Objective
To evaluate the test accuracy of non‐invasive prenatal testing (NIPT) for fetal trisomy 21, 18, and 13 using cell‐free (cf) DNA analysis in maternal plasma with microarray quantitation.
...Method
Systematic review and meta‐analysis. Searches in MEDLINE, Pre‐MEDLINE, EMBASE, Web of Science, and the Cochrane Library to 09.07.2018.
Results
Five studies analyzing 3074 samples, including 187 trisomy 21, 43 trisomy 18, and 19 trisomy 13 cases, were identified. Risk of bias was high in all studies, introduced particularly by exclusions from analysis and by the role of the sponsor. Sensitivity of microarray‐based cfDNA testing was 99.5% (95%CI 96.3%‐99.9%) for trisomy 21, 97.7% (95%CI 87.9%‐99.6%) for trisomy 18, and 100% (95%CI 83.2%‐100%) for trisomy 13. Specificity was 100% (95% CI 99.87%‐100%) for trisomy 21, 99.97% (95%CI 99.81%‐99.99%) for trisomy 18, and 99.97% (95%CI 99.81%‐99.99%) for trisomy 13. Pooled test failure rate was 1.1%. A direct comparison of microarray‐ and sequencing‐based cfDNA found equivalent test accuracy.
Conclusion
Included studies suggest that NIPT using microarray‐based cfDNA testing has high sensitivity and specificity for detecting fetal trisomy 21, 18, and 13. However, the evidence base is small and at high risk of bias.
In this article, we explore the evidence around the relative benefits and harms of breast cancer screening using a single radiologist to examine each female's mammograms for signs of cancer (single ...reading), or two radiologists (double reading). First, we briefly explore the historical evidence using film-screen mammography, before providing an in-depth description of evidence using digital mammography. We classify studies according to which exact version of double reading they use, because the evidence suggests that effectiveness of double reading is contingent on whether the two radiologists are blinded to one another's decisions, and how the decisions of the two radiologists are integrated. Finally, we explore the implications for future mammography, including using artificial intelligence as the second reader, and applications to more complex three-dimensional imaging techniques such as tomosynthesis.
Background: Rapid reviews are increasingly used to replace/complement systematic reviews to support evidence-based decision-making. Little is known about how this expedited process affects results. ...Objectives: To assess differences between rapid and systematic review approaches for a case study of test accuracy of succinylacetone for detecting tyrosinemia type 1. Methods: Two reviewers conducted an "enhanced" rapid review then a systematic review. The enhanced rapid review involved narrower searches, a single reviewer checking 20% of titles/abstracts and data extraction, and quality assessment using an unadjusted QUADAS-2. Two reviewers performed the systematic review with a tailored QUADAS-2. Post hoc analysis examined rapid reviewing with a single reviewer (basic rapid review). Results: Ten papers were included. Basic rapid reviews would have missed 1 or 4 of these (dependent on which reviewer). Enhanced rapid and systematic reviews identified all 10 papers; one paper was only identified in the rapid review through reference checking. Two thousand one hundred seventy-six fewer title/abstracts and 129 fewer full texts were screened during the enhanced rapid review than the systematic review. The unadjusted QUADAS-2 generated more "unclear" ratings than the adjusted QUADAS-2 29/70 (41.4%) versus 16/70 (22.9%), and fewer "high" ratings 22/70 (31.4%) versus 42/70 (60.0%). Basic rapid reviews contained important inaccuracies in data extraction, which were detected by a second reviewer in the enhanced rapid and systematic reviews. Conclusions: Enhanced rapid reviews with 20% checking by a second reviewer may be an appropriate tool for policymakers to expeditiously assess evidence. Basic rapid reviews (single reviewer) have higher risks of important inaccuracies and omissions.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting COVID-19 pandemic present important diagnostic challenges. Several diagnostic strategies are available to identify or ...rule out current infection, identify people in need of care escalation, or to test for past infection and immune response. Point-of-care antigen and molecular tests to detect current SARS-CoV-2 infection have the potential to allow earlier detection and isolation of confirmed cases compared to laboratory-based diagnostic methods, with the aim of reducing household and community transmission.
