Diagnostic accuracy and reproducibility of tendency oriented perimetry in glaucoma

PURPOSE. To evaluate the diagnostic capability of tendency oriented perimetry (TOP) in glaucoma. METHODS. A): The diagnostic accuracy of mean defect (MD), square-root of the loss variance (sLV), and number of pathologic points (NPP) was calculated in 295 normal and 414 glaucoma eyes (179 early, 112 moderate, and 123 advanced) examined with TOP. B): Threshold fluctuation (F) and its relationship with the loss variance (LV) was measured in 34 normal and 33 glaucoma eyes (mean MD=3 dB; SD=3.9) for TOP and for full-threshold perimetry (FT). C): Twenty-eight eyes with stable glaucoma (mean MD=9.5 dB; SD=7.2) were examined six times to quantify LV error. D): TOP and FT were tested with the simulation program PeriSim using different behavior models. RESULTS. A): The best diagnostic index in early glaucoma (MD

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.

Hui and Walter's latent-class model extended to estimate diagnostic test properties from surveillance data: a latent model for latent data

Diagnostic test sensitivity and specificity are probabilistic estimates with far reaching implications for disease control, management and genetic studies. In the absence of 'gold standard' tests, traditional Bayesian latent class models may be used to assess diagnostic test accuracies through the comparison of two or more tests performed on the same groups of individuals. The aim of this study was to extend such models to estimate diagnostic test parameters and true cohort-specific prevalence, using disease surveillance data. The traditional Hui-Walter latent class methodology was extended to allow for features seen in such data, including (i) unrecorded data (i.e. data for a second test available only on a subset of the sampled population) and (ii) cohort-specific sensitivities and specificities. The model was applied with and without the modelling of conditional dependence between tests. The utility of the extended model was demonstrated through application to bovine tuberculosis surveillance data from Northern and the Republic of Ireland. Simulation coupled with re-sampling techniques, demonstrated that the extended model has good predictive power to estimate the diagnostic parameters and true herd-level prevalence from surveillance data. Our methodology can aid in the interpretation of disease surveillance data, and the results can potentially refine disease control strategies.

Diagnostic performance on briefly presented digital pathology images

Background: Identifying new and more robust assessments of proficiency/expertise (finding new "biomarkers of expertise") in histopathology is desirable for many reasons. Advances in digital pathology permit new and innovative tests such as flash viewing tests and eye tracking and slide navigation analyses that would not be possible with a traditional microscope. The main purpose of this study was to examine the usefulness of time-restricted testing of expertise in histopathology using digital images.
Methods: 19 novices (undergraduate medical students), 18 intermediates (trainees), and 19 experts (consultants) were invited to give their opinion on 20 general histopathology cases after 1 s and 10 s viewing times. Differences in performance between groups were measured and the internal reliability of the test was calculated.
Results: There were highly significant differences in performance between the groups using the Fisher's least significant difference method for multiple comparisons. Differences between groups were consistently greater in the 10-s than the 1-s test. The Kuder-Richardson 20 internal reliability coefficients were very high for both tests: 0.905 for the 1-s test and 0.926 for the 10-s test. Consultants had levels of diagnostic accuracy of 72% at 1 s and 83% at 10 s.
Conclusions: Time-restricted tests using digital images have the potential to be extremely reliable tests of diagnostic proficiency in histopathology. A 10-s viewing test may be more reliable than a 1-s test. Over-reliance on "at a glance" diagnoses in histopathology is a potential source of medical error due to over-confidence bias and premature closure.

Variation in pre-PCR processing of FFPE samples leads to discrepancies in BRAF and EGFR mutation detection: a diagnostic RING trial.

AIMS: Mutation detection accuracy has been described extensively; however, it is surprising that pre-PCR processing of formalin-fixed paraffin-embedded (FFPE) samples has not been systematically assessed in clinical context. We designed a RING trial to (i) investigate pre-PCR variability, (ii) correlate pre-PCR variation with EGFR/BRAF mutation testing accuracy and (iii) investigate causes for observed variation. METHODS: 13 molecular pathology laboratories were recruited. 104 blinded FFPE curls including engineered FFPE curls, cell-negative FFPE curls and control FFPE tissue samples were distributed to participants for pre-PCR processing and mutation detection. Follow-up analysis was performed to assess sample purity, DNA integrity and DNA quantitation. RESULTS: Rate of mutation detection failure was 11.9%. Of these failures, 80% were attributed to pre-PCR error. Significant differences in DNA yields across all samples were seen using analysis of variance (p

Keeping a sense of proportion but losing all perspective: a critique of Gorard's notion of the 'Politician's Error'

