Perfilação da Expressão Gênica , Humanos , Modelos Biológicos , Distribuição Normal , Saccharomyces cerevisiaeRESUMO
A major challenge in systems biology is the ability to model complex regulatory interactions, such as gene regulatory networks, and a number of computational approaches have been developed over recent years to address this challenge. This paper reviews a number of these approaches, with a focus on probabilistic graphical models and the integration of diverse data sets, such as gene expression and transcription factor binding site location and activity.
Assuntos
Imunoprecipitação da Cromatina/métodos , Expressão Gênica , Redes Reguladoras de Genes , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sequência de DNA/métodos , Biologia de Sistemas/métodosRESUMO
MOTIVATION: We present a method for directly inferring transcriptional modules (TMs) by integrating gene expression and transcription factor binding (ChIP-chip) data. Our model extends a hierarchical Dirichlet process mixture model to allow data fusion on a gene-by-gene basis. This encodes the intuition that co-expression and co-regulation are not necessarily equivalent and hence we do not expect all genes to group similarly in both datasets. In particular, it allows us to identify the subset of genes that share the same structure of transcriptional modules in both datasets. RESULTS: We find that by working on a gene-by-gene basis, our model is able to extract clusters with greater functional coherence than existing methods. By combining gene expression and transcription factor binding (ChIP-chip) data in this way, we are better able to determine the groups of genes that are most likely to represent underlying TMs. AVAILABILITY: If interested in the code for the work presented in this article, please contact the authors. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Assuntos
Perfilação da Expressão Gênica/métodos , Fatores de Transcrição/metabolismo , Teorema de Bayes , Sítios de Ligação , Família Multigênica , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
BACKGROUND: Although the use of clustering methods has rapidly become one of the standard computational approaches in the literature of microarray gene expression data analysis, little attention has been paid to uncertainty in the results obtained. RESULTS: We present an R/Bioconductor port of a fast novel algorithm for Bayesian agglomerative hierarchical clustering and demonstrate its use in clustering gene expression microarray data. The method performs bottom-up hierarchical clustering, using a Dirichlet Process (infinite mixture) to model uncertainty in the data and Bayesian model selection to decide at each step which clusters to merge. CONCLUSION: Biologically plausible results are presented from a well studied data set: expression profiles of A. thaliana subjected to a variety of biotic and abiotic stresses. Our method avoids several limitations of traditional methods, for example how many clusters there should be and how to choose a principled distance metric.
Assuntos
Perfilação da Expressão Gênica/métodos , Design de Software , Algoritmos , Arabidopsis/genética , Teorema de Bayes , Análise por Conglomerados , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de TempoRESUMO
resumen está disponible en el texto completo
ABSTRACT The CONSORT 2010 statement provides minimum guidelines for reporting randomized trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human-AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes.
RESUMO A declaração CONSORT 2010 apresenta diretrizes mínimas para relatórios de ensaios clínicos randomizados. Seu uso generalizado tem sido fundamental para garantir a transparência na avaliação de novas intervenções. Recentemente, tem-se reconhecido cada vez mais que intervenções que incluem inteligência artificial (IA) precisam ser submetidas a uma avaliação rigorosa e prospectiva para demonstrar seus impactos sobre os resultados de saúde. A extensão CONSORT-AI (Consolidated Standards of Reporting Trials - Artificial Intelligence) é uma nova diretriz para relatórios de ensaios clínicos que avaliam intervenções com um componente de IA. Ela foi desenvolvida em paralelo à sua declaração complementar para protocolos de ensaios clínicos, a SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials - Artificial Intelligence). Ambas as diretrizes foram desenvolvidas por meio de um processo de consenso em etapas que incluiu revisão da literatura e consultas a especialistas para gerar 29 itens candidatos. Foram feitas consultas sobre esses itens a um grupo internacional composto por 103 interessados diretos, que participaram de uma pesquisa Delphi em duas etapas. Chegou-se a um acordo sobre os itens em uma reunião de consenso que incluiu 31 interessados diretos, e os itens foram refinados por meio de uma lista de verificação piloto que envolveu 34 participantes. A extensão CONSORT-AI inclui 14 itens novos que, devido à sua importância para as intervenções de IA, devem ser informados rotineiramente juntamente com os itens básicos da CONSORT 2010. A CONSORT-AI preconiza que os pesquisadores descrevam claramente a intervenção de IA, incluindo instruções e as habilidades necessárias para seu uso, o contexto no qual a intervenção de IA está inserida, considerações sobre o manuseio dos dados de entrada e saída da intervenção de IA, a interação humano-IA e uma análise dos casos de erro. A CONSORT-AI ajudará a promover a transparência e a integralidade nos relatórios de ensaios clínicos com intervenções que utilizam IA. Seu uso ajudará editores e revisores, bem como leitores em geral, a entender, interpretar e avaliar criticamente a qualidade do desenho do ensaio clínico e o risco de viés nos resultados relatados.