To assess the diagnostic accuracy of point-of-care antigen and molecular-based tests to determine if a person presenting in the community or in primary or secondary care has current SARS-CoV-2 infection.
On 25 May 2020 we undertook electronic searches in the Cochrane COVID-19 Study Register and the COVID-19 Living Evidence Database from the University of Bern, which is updated daily with published articles from PubMed and Embase and with preprints from medRxiv and bioRxiv. In addition, we checked repositories of COVID-19 publications. We did not apply any language restrictions.
We included studies of people with suspected current SARS-CoV-2 infection, known to have, or not to have SARS-CoV-2 infection, or where tests were used to screen for infection. We included test accuracy studies of any design that evaluated antigen or molecular tests suitable for a point-of-care setting (minimal equipment, sample preparation, and biosafety requirements, with results available within two hours of sample collection). We included all reference standards to define the presence or absence of SARS-CoV-2 (including reverse transcription polymerase chain reaction (RT-PCR) tests and established clinical diagnostic criteria).
Two review authors independently screened studies and resolved any disagreements by discussion with a third review author. One review author independently extracted study characteristics, which were checked by a second review author. Two review authors independently extracted 2x2 contingency table data and assessed risk of bias and applicability of the studies using the QUADAS-2 tool. We present sensitivity and specificity, with 95% confidence intervals (CIs), for each test using paired forest plots. We pooled data using the bivariate hierarchical model separately for antigen and molecular-based tests, with simplifications when few studies were available. We tabulated available data by test manufacturer.
We included 22 publications reporting on a total of 18 study cohorts with 3198 unique samples, of which 1775 had confirmed SARS-CoV-2 infection. Ten studies took place in North America, two in South America, four in Europe, one in China and one was conducted internationally. We identified data for eight commercial tests (four antigen and four molecular) and one in-house antigen test. Five of the studies included were only available as preprints. We did not find any studies at low risk of bias for all quality domains and had concerns about applicability of results across all studies. We judged patient selection to be at high risk of bias in 50% of the studies because of deliberate over-sampling of samples with confirmed COVID-19 infection and unclear in seven out of 18 studies because of poor reporting. Sixteen (89%) studies used only a single, negative RT-PCR to confirm the absence of COVID-19 infection, risking missing infection. There was a lack of information on blinding of index test (n = 11), and around participant exclusions from analyses (n = 10). We did not observe differences in methodological quality between antigen and molecular test evaluations. Antigen tests Sensitivity varied considerably across studies (from 0% to 94%): the average sensitivity was 56.2% (95% CI 29.5 to 79.8%) and average specificity was 99.5% (95% CI 98.1% to 99.9%; based on 8 evaluations in 5 studies on 943 samples). Data for individual antigen tests were limited with no more than two studies for any test. Rapid molecular assays Sensitivity showed less variation compared to antigen tests (from 68% to 100%), average sensitivity was 95.2% (95% CI 86.7% to 98.3%) and specificity 98.9% (95% CI 97.3% to 99.5%) based on 13 evaluations in 11 studies of on 2255 samples. Predicted values based on a hypothetical cohort of 1000 people with suspected COVID-19 infection (with a prevalence of 10%) result in 105 positive test results including 10 false positives (positive predictive value 90%), and 895 negative results including 5 false negatives (negative predictive value 99%). Individual tests We calculated pooled results of individual tests for ID NOW (Abbott Laboratories) (5 evaluations) and Xpert Xpress (Cepheid Inc) (6 evaluations). Summary sensitivity for the Xpert Xpress assay (99.4%, 95% CI 98.0% to 99.8%) was 22.6 (95% CI 18.8 to 26.3) percentage points higher than that of ID NOW (76.8%, (95% CI 72.9% to 80.3%), whilst the specificity of Xpert Xpress (96.8%, 95% CI 90.6% to 99.0%) was marginally lower than ID NOW (99.6%, 95% CI 98.4% to 99.9%; a difference of -2.8% (95% CI -6.4 to 0.8)) AUTHORS' CONCLUSIONS: This review identifies early-stage evaluations of point-of-care tests for detecting SARS-CoV-2 infection, largely based on remnant laboratory samples. The findings currently have limited applicability, as we are uncertain whether tests will perform in the same way in clinical practice, and according to symptoms of COVID-19, duration of symptoms, or in asymptomatic people. Rapid tests have the potential to be used to inform triage of RT-PCR use, allowing earlier detection of those testing positive, but the evidence currently is not strong enough to determine how useful they are in clinical practice. Prospective and comparative evaluations of rapid tests for COVID-19 infection in clinically relevant settings are urgently needed. Studies should recruit consecutive series of eligible participants, including both those presenting for testing due to symptoms and asymptomatic people who may have come into contact with confirmed cases. Studies should clearly describe symptomatic status and document time from symptom onset or time since exposure. Point-of-care tests must be conducted on samples according to manufacturer instructions for use and be conducted at the point of care. Any future research study report should conform to the Standards for Reporting of Diagnostic Accuracy (STARD) guideline.
