Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19), which at the time of writing (January 2021) was responsible for more than ...2.25 million deaths worldwide and over 100,000 deaths in the UK. SARS-CoV-2 appears to be highly transmissible and could rapidly spread in residential care homes.
The work undertaken aimed to estimate the clinical effectiveness and cost-effectiveness of viral detection point-of-care tests for detecting SARS-CoV-2 compared with laboratory-based tests in the setting of a hypothetical care home facility for elderly residents.
The perspective was that of the NHS in 2020. The setting was a hypothetical care home facility for elderly residents. Care homes with en suite rooms and with shared facilities were modelled separately.
A discrete event simulation model was constructed to model individual residents and simulate the spread of SARS-CoV-2 once it had entered the residential care facility. The numbers of COVID-19-related deaths and critical cases were recorded in addition to the number of days spent in isolation. Thirteen strategies involving different hypothetical SARS-CoV-2 tests were modelled. Recently published desirable and acceptable target product profiles for SARS-CoV-2 point-of-care tests and for hospital-based SARS-CoV-2 tests were modelled. Scenario analyses modelled early release from isolation based on receipt of a negative SARS-CoV-2 test result and the impact of vaccination. Incremental analyses were undertaken using both incremental cost-effectiveness ratios and net monetary benefits.
Cost-effectiveness results depended on the proportion of residential care facilities penetrated by SARS-CoV-2. SARS-CoV-2 point-of-care tests with desirable target product profiles appear to have high net monetary benefit values. In contrast, SARS-CoV-2 point-of-care tests with acceptable target product profiles had low net monetary benefit values because of unnecessary isolations. The benefit of allowing early release from isolation depended on whether or not the facility had en suite rooms. The greater the assumed efficacy of vaccination, the lower the net monetary benefit values associated with SARS-CoV-2 point-of-care tests, when assuming that a vaccine lowers the risk of contracting SARS-CoV-2.
There is considerable uncertainty in the values for key parameters within the model, although calibration was undertaken in an attempt to mitigate this. Some degree of Monte Carlo sampling error persists because of the timelines of the project. The example care home simulated will also not match those of decision-makers deciding on the clinical effectiveness and cost-effectiveness of introducing SARS-CoV-2 point-of-care tests. Given these limitations, the results should be taken as indicative rather than definitive, particularly the cost-effectiveness results when the relative cost per SARS-CoV-2 point-of-care test is uncertain.
SARS-CoV-2 point-of-care tests have considerable potential for benefit for use in residential care facilities, but whether or not this materialises depends on the diagnostic accuracy and costs of forthcoming SARS-CoV-2 point-of-care tests.
More accurate results would be obtained when there is more certainty on the diagnostic accuracy of and the reduction in time to test result associated with SARS-CoV-2 point-of-care tests when used in the context of residential care facilities, the proportion of care home penetrated by SARS-CoV-2 and the levels of immunity once vaccination is administered. These parameters are currently uncertain.
This report was commissioned by the National Institute for Health Research (NIHR) Evidence Synthesis programme as project number 132154. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in
; Vol. 25, No. 39. See the NIHR Journals Library website for further project information.
The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression ...or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types.
The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded.
The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods).
We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.
Novel diagnostic triage and testing strategies to support early detection of cancer could improve clinical outcomes. Most apparently promising diagnostic tests ultimately fail because of inadequate ...performance in real-world, low prevalence populations such as primary care or general community populations. They should therefore be systematically evaluated before implementation to determine whether they lead to earlier detection, are cost-effective, and improve patient safety and quality of care, while minimising over-investigation and over-diagnosis.
We performed a systematic scoping review of frameworks for the evaluation of tests and diagnostic approaches.
We identified 16 frameworks: none addressed the entire continuum from test development to impact on diagnosis and patient outcomes in the intended population, nor the way in which tests may be used for triage purposes as part of a wider diagnostic strategy. Informed by these findings, we developed a new framework, the 'CanTest Framework', which proposes five iterative research phases forming a clear translational pathway from new test development to health system implementation and evaluation.