RESUMO
resumen está disponible en el texto completo
ABSTRACT The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes. The SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trial protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 26 candidate items, which were consulted upon by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The SPIRIT-AI extension includes 15 new items that were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations for the handling of input and output data, the human-AI interaction and analysis of error cases. SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial.
RESUMO A declaração SPIRIT 2013 tem como objetivo melhorar a integralidade dos relatórios dos protocolos de ensaios clínicos, fornecendo recomendações baseadas em evidências para o conjunto mínimo de itens que devem ser abordados. Essas orientações têm sido fundamentais para promover uma avaliação transparente de novas intervenções. Recentemente, tem-se reconhecido cada vez mais que intervenções que incluem inteligência artificial (IA) precisam ser submetidas a uma avaliação rigorosa e prospectiva para demonstrar seus impactos sobre os resultados de saúde. A extensão SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials - Artificial Intelligence) é uma nova diretriz de relatório para protocolos de ensaios clínicos que avaliam intervenções com um componente de IA. Essa diretriz foi desenvolvida em paralelo à sua declaração complementar para relatórios de ensaios clínicos, CONSORT-AI (Consolidated Standards of Reporting Trials - Artificial Intelligence). Ambas as diretrizes foram desenvolvidas por meio de um processo de consenso em etapas que incluiu revisão da literatura e consultas a especialistas para gerar 26 itens candidatos. Foram feitas consultas sobre esses itens a um grupo internacional composto por 103 interessados diretos, que participaram de uma pesquisa Delphi em duas etapas. Chegou-se a um acordo sobre os itens em uma reunião de consenso que incluiu 31 interessados diretos, e os itens foram refinados por meio de uma lista de verificação piloto que envolveu 34 participantes. A extensão SPIRIT-AI inclui 15 itens novos que foram considerados suficientemente importantes para os protocolos de ensaios clínicos com intervenções que utilizam IA. Esses itens novos devem constar dos relatórios de rotina, juntamente com os itens básicos da SPIRIT 2013. A SPIRIT-AI preconiza que os pesquisadores descrevam claramente a intervenção de IA, incluindo instruções e as habilidades necessárias para seu uso, o contexto no qual a intervenção de IA será integrada, considerações sobre o manuseio dos dados de entrada e saída, a interação humano-IA e a análise de casos de erro. A SPIRIT-AI ajudará a promover a transparência e a integralidade nos protocolos de ensaios clínicos com intervenções que utilizam IA. Seu uso ajudará editores e revisores, bem como leitores em geral, a entender, interpretar e avaliar criticamente o delineamento e o risco de viés de um futuro estudo clínico.