There may be a risk of COVID-19 transmission to rescuers delivering treatment for cardiac arrest. The aim of this review was to identify the potential risk of transmission associated with key ...interventions (chest compressions, defibrillation, cardiopulmonary resuscitation) to inform international treatment recommendations.
We undertook a systematic review comprising three questions: (1) aerosol generation associated with key interventions; (2) risk of airborne infection transmission associated with key interventions; and (3) the effect of different personal protective equipment strategies. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and the World Health Organization COVID-19 database on 24th March 2020. Eligibility criteria were developed individually for each question. We assessed risk of bias for individual studies, and used the GRADE process to assess evidence certainty by outcome.
We included eleven studies: two cohort studies, one case control study, five case reports, and three manikin randomised controlled trials. We did not find any direct evidence that chest compressions or defibrillation either are or are not associated with aerosol generation or transmission of infection. Data from manikin studies indicates that donning of personal protective equipment delays treatment delivery. Studies provided only indirect evidence, with no study describing patients with COVID-19. Evidence certainty was low or very low for all outcomes.
It is uncertain whether chest compressions or defibrillation cause aerosol generation or transmission of COVID-19 to rescuers. There is very limited evidence and a rapid need for further studies.
Review registration: PROSPERO CRD42020175594.
Accurate rapid diagnostic tests for SARS-CoV-2 infection would be a useful tool to help manage the COVID-19 pandemic. Testing strategies that use rapid antigen tests to detect current infection have ...the potential to increase access to testing, speed detection of infection, and inform clinical and public health management decisions to reduce transmission. This is the second update of this review, which was first published in 2020.
To assess the diagnostic accuracy of rapid, point-of-care antigen tests for diagnosis of SARS-CoV-2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups. Sources of heterogeneity investigated included setting and indication for testing, assay format, sample site, viral load, age, timing of test, and study design.
We searched the COVID-19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) on 08 March 2021. We included independent evaluations from national reference laboratories, FIND and the Diagnostics Global Health website. We did not apply language restrictions.
We included studies of people with either suspected SARS-CoV-2 infection, known SARS-CoV-2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen tests. We included evaluations of single applications of a test (one test result reported per person) and evaluations of serial testing (repeated antigen testing over time). Reference standards for presence or absence of infection were any laboratory-based molecular test (primarily reverse transcription polymerase chain reaction (RT-PCR)) or pre-pandemic respiratory sample.
We used standard screening procedures with three people. Two people independently carried out quality assessment (using the QUADAS-2 tool) and extracted study results. Other study characteristics were extracted by one review author and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test, and pooled data using the bivariate model. We investigated heterogeneity by including indicator variables in the random-effects logistic regression models. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status.