This framework is suitable for testing in low prevalence populations, where tests are often applied for triage testing and incorporated into a wider diagnostic strategy. It has relevance for a wide range of stakeholders including patients, policymakers, purchasers, healthcare providers and industry.
The aim of this study was to identify and validate novel predictive and/or prognostic serum proteomic biomarkers in patients with epithelial ovarian cancer (EOC) treated as part of the phase III ...international ICON7 clinical trial.
ICON7 was a phase III international trial in EOC which showed a modest but statistically significant benefit in progression-free survival (PFS) with the addition of bevacizumab to standard chemotherapy. Serum samples from 10 patients who received bevacizumab (five responders and five nonresponders) were analyzed by mass spectrometry to identify candidate biomarkers. Initial validation and exploration by immunoassay was undertaken in an independent cohort of 92 patients, followed by a second independent cohort of 115 patients (taken from across both arms of the trial).
Three candidate biomarkers were identified: mesothelin, fms-like tyrosine kinase-4 (FLT4), and α1-acid glycoprotein (AGP). Each showed evidence of independent prognostic potential when adjusting for high-risk status in initial (P < 0.02) and combined (P < 0.01) validation cohorts. In cohort I, individual biomarkers were not predictive of bevacizumab benefit; however, when combined with CA-125, a signature was developed that was predictive of bevacizumab response and discriminated benefit attributable to bevacizumab better than clinical characteristics. The signature showed weaker evidence of predictive ability in validation cohort II, but was still strongly predictive considering all samples (P = 0.001), with an improvement in median PFS of 5.5 months in signature-positive patients in the experimental arm compared with standard arm.
This study shows a discriminatory signature comprising mesothelin, FLT4, AGP, and CA-125 as potentially identifying those patients with EOC more likely to benefit from bevacizumab. These results require validation in further patient cohorts.
A Target Product Profile (TPP) outlines the necessary characteristics of an innovative product to address an unmet clinical need. TPPs could be used to better guide manufacturers in the development ...of 'fit for purpose' tests, thus increasing the likelihood that novel tests will progress from bench to bedside. However, there is currently no guidance on how to produce a TPP specifically for medical tests.
A systematic review was conducted to summarise the methods currently used to develop TPPs for medical tests, the sources used to inform these recommendations and the test characteristics for which targets are made. Database and website searches were conducted in November 2018. TPPs written in English for any medical test were included. Based on an existing framework, test characteristics were clustered into commonly recognised themes.
Forty-four TPPs were identified, all of which focused on diagnostic tests for infectious diseases. Three core decision-making phases for developing TPPs were identified: scoping, drafting and consensus-building. Consultations with experts and the literature mostly informed the scoping and drafting of TPPs. All TPPs provided information on unmet clinical need and desirable analytical performance, and the majority specified clinical validity characteristics. Few TPPs described specifications for clinical utility, and none included cost-effectiveness.
We have identified a commonly used framework that could be beneficial for anyone interested in drafting a TPP for a medical test. Currently, key outcomes such as utility and cost-effectiveness are largely overlooked within TPPs though and we foresee this as an area for further improvement.
Acute kidney injury (AKI) is highly prevalent in hospital inpatient populations, leading to significant mortality and morbidity, reduced quality of life and high short- and long-term health-care ...costs for the NHS. New diagnostic tests may offer an earlier diagnosis or improved care, but evidence of benefit to patients and of value to the NHS is required before national adoption.
To evaluate the potential for AKI in vitro diagnostic tests to enhance the NHS care of patients admitted to the intensive care unit (ICU) and identify an efficient supporting research strategy.
We searched ClinicalTrials.gov, The Cochrane Library databases, Embase, Health Management Information Consortium, International Clinical Trials Registry Platform, MEDLINE,
Register of Current Controlled Trials, PubMed and Web of Science databases from their inception dates until September 2014 (review 1), November 2015 (review 2) and July 2015 (economic model). Details of databases used for each review and coverage dates are listed in the main report.