RESUMO
MOTIVATION: The measurement of disease biomarkers in easily-obtained bodily fluids has opened the door to a new type of non-invasive medical diagnostics. New technologies are being developed and fine-tuned in order to make this possibility a reality. One such technology is Field Asymmetric Ion Mobility Spectrometry (FAIMS), which allows the measurement of volatile organic compounds (VOCs) in biological samples such as urine. These VOCs are known to contain a range of information on the relevant person's metabolism and can in principle be used for disease diagnostic purposes. Key to the effective use of such data are well-developed data processing pipelines, which are necessary to extract the most useful data from the complex underlying biological structure. RESULTS: In this study, we present a new data analysis pipeline for FAIMS data, and demonstrate a number of improvements over previously used methods. We evaluate the effect of a series of candidate operational steps during data processing, such as the use of wavelet transforms, principal component analysis (PCA), and classifier ensembles. We also demonstrate the use of FAIMS data in our pipeline to diagnose diabetes on the basis of a simple urine sample using machine learning classifiers. We present results for data generated from a case-control study of 115 urine samples, collected from 72 type II diabetic patients, with 43 healthy volunteers as negative controls. The resulting pipeline combines the steps that resulted in the best classification model performance. These include the use of a two-dimensional discrete wavelet transform, and the Wilcoxon rank-sum test for feature selection. We are able to achieve a best ROC curve AUC of 0.825 (0.747-0.9, 95% CI) for classification of diabetes vs control. We also note that this result is robust to changes in the data pipeline and different analysis runs, with AUC > 0.80 achieved in a range of cases. This is a substantial improvement in performance over previously used data processing methods in this area. Our ability to make strong statements about FAIMS ability to diagnose diabetes is sadly limited, as we found confounding effects from the demographics when including these data in the pipeline. The demographics alone produced a best AUC of 0.87 (0.795-0.94, 95% CI). While the combination of the demographics and FAIMS data resulted in an improvement on the AUC (0.907; 0.848-0.97, 95% CI), it did not prove to be a significant difference. Nevertheless, the pipeline itself shows a significant improvement in performance over more basic methods which have been used with FAIMS data in the past.
Assuntos
Diabetes Mellitus/urina , Diagnóstico por Computador/métodos , Compostos Orgânicos Voláteis/urina , Área Sob a Curva , Biomarcadores/urina , Feminino , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
resumen está disponible en el texto completo
ABSTRACT The SPIRIT 2013 statement aims to improve the completeness of clinical trial protocol reporting by providing evidence-based recommendations for the minimum set of items to be addressed. This guidance has been instrumental in promoting transparent evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate their impact on health outcomes. The SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials-Artificial Intelligence) extension is a new reporting guideline for clinical trial protocols evaluating interventions with an AI component. It was developed in parallel with its companion statement for trial reports: CONSORT-AI (Consolidated Standards of Reporting Trials-Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 26 candidate items, which were consulted upon by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The SPIRIT-AI extension includes 15 new items that were considered sufficiently important for clinical trial protocols of AI interventions. These new items should be routinely reported in addition to the core SPIRIT 2013 items. SPIRIT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention will be integrated, considerations for the handling of input and output data, the human-AI interaction and analysis of error cases. SPIRIT-AI will help promote transparency and completeness for clinical trial protocols for AI interventions. Its use will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the design and risk of bias for a planned clinical trial.
RESUMO A declaração SPIRIT 2013 tem como objetivo melhorar a integralidade dos relatórios dos protocolos de ensaios clínicos, fornecendo recomendações baseadas em evidências para o conjunto mínimo de itens que devem ser abordados. Essas orientações têm sido fundamentais para promover uma avaliação transparente de novas intervenções. Recentemente, tem-se reconhecido cada vez mais que intervenções que incluem inteligência artificial (IA) precisam ser submetidas a uma avaliação rigorosa e prospectiva para demonstrar seus impactos sobre os resultados de saúde. A extensão SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials - Artificial Intelligence) é uma nova diretriz de relatório para protocolos de ensaios clínicos que avaliam intervenções com um componente de IA. Essa diretriz foi desenvolvida em paralelo à sua declaração complementar para relatórios de ensaios clínicos, CONSORT-AI (Consolidated Standards of Reporting Trials - Artificial Intelligence). Ambas as diretrizes foram desenvolvidas por meio de um processo de consenso em etapas que incluiu revisão da literatura e consultas a especialistas para gerar 26 itens candidatos. Foram feitas consultas sobre esses itens a um grupo internacional composto por 103 interessados diretos, que participaram de uma pesquisa Delphi em duas etapas. Chegou-se a um acordo sobre os itens em uma reunião de consenso que incluiu 31 interessados diretos, e os itens foram refinados por meio de uma lista de verificação piloto que envolveu 34 participantes. A extensão SPIRIT-AI inclui 15 itens novos que foram considerados suficientemente importantes para os protocolos de ensaios clínicos com intervenções que utilizam IA. Esses itens novos devem constar dos relatórios de rotina, juntamente com os itens básicos da SPIRIT 2013. A SPIRIT-AI preconiza que os pesquisadores descrevam claramente a intervenção de IA, incluindo instruções e as habilidades necessárias para seu uso, o contexto no qual a intervenção de IA será integrada, considerações sobre o manuseio dos dados de entrada e saída, a interação humano-IA e a análise de casos de erro. A SPIRIT-AI ajudará a promover a transparência e a integralidade nos protocolos de ensaios clínicos com intervenções que utilizam IA. Seu uso ajudará editores e revisores, bem como leitores em geral, a entender, interpretar e avaliar criticamente o delineamento e o risco de viés de um futuro estudo clínico.