We included 155 study cohorts (described in 166 study reports, with 24 as preprints). The main results relate to 152 evaluations of single test applications including 100,462 unique samples (16,822 with confirmed SARS-CoV-2). Studies were mainly conducted in Europe (101/152, 66%), and evaluated 49 different commercial antigen assays. Only 23 studies compared two or more brands of test. Risk of bias was high because of participant selection (40, 26%); interpretation of the index test (6, 4%); weaknesses in the reference standard for absence of infection (119, 78%); and participant flow and timing 41 (27%). Characteristics of participants (45, 30%) and index test delivery (47, 31%) differed from the way in which and in whom the test was intended to be used. Nearly all studies (91%) used a single RT-PCR result to define presence or absence of infection. The 152 studies of single test applications reported 228 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies, with consistently high specificities. Average sensitivity was higher in symptomatic (73.0%, 95% CI 69.3% to 76.4%; 109 evaluations; 50,574 samples, 11,662 cases) compared to asymptomatic participants (54.7%, 95% CI 47.7% to 61.6%; 50 evaluations; 40,956 samples, 2641 cases). Average sensitivity was higher in the first week after symptom onset (80.9%, 95% CI 76.9% to 84.4%; 30 evaluations, 2408 cases) than in the second week of symptoms (53.8%, 95% CI 48.0% to 59.6%; 40 evaluations, 1119 cases). For those who were asymptomatic at the time of testing, sensitivity was higher when an epidemiological exposure to SARS-CoV-2 was suspected (64.3%, 95% CI 54.6% to 73.0%; 16 evaluations; 7677 samples, 703 cases) compared to where COVID-19 testing was reported to be widely available to anyone on presentation for testing (49.6%, 95% CI 42.1% to 57.1%; 26 evaluations; 31,904 samples, 1758 cases). Average specificity was similarly high for symptomatic (99.1%) or asymptomatic (99.7%) participants. We observed a steady decline in summary sensitivities as measures of sample viral load decreased. Sensitivity varied between brands. When tests were used according to manufacturer instructions, average sensitivities by brand ranged from 34.3% to 91.3% in symptomatic participants (20 assays with eligible data) and from 28.6% to 77.8% for asymptomatic participants (12 assays). For symptomatic participants, summary sensitivities for seven assays were 80% or more (meeting acceptable criteria set by the World Health Organization (WHO)). The WHO acceptable performance criterion of 97% specificity was met by 17 of 20 assays when tests were used according to manufacturer instructions, 12 of which demonstrated specificities above 99%. For asymptomatic participants the sensitivities of only two assays approached but did not meet WHO acceptable performance standards in one study each; specificities for asymptomatic participants were in a similar range to those observed for symptomatic people. At 5% prevalence using summary data in symptomatic people during the first week after symptom onset, the positive predictive value (PPV) of 89% means that 1 in 10 positive results will be a false positive, and around 1 in 5 cases will be missed. At 0.5% prevalence using summary data for asymptomatic people, where testing was widely available and where epidemiological exposure to COVID-19 was suspected, resulting PPVs would be 38% to 52%, meaning that between 2 in 5 and 1 in 2 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed.
Antigen tests vary in sensitivity. In people with signs and symptoms of COVID-19, sensitivities are highest in the first week of illness when viral loads are higher. Assays that meet appropriate performance standards, such as those set by WHO, could replace laboratory-based RT-PCR when immediate decisions about patient care must be made, or where RT-PCR cannot be delivered in a timely manner. However, they are more suitable for use as triage to RT-PCR testing. The variable sensitivity of antigen tests means that people who test negative may still be infected. Many commercially available rapid antigen tests have not been evaluated in independent validation studies. Evidence for testing in asymptomatic cohorts has increased, however sensitivity is lower and there is a paucity of evidence for testing in different settings. Questions remain about the use of antigen test-based repeat testing strategies. Further research is needed to evaluate the effectiveness of screening programmes at reducing transmission of infection, whether mass screening or targeted approaches including schools, healthcare setting and traveller screening.