The AKI-Diagnostics project included horizon scanning, systematic reviewing, meta-analysis of sensitivity and specificity, appraisal of analytical validity, care pathway analysis, model-based lifetime economic evaluation from a UK NHS perspective and value of information (VOI) analysis.
The horizon-scanning search identified 152 potential tests and biomarkers. Three tests, Nephrocheck
(Astute Medical, Inc., San Diego, CA, USA), NGAL and cystatin C, were subjected to detailed review. The meta-analysis was limited by variable reporting standards, study quality and heterogeneity, but sensitivity was between 0.54 and 0.92 and specificity was between 0.49 and 0.95 depending on the test. A bespoke critical appraisal framework demonstrated that analytical validity was also poorly reported in many instances. In the economic model the incremental cost-effectiveness ratios ranged from £11,476 to £19,324 per quality-adjusted life-year (QALY), with a probability of cost-effectiveness between 48% and 54% when tests were compared with current standard care.
The major limitation in the evidence on tests was the heterogeneity between studies in the definitions of AKI and the timing of testing.
Diagnostic tests for AKI in the ICU offer the potential to improve patient care and add value to the NHS, but cost-effectiveness remains highly uncertain. Further research should focus on the mechanisms by which a new test might change current care processes in the ICU and the subsequent cost and QALY implications. The VOI analysis suggested that further observational research to better define the prevalence of AKI developing in the ICU would be worthwhile. A formal randomised controlled trial of biomarker use linked to a standardised AKI care pathway is necessary to provide definitive evidence on whether or not adoption of tests by the NHS would be of value.
The systematic review within this study is registered as PROSPERO CRD42014013919.
The National Institute for Health Research Health Technology Assessment programme.
Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, ...before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67–0.85) for ACY-1, 0.9 (0.84–0.95) for cystatin C, and 0.93 (0.88–0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor–brain–dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation.
Summary
Although successful and persistent colonization of the gastric mucosa depends on the ability to respond to changing environmental conditions and co‐ordinate the expression of virulence ...factors during the course of infection, Helicobacter pylori possesses relatively few transcriptional regulators. We therefore investigated the contribution of the regulatory protein CsrA to global gene regulation in this important human pathogen. CsrA was necessary for full motility and survival of H. pylori under conditions of oxidative stress. Loss of csrA expression deregulated the oxidant‐induced transcriptional responses of napA and ahpC, the acid induction of napA, cagA, vacA, the urease operon, and fur, as well as the heat shock responses of napA, groESL and hspR. Although the level of napA transcript was higher in the csrA mutant, its stability was similar in the wild‐type and mutant strains, and less NapA protein was produced in the mutant strain. Finally, H. pylori strains deficient in the production of CsrA were significantly attenuated for virulence in a mouse model of infection. This work provides evidence that CsrA has a broad role in regulating the physiology of H. pylori in response to environmental stimuli, and may be important in facilitating adaptation to the different environments encountered during colonization of the gastric mucosa. Furthermore, CsrA appears to mediate its effects in H. pylori at the post‐transcriptional level by influencing the processing and translation of target transcripts, with minimal effect on the stability of the target mRNAs.
Lack of reproducibility is an ongoing problem in some areas of the biomedical sciences. Poor experimental design and a failure to engage with experienced statisticians at key stages in the design and ...analysis of experiments are two factors that contribute to this problem. The RIPOSTE (Reducing IrreProducibility in labOratory STudiEs) framework has been developed to support early and regular discussions between scientists and statisticians in order to improve the design, conduct and analysis of laboratory studies and, therefore, to reduce irreproducibility. This framework is intended for use during the early stages of a research project, when specific questions or hypotheses are proposed. The essential points within the framework are explained and illustrated using three examples (a medical equipment test, a macrophage study and a gene expression study). Sound study design minimises the possibility of bias being introduced into experiments and leads to higher quality research with more reproducible results.
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