RESUMO
OBJECTIVES: New point of care diagnostics are urgently needed to reduce the over-prescription of antimicrobials for bacterial respiratory tract infection (RTI). We performed a pilot cross sectional study to assess the feasibility of gas-capillary column ion mobility spectrometer (GC-IMS), for the analysis of volatile organic compounds (VOC) in exhaled breath to diagnose bacterial RTI in hospital inpatients. METHODS: 71 patients were prospectively recruited from the Acute Medical Unit of the Royal Liverpool University Hospital between March and May 2016 and classified as confirmed or probable bacterial or viral RTI on the basis of microbiologic, biochemical and radiologic testing. Breath samples were collected at the patient's bedside directly into the electronic nose device, which recorded a VOC spectrum for each sample. Sparse principal component analysis and sparse logistic regression were used to develop a diagnostic model to classify VOC spectra as being caused by bacterial or non-bacterial RTI. RESULTS: Summary area under the receiver operator characteristic curve was 0.73 (95% CI 0.61-0.86), summary sensitivity and specificity were 62% (95% CI 41-80%) and 80% (95% CI 64-91%) respectively (p = 0.00147). CONCLUSIONS: GC-IMS analysis of exhaled VOC for the diagnosis of bacterial RTI shows promise in this pilot study and further trials are warranted to assess this technique.
Assuntos
Infecções Bacterianas/diagnóstico , Nariz Eletrônico , Metabolômica , Infecções Respiratórias/diagnóstico , Compostos Orgânicos Voláteis/análise , Idoso , Infecções Bacterianas/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Curva ROC , Infecções Respiratórias/microbiologiaRESUMO
BACKGROUND AND OBJECTIVES: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), remains challenging to diagnose. Diagnostic work-up carries a high burden, especially in paediatric patients, due to invasive endoscopic procedures. IBD is associated with alterations in intestinal microbiota composition. Faecal volatile organic compounds (VOCs) reflect gut microbiota composition. The aim of this study was to assess the diagnostic accuracy of faecal VOC profiling as a non-invasive diagnostic biomarker for paediatric IBD. METHODS: In this diagnostic accuracy study performed in two tertiary centres in the Netherlands, faecal VOC profiles of 36 de novo, treatment-naïve paediatric IBD patients (23 CD, 13 UC), and 24 healthy, matched controls were measured by field asymmetric ion mobility spectrometry (Owlstone Ltd, Lonestar®, UK). RESULTS: Faecal VOC profiles of de novo paediatric IBD patients could be differentiated from healthy controls (AUC ± 95% CI, p-value, sensitivity, specificity; 0.76 ± 0.14, p < 0.001, 79%, 78%). This discrimination from controls was observed in both CD (0.90 ± 0.10, p < 0.0001, 83%, 83%) and UC (0.74 ± 0.19, p = 0.02, 77%, 75%). VOC profiles from UC could not be discriminated from CD (0.67 ± 0.19, p = 0.0996, 65%, 62%). CONCLUSION: Field asymmetric ion mobility spectrometry allowed for discrimination between faecal VOC profiles of de novo paediatric IBD patients and healthy controls, confirming the potential of faecal VOC analysis as a non-invasive diagnostic biomarker for paediatric IBD. This method may serve as a complementary, non-invasive technique in the diagnosis of IBD, possibly limiting the number of endoscopies needed in children suspected for IBD.