ObjectiveTo measure test accuracy of non-invasive prenatal testing (NIPT) for Down, Edwards and Patau syndromes using cell-free fetal DNA and identify factors affecting accuracy.DesignSystematic ...review and meta-analysis of published studies.Data sourcesPubMed, Ovid Medline, Ovid Embase and the Cochrane Library published from 1997 to 9 February 2015, followed by weekly autoalerts until 1 April 2015.Eligibility criteria for selecting studiesEnglish language journal articles describing case–control studies with ≥15 trisomy cases or cohort studies with ≥50 pregnant women who had been given NIPT and a reference standard.Results41, 37 and 30 studies of 2012 publications retrieved were included in the review for Down, Edwards and Patau syndromes. Quality appraisal identified high risk of bias in included studies, funnel plots showed evidence of publication bias. Pooled sensitivity was 99.3% (95% CI 98.9% to 99.6%) for Down, 97.4% (95.8% to 98.4%) for Edwards, and 97.4% (86.1% to 99.6%) for Patau syndrome. The pooled specificity was 99.9% (99.9% to 100%) for all three trisomies. In 100 000 pregnancies in the general obstetric population we would expect 417, 89 and 40 cases of Downs, Edwards and Patau syndromes to be detected by NIPT, with 94, 154 and 42 false positive results. Sensitivity was lower in twin than singleton pregnancies, reduced by 9% for Down, 28% for Edwards and 22% for Patau syndrome. Pooled sensitivity was also lower in the first trimester of pregnancy, in studies in the general obstetric population, and in cohort studies with consecutive enrolment.ConclusionsNIPT using cell-free fetal DNA has very high sensitivity and specificity for Down syndrome, with slightly lower sensitivity for Edwards and Patau syndrome. However, it is not 100% accurate and should not be used as a final diagnosis for positive cases.Trial registration numberCRD42014014947.
Gastroenteritis is a common, transient disorder usually caused by infection and characterised by the acute onset of diarrhoea. Multiplex gastrointestinal pathogen panel (GPP) tests simultaneously ...identify common bacterial, viral and parasitic pathogens using molecular testing. By providing test results more rapidly than conventional testing methods, GPP tests might positively influence the treatment and management of patients presenting in hospital or in the community.
To systematically review the evidence for GPP tests xTAG
(Luminex, Toronto, ON, Canada), FilmArray (BioFire Diagnostics, Salt Lake City, UT, USA) and Faecal Pathogens B (AusDiagnostics, Beaconsfield, NSW, Australia) and to develop a de novo economic model to compare the cost-effectiveness of GPP tests with conventional testing in England and Wales.
Multiple electronic databases including MEDLINE, EMBASE, Web of Science and the Cochrane Database were searched from inception to January 2016 (with supplementary searches of other online resources).
Eligible studies included patients with acute diarrhoea; comparing GPP tests with standard microbiology techniques; and patient, management, test accuracy or cost-effectiveness outcomes. Quality assessment of eligible studies used tailored Quality Assessment of Diagnostic Accuracy Studies-2, Consolidated Health Economic Evaluation Reporting Standards and Philips checklists. The meta-analysis included positive and negative agreement estimated for each pathogen. A de novo decision tree model compared patients managed with GPP testing or comparable coverage with patients managed using conventional tests, within the Public Health England pathway. Economic models included hospital and community management of patients with suspected gastroenteritis. The model estimated costs (in 2014/15 prices) and quality-adjusted life-year losses from a NHS and Personal Social Services perspective.
Twenty-three studies informed the review of clinical evidence (17 xTAG, four FilmArray, two xTAG and FilmArray, 0 Faecal Pathogens B). No study provided an adequate reference standard with which to compare the test accuracy of GPP with conventional tests. A meta-analysis (of 10 studies) found considerable heterogeneity; however, GPP testing produces a greater number of pathogen-positive findings than conventional testing. It is unclear whether or not these additional 'positives' are clinically important. The review identified no robust evidence to inform consequent clinical management of patients. There is considerable uncertainty about the cost-effectiveness of GPP panels used to test for suspected infectious gastroenteritis in hospital and community settings. Uncertainties in the model include length of stay, assumptions about false-positive findings and the costs of tests. Although there is potential for cost-effectiveness in both settings, key modelling assumptions need to be verified and model findings remain tentative.
