Rapid detection of health-care-associated bloodstream infection in critical care using multipathogen real-time polymerase chain reaction technology: a diagnostic accuracy study and systematic review

Background: There is growing interest in the potential utility of real-time polymerase chain reaction (PCR) in diagnosing bloodstream infection by detecting pathogen deoxyribonucleic acid (DNA) in blood samples within a few hours. SeptiFast (Roche Diagnostics GmBH, Mannheim, Germany) is a multipathogen probe-based system targeting ribosomal DNA sequences of bacteria and fungi. It detects and identifies the commonest pathogens causing bloodstream infection. As background to this study, we report a systematic review of Phase III diagnostic accuracy studies of SeptiFast, which reveals uncertainty about its likely clinical utility based on widespread evidence of deficiencies in study design and reporting with a high risk of bias. 

Objective: Determine the accuracy of SeptiFast real-time PCR for the detection of health-care-associated bloodstream infection, against standard microbiological culture. 

Design: Prospective multicentre Phase III clinical diagnostic accuracy study using the standards for the reporting of diagnostic accuracy studies criteria. 

Setting: Critical care departments within NHS hospitals in the north-west of England. 

Participants: Adult patients requiring blood culture (BC) when developing new signs of systemic inflammation. 

Main outcome measures: SeptiFast real-time PCR results at species/genus level compared with microbiological culture in association with independent adjudication of infection. Metrics of diagnostic accuracy were derived including sensitivity, specificity, likelihood ratios and predictive values, with their 95% confidence intervals (CIs). Latent class analysis was used to explore the diagnostic performance of culture as a reference standard. 

Results: Of 1006 new patient episodes of systemic inflammation in 853 patients, 922 (92%) met the inclusion criteria and provided sufficient information for analysis. Index test assay failure occurred on 69 (7%) occasions. Adult patients had been exposed to a median of 8 days (interquartile range 4–16 days) of hospital care, had high levels of organ support activities and recent antibiotic exposure. SeptiFast real-time PCR, when compared with culture-proven bloodstream infection at species/genus level, had better specificity (85.8%, 95% CI 83.3% to 88.1%) than sensitivity (50%, 95% CI 39.1% to 60.8%). When compared with pooled diagnostic metrics derived from our systematic review, our clinical study revealed lower test accuracy of SeptiFast real-time PCR, mainly as a result of low diagnostic sensitivity. There was a low prevalence of BC-proven pathogens in these patients (9.2%, 95% CI 7.4% to 11.2%) such that the post-test probabilities of both a positive (26.3%, 95% CI 19.8% to 33.7%) and a negative SeptiFast test (5.6%, 95% CI 4.1% to 7.4%) indicate the potential limitations of this technology in the diagnosis of bloodstream infection. However, latent class analysis indicates that BC has a low sensitivity, questioning its relevance as a reference test in this setting. Using this analysis approach, the sensitivity of the SeptiFast test was low but also appeared significantly better than BC. Blood samples identified as positive by either culture or SeptiFast real-time PCR were associated with a high probability (> 95%) of infection, indicating higher diagnostic rule-in utility than was apparent using conventional analyses of diagnostic accuracy. 

Conclusion: SeptiFast real-time PCR on blood samples may have rapid rule-in utility for the diagnosis of health-care-associated bloodstream infection but the lack of sensitivity is a significant limiting factor. Innovations aimed at improved diagnostic sensitivity of real-time PCR in this setting are urgently required. Future work recommendations include technology developments to improve the efficiency of pathogen DNA extraction and the capacity to detect a much broader range of pathogens and drug resistance genes and the application of new statistical approaches able to more reliably assess test performance in situation where the reference standard (e.g. blood culture in the setting of high antimicrobial use) is prone to error.

The Determinants of Brownfields Redevelopment in England

This paper uses discrete choice models, supported by GIS data, to analyse the National Land Use Database, a register of more than 21,000 English brownfields - previously used sites with or without contamination that are currently unused or underused. Using spatial discrete choice models, including the first application of a spatial probit latent class model with class-specific neighbourhood effects, we find evidence of large local differences in the determinants of brownfields redevelopment in England and that the reuse decisions of adjacent sites affect the reuse of a site. We also find that sites with a history of industrial activities, large sites, and sites that are located in the poorest and bleakest areas of cities and regions of England are more difficult to redevelop. In particular, we find that the probability of reusing a brownfield increases by up to 8.5% for a site privately owned compared to a site publicly owned and between 15% - 30% if a site is located in London compared to the North West of England. We suggest that local tailored policies are more suitable than regional or national policies to boost the reuse of brownfield sites.

Irish Credit Unions: Differential Regulation based on Business Model Complexity

This study examines the business model complexity of Irish credit unions using a latent class approach to measure structural performance over the period 2002 to 2013. The latent class approach allows the endogenous identification of a multi-class framework for business models based on credit union specific characteristics. The analysis finds a three class system to be appropriate with the multi-class model dependent on three financial viability characteristics. This finding is consistent with the deliberations of the Irish Commission on Credit Unions (2012) which identified complexity and diversity in the business models of Irish credit unions and recommended that such complexity and diversity could not be accommodated within a one size fits all regulatory framework. The analysis also highlights that two of the classes are subject to diseconomies of scale. This may suggest credit unions would benefit from a reduction in scale or perhaps that there is an imbalance in the present change process. Finally, relative performance differences are identified for each class in terms of technical efficiency. This suggests that there is an opportunity for credit unions to improve their performance by using within-class best practice or alternatively by switching to another class.

A latent feature analysis of the neural representation of conceptual knowledge

Bayesian probabilistic analysis offers a new approach to characterize semantic representations by inferring the most likely feature structure directly from the patterns of brain activity. In this study, infinite latent feature models [1] are used to recover the semantic features that give rise to the brain activation vectors when people think about properties associated with 60 concrete concepts. The semantic features recovered by ILFM are consistent with the human ratings of the shelter, manipulation, and eating factors that were recovered by a previous factor analysis. Furthermore, different areas of the brain encode different perceptual and conceptual features. This neurally-inspired semantic representation is consistent with some existing conjectures regarding the role of different brain areas in processing different semantic and perceptual properties. © 2012 Springer-Verlag.

The Inferential Complexity of Bayesian and Credal Networks

This paper presents new results on the complexity of graph-theoretical models that represent probabilities (Bayesian networks) and that represent interval and set valued probabilities (credal networks). We define a new class of networks with bounded width, and introduce a new decision problem for Bayesian networks, the maximin a posteriori. We present new links between the Bayesian and credal networks, and present new results both for Bayesian networks (most probable explanation with observations, maximin a posteriori) and for credal networks (bounds on probabilities a posteriori, most probable explanation with and without observations, maximum a posteriori).