Assuntos
Fezes/química , Doenças Inflamatórias Intestinais/diagnóstico , Espectrometria de Mobilidade Iônica/métodos , Compostos Orgânicos Voláteis/análise , Adolescente , Área Sob a Curva , Testes Respiratórios , Estudos de Casos e Controles , Criança , Pré-Escolar , Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Feminino , Humanos , Masculino , Países Baixos , Sensibilidade e EspecificidadeRESUMO
Predicting response to treatment and disease-specific deaths are key tasks in cancer research yet there is a lack of methodologies to achieve these. Large-scale 'omics and digital pathology technologies have led to the need for effective statistical methods for data fusion to extract the most useful patterns from these diverse data types. We present FusionGP, a method for combining heterogeneous data types designed specifically for predicting outcome of treatment and disease. FusionGP is a Gaussian process model that includes a generalization of feature selection for biomarker discovery, allowing for simultaneous, sparse feature selection across multiple data types. Importantly, it can accommodate highly nonlinear structure in the data, and automatically infers the optimal contribution from each input data type. FusionGP compares favourably to several popular classification methods, including the Random Forest classifier, a stepwise logistic regression model and the Support Vector Machine on single data types. By combining gene expression, copy number alteration and digital pathology image data in 119 estrogen receptor (ER)-negative and 345 ER-positive breast tumours, we aim to predict two important clinical outcomes: death and chemoinsensitivity. While gene expression data give the best predictive performance in the majority of cases, the digital pathology data are much better for predicting death in ER cases. Thus, FusionGP is a new tool for selecting informative features from heterogeneous data types and predicting treatment response and prognosis.
RESUMO
BACKGROUND: There is currently no blood-based test for detection of early-stage osteoarthritis (OA) and the anti-cyclic citrullinated peptide (CCP) antibody test for rheumatoid arthritis (RA) has relatively low sensitivity for early-stage disease. Morbidity in arthritis could be markedly decreased if early-stage arthritis could be routinely detected and classified by clinical chemistry test. We hypothesised that damage to proteins of the joint by oxidation, nitration and glycation, and with signatures released in plasma as oxidized, nitrated and glycated amino acids may facilitate early-stage diagnosis and typing of arthritis. METHODS: Patients with knee joint early-stage and advanced OA and RA or other inflammatory joint disease (non-RA) and healthy subjects with good skeletal health were recruited for the study (n = 225). Plasma/serum and synovial fluid was analysed for oxidized, nitrated and glycated proteins and amino acids by quantitative liquid chromatography-tandem mass spectrometry. Data-driven machine learning methods were employed to explore diagnostic utility of the measurements for detection and classifying early-stage OA and RA, non-RA and good skeletal health with training set and independent test set cohorts. RESULTS: Glycated, oxidized and nitrated proteins and amino acids were detected in synovial fluid and plasma of arthritic patients with characteristic patterns found in early and advanced OA and RA, and non-RA, with respect to healthy controls. In early-stage disease, two algorithms for consecutive use in diagnosis were developed: (1) disease versus healthy control, and (2) classification as OA, RA and non-RA. The algorithms featured 10 damaged amino acids in plasma, hydroxyproline and anti-CCP antibody status. Sensitivities/specificities were: (1) good skeletal health, 0.92/0.91; (2) early-stage OA, 0.92/0.90; early-stage RA, 0.80/0.78; and non-RA, 0.70/0.65 (training set). These were confirmed in independent test set validation. Damaged amino acids increased further in severe and advanced OA and RA. CONCLUSIONS: Oxidized, nitrated and glycated amino acids combined with hydroxyproline and anti-CCP antibody status provided a plasma-based biochemical test of relatively high sensitivity and specificity for early-stage diagnosis and typing of arthritic disease.