No test-treat trials were retrieved. The economic model reflects one pattern of care, which will vary across the NHS.
The systematic review and cost-effectiveness model identify uncertainties about the adoption of GPP tests within the NHS. GPP testing will generally correctly identify pathogens identified by conventional testing; however, these tests also generate considerable additional positive results of uncertain clinical importance.
An independent reference standard may not exist to evaluate alternative approaches to testing. A test-treat trial might ascertain whether or not additional GPP 'positives' are clinically important or result in overdiagnoses, whether or not earlier diagnosis leads to earlier discharge in patients and what the health consequences of earlier intervention are. Future work might also consider the public health impact of different testing treatments, as test results form the basis for public health surveillance.
This study is registered as PROSPERO CRD2016033320.
The National Institute for Health Research Health Technology Assessment programme.
Our knowledge of the incidence and prevalence of inflammatory bowel disease (IBD) is uncertain. Recent studies reported an increase in prevalence. However, they excluded a high proportion of ...ambiguous cases from general practice. Estimates are needed to inform health care providers who plan the provision of services for IBD patients. We aimed to estimate the IBD incidence and prevalence in UK general practice.
We undertook a retrospective cohort study of routine electronic health records from the IQVIA Medical Research Database covering 14 million patients. Adult patients from 2006 to 2016 were included. IBD was defined as an IBD related Read code or record of IBD specific medication. Annual incidence and 12-month period prevalence were calculated.
The prevalence of IBD increased between 2006 and 2016 from 106.2 (95% CI 105.2-107.3) to 142.1 (95% CI 140.7-143.5) IBD cases per 10,000 patients which is a 33.8% increase. Incidence varied across the years. The incidence across the full study period was 69.5 (95% CI 68.6-70.4) per 100,000 person years.
In this large study we found higher estimates of IBD incidence and prevalence than previously reported. Estimates are highly dependent on definitions of disease and previously may have been underestimated.
ObjectiveAttendance at population-based breast cancer (mammographic) screening varies. This comprehensive systematic review and meta-analysis assesses all identified patient-level factors associated ...with routine population breast screening attendance.DesignCINAHL, Cochrane Library, Embase, Medline, OVID, PsycINFO and Web of Science were searched for studies of any design, published January 1987–June 2019, and reporting attendance in relation to at least one patient-level factor.Data synthesisIndependent reviewers performed screening, data extraction and quality appraisal. OR and 95% CIs were calculated for attendance for each factor and random-effects meta-analysis was undertaken where possible.ResultsOf 19 776 studies, 335 were assessed at full text and 66 studies (n=22 150 922) were included. Risk of bias was generally low. In meta-analysis, increased attendance was associated with higher socioeconomic status (SES) (n=11 studies; OR 1.45, 95% CI: 1.20 to 1.75); higher income (n=5 studies; OR 1.96, 95% CI: 1.68 to 2.29); home ownership (n=3 studies; OR 2.16, 95% CI: 2.08 to 2.23); being non-immigrant (n=7 studies; OR 2.23, 95% CI: 2.00 to 2.48); being married/cohabiting (n=7 studies; OR 1.86, 95% CI: 1.58 to 2.19) and medium (vs low) level of education (n=6 studies; OR 1.24, 95% CI: 1.09 to 1.41). Women with previous false-positive results were less likely to reattend (n=6 studies; OR 0.77, 95% CI: 0.68 to 0.88). There were no differences by age group or by rural versus urban residence.ConclusionsAttendance was lower in women with lower SES, those who were immigrants, non-homeowners and those with previous false-positive results. Variations in service delivery, screening programmes and study populations may influence findings. Our findings are of univariable associations. Underlying causes of lower uptake such as practical, physical, psychological or financial barriers should be investigated.Trial registration numberCRD42016051597.
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