In 1999 Stephen Gorard published an article in this journal in which he provided a trenchant critique of what he termed the `politician's error' in analysing differences in educational attainment. The main consequence of this error, he argued, has been the production of misleading findings in relation to trends in educational performance over time that have, in turn, led to misguided and potentially damaging policy interventions. By using gender differences in educational attainment as a case study, this article begins by showing how Gorard's notion of the politician's error has been largely embraced and adopted uncritically by those within the field. However, the article goes on to demonstrate how Gorard's own preferred way of analysing such differences – by calculating and comparing proportionate changes in performance between groups – is also inherently problematic and can lead to the production of equally misleading findings. The article will argue that there is a need to develop a more reliable and valid way of measuring trends in educational performance over time and will show that one of the simplest ways of doing this is to make use of existing, and widely accepted, measures of effect size.

Can diagnostic triage by general practitioners or rheumatology nurses improve the positive predictive value of referrals to early arthritis clinics?

Objectives: To determine whether diagnostic triage by general practitioners (GPs) or rheumatology nurses (RNs) can improve the positive predictive value of referrals to early arthritis clinics (EACs).

Methods: Four GPs and two RNs were trained in the assessment of early in?ammatory arthritis (IA) by four visits to an EAC supervised by hospital rheumatologists. Patients referred to one of three EACs were recruited for study and assessed independently by a GP, an RN and one of six rheumatologists. Each assessor was asked to record their clinical ?ndings and whether they considered the patient to have IA. Each was then asked to judge the appropriateness of the referral according to predetermined guidelines. The rheumatologists had been shown previously to have a satisfactory level of agreement in the assessment of IA.

Results: Ninety-six patients were approached and all consented to take part in the study. In 49 cases (51%), the rheumatologist judged that the patient had IA and that the referral was appropriate. The assessments of GPs and RNs were compared with those of the rheumatologists. Levels of agreement were measured using the kappa value, where 1.0 represents total unanimity. The kappa value was
0.77 for the GPs when compared with the rheumatologists and 0.79 for the RNs. Signi?cant stiffness in the morning or after rest and objective joint swelling were the most important clinical features enabling the GPs and RNs to discriminate between IA and non-IA conditions.

Conclusion: Diagnostic triage by GPs or RNs improved the positive predictive value of referrals to an EAC with a degree of accuracy approaching that of a group of experienced rheumatologists.

A novel diagnostic test detects a low frequency of the hemicentin Gln5345Arg variant among Northern Irish age related macular degeneration patients.

Purpose: Age related macular degeneration (AMD) is a common cause of severe vision loss. Identification of genes involved in AMD will facilitate early detection and ultimately help to identify pathways for treatment for this disorder. The A16,263G mutation in the HEMICENTIN-1 gene produces a non-conservative substitution of arginine for glutamine at codon 5345 which has been implicated in familial AMD. The aim of this study is to develop a rapid diagnostic assay for the detection of this mutation and to evaluate its frequency in a sample of AMD patients. Methods: A primer probe set was designed from exon 104 of the HEMICENTIN-1 gene to differentiate between mutant and wild type alleles. A region spanning the mutation was amplified by PCR using a LightCycler (Roche Diagnostic). The mutation was then detected by melt curve analysis of the hybrid formed between the PCR product and a specific fluorescent probe. The frequency of the mutation within the Northern Ireland population was evaluated by assaying 508 affected AMD patients, 25 possibly affected and 163 controls. Results: This assay clearly discriminates between the A16,263G mutant and wild type HEMICENTIN-1 alleles. The wild type sequence has a single base mismatch with the probe which decreases the stability of the hybrid, resulting in a lower TM (TM=51.27 °C) than that observed for the perfectly matched mutant allele (TM=59.9 °C). The mutant allele was detected in only one of the 696 subjects, an affected AMD patient. Conclusions: We describe a rapid assay for the genotyping of the Gln5345Arg mutation using real-time fluorescence PCR to facilitate rapid processing of samples through combined amplification and detection steps. These characteristics are suitable for a clinical setting where high throughput diagnostic procedures are required. The frequency of this mutation within the Northern Ireland population has been estimated at 0.2%, concurring with previous findings that this mutation is a rare variant associated with AMD. A rapid diagnostic assay will facilitate a reliable and convenient evaluation of the frequency of the Gln5345Arg mutation and its association with AMD within other populations.

Error sensitive historical GIS: Identifying areal interpolation errors in time series data

Historical GIS has the potential to re-invigorate our use of statistics from historical censuses and related sources. In particular, areal interpolation can be used to create long-run time-series of spatially detailed data that will enable us to enhance significantly our understanding of geographical change over periods of a century or more. The difficulty with areal interpolation, however, is that the data that it generates are estimates which will inevitably contain some error. This paper describes a technique that allows the automated identification of possible errors at the level of the individual data values.