Assuntos
Biomarcadores/sangue , Diagnóstico Precoce , Osteoartrite do Joelho/diagnóstico , Processamento de Proteína Pós-Traducional , Adulto , Idoso , Algoritmos , Aminoácidos/metabolismo , Área Sob a Curva , Cromatografia Líquida , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitrosação , Osteoartrite do Joelho/sangue , Oxirredução , Estresse Oxidativo , Curva ROC , Sensibilidade e Especificidade , Espectrometria de Massas em TandemRESUMO
INTRODUCTION: Early inflammatory bowel disease (IBD) diagnosis remains a clinical challenge. Volatile organic compounds (VOCs) have shown distinct patterns in Crohn's disease (CD) and ulcerative colitis (UC). VOC production, reflecting gut fermentome metabolites, is perturbed in IBD. VOC sampling is non-invasive, with various compounds identified from faecal, breath and urine samples. This study aimed to determine if FAIMS (field asymmetric ion mobility spectroscopy) analysis of exhaled VOCs could distinguish IBD from controls. METHODS: Seventy-six subjects were recruited, 54 established IBD (25 CD, 29 UC) and 22 healthy controls. End expiratory breath was captured using a Warwick device and analysed by FAIMS. Data were pre-processed using wavelet transformation, and classification performed in a 10-fold cross-validation. Feature selection was performed using Wilcoxon rank sum test, and sparse logistic regression gave class predictions, to calculate sensitivity and specificity. RESULTS: FAIMS breath VOC analysis showed clear separation of IBD from controls, sensitivity: 0.74 (0.65-0.82), specificity: 0.75 (0.53-0.90), AUROC: 0.82 (0.74-0.89), p-value 6.2×10(-7). IBD subgroup analysis distinguished UC from CD: sensitivity of 0.67 (0.54-0.79), specificity: 0.67 (0.54-0.79), AUROC: 0.70 (0.60-0.80), p-value 9.23×10(-4). CONCLUSION: This confirms the utility of exhaled VOC analysis to distinguish IBD from healthy controls, and UC from CD. It conforms to other studies using different technology, whilst affirming exhaled VOCs as biomarkers for diagnosing IBD.
Assuntos
Colite Ulcerativa/diagnóstico , Doença de Crohn/diagnóstico , Fermentação , Microbioma Gastrointestinal , Compostos Orgânicos Voláteis/análise , Adulto , Biomarcadores , Testes Respiratórios , Estudos de Casos e Controles , Feminino , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Análise EspectralRESUMO
Tuberculosis (TB) remains one of the world's major health burdens with 9.6 million new infections globally. Though considerable progress has been made in reduction of TB incidence and mortality, there is a continuous need for lower cost, simpler and more robust means of diagnosis. One method that may fulfil these requirements is in the area of breath analysis. In this study we analysed the breath of 21 patients with pulmonary or extra-pulmonary TB, recruited from a UK teaching hospital (University Hospital Coventry and Warwickshire) before or within 1 week of commencing treatment for TB. TB diagnosis was confirmed by reference tests (mycobacterial culture), histology or radiology. 19 controls were recruited to calculate specificity; these patients were all interferon-gamma release assay negative (T.SPOT(®).TB, Oxford Immunotec Ltd.). Whole breath samples were collected with subsequent chemical analysis undertaken by Ion Mobility Spectrometry. Our results produced a sensitivity of 81% and a specificity of 79% for all cases of TB (pulmonary and extra-pulmonary). Though lower than other studies analysing pulmonary TB alone, we believe that this technique shows promise, and a higher sensitivity could be achieved by further improving our sample capture methodology.
Assuntos
Testes Respiratórios/métodos , Íons , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antituberculosos/uso terapêutico , Área Sob a Curva , Técnicas Bacteriológicas , Testes Respiratórios/instrumentação , Estudos de Casos e Controles , Inglaterra , Desenho de Equipamento , Feminino , Hospitais de Ensino , Humanos , Testes de Liberação de Interferon-gama , Masculino , Pessoa de Meia-Idade , Movimento (Física) , Mycobacterium tuberculosis/efeitos dos fármacos , Projetos Piloto , Valor Preditivo dos Testes , Curva ROC , Reprodutibilidade dos Testes , Análise Espectral , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Adulto JovemRESUMO
BACKGROUND: Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA. METHODS: DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free). RESULTS: Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity). CONCLUSION: This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.