A synthesis of qualitative evidence of barriers and facilitators in implementing guidelines for TB testing in healthcare settings.

INTRODUCTION: The suboptimal case notification rates for tuberculosis (TB) globally could partly be due to the poor implementation of TB testing guidelines or policies. We identified, appraised and synthesized qualitative evidence exploring the barriers and facilitators to implementing TB testing guidelines. METHODS: We searched electronic databases and grey literature and included studies based on predefined inclusion criteria (PROSPERO registered protocol CRD42016039790) until 9th February 2023. We used the Critical Appraisal Skills Programme tool to assess the methodological quality of the included studies. Two authors reviewed the search output, extracted data and assessed methodological quality independently, resolving disagreements by consensus. We used the Supporting the Use of Research Evidence framework to identify themes and analyse and synthesize our data. We applied the Confidence in the Evidence from Reviews of Qualitative Research approach to assess the confidence of the review findings. RESULTS: Our search output was 6976 articles, from which we included 25 qualitative studies, mostly from low- and middle-income countries (n=19) and about national guidelines (n=22). All studies were from healthcare settings. Most barriers revolved around health system constraints involving the guidelines (low trust and adherence, ambiguous and poorly developed or adapted guidelines) and poorly resourced and organized health facilities to enable the implementation of the guidelines. Individual-level barriers included low trust and low awareness among recipients and providers of care. Donor dependence was the main socio-political constraint. These barriers were similar across all income settings except poorly resourced health facilities and social and political constraints which were only reported in low- and middle-income settings. The reported facilitators were improved trust and knowledge of guidelines, national leadership support and availability of training tools and opportunities for guidelines across all income settings. We had high confidence in most of the review findings. CONCLUSION: Limited guideline knowledge, trust and adherence related to poorly developed and disseminated guidelines in all income settings and poorly resourced facilities in low- and middle-income countries hinder the implementation of TB testing guidelines. This could be improved by better guideline training and adaptation and resourcing of health facilities. TRIAL REGISTRATION: The protocol of this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42016039790, and published in a peer-reviewed journal.

Rapid molecular tests for tuberculosis and tuberculosis drug resistance: a qualitative evidence synthesis of recipient and provider views.

BACKGROUND: Programmes that introduce rapid molecular tests for tuberculosis and tuberculosis drug resistance aim to bring tests closer to the community, and thereby cut delay in diagnosis, ensure early treatment, and improve health outcomes, as well as overcome problems with poor laboratory infrastructure and inadequately trained personnel. Yet, diagnostic technologies only have an impact if they are put to use in a correct and timely manner. Views of the intended beneficiaries are important in uptake of diagnostics, and their effective use also depends on those implementing testing programmes, including providers, laboratory professionals, and staff in health ministries. Otherwise, there is a risk these technologies will not fit their intended use and setting, cannot be made to work and scale up, and are not used by, or not accessible to, those in need. OBJECTIVES: To synthesize end-user and professional user perspectives and experiences with low-complexity nucleic acid amplification tests (NAATs) for detection of tuberculosis and tuberculosis drug resistance; and to identify implications for effective implementation and health equity. SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, PsycInfo and Science Citation Index Expanded databases for eligible studies from 1 January 2007 up to 20 October 2021. We limited all searches to 2007 onward because the development of Xpert MTB/RIF, the first rapid molecular test in this review, was completed in 2009. SELECTION CRITERIA: We included studies that used qualitative methods for data collection and analysis, and were focused on perspectives and experiences of users and potential users of low-complexity NAATs to diagnose tuberculosis and drug-resistant tuberculosis. NAATs included Xpert MTB/RIF, Xpert MTB/RIF Ultra, Xpert MTB/XDR, and the Truenat assays. Users were people with presumptive or confirmed tuberculosis and drug-resistant tuberculosis (including multidrug-resistant (MDR-TB)) and their caregivers, healthcare providers, laboratory technicians and managers, and programme officers and staff; and were from any type of health facility and setting globally. MDR-TB is tuberculosis caused by resistance to at least rifampicin and isoniazid, the two most effective first-line drugs used to treat tuberculosis. DATA COLLECTION AND ANALYSIS: We used a thematic analysis approach for data extraction and synthesis, and assessed confidence in the findings using GRADE CERQual approach. We developed a conceptual framework to illustrate how the findings relate. MAIN RESULTS: We found 32 studies. All studies were conducted in low- and middle-income countries. Twenty-seven studies were conducted in high-tuberculosis burden countries and 21 studies in high-MDR-TB burden countries. Only one study was from an Eastern European country. While the studies covered a diverse use of low-complexity NAATs, in only a minority of studies was it used as the initial diagnostic test for all people with presumptive tuberculosis. We identified 18 review findings and grouped them into three overarching categories. Critical aspects users value People with tuberculosis valued reaching diagnostic closure with an accurate diagnosis, avoiding diagnostic delays, and keeping diagnostic-associated cost low. Similarly, healthcare providers valued aspects of accuracy and the resulting confidence in low-complexity NAAT results, rapid turnaround times, and keeping cost to people seeking a diagnosis low. In addition, providers valued diversity of sample types (for example, gastric aspirate specimens and stool in children) and drug resistance information. Laboratory professionals appreciated the improved ease of use, ergonomics, and biosafety of low-complexity NAATs compared to sputum microscopy, and increased staff satisfaction. Challenges reported to realizing those values People with tuberculosis and healthcare workers were reluctant to test for tuberculosis (including MDR-TB) due to fears, stigma, or cost concerns. Thus, low-complexity NAAT testing is not implemented with sufficient support or discretion to overcome barriers that are common to other approaches to testing for tuberculosis. Delays were reported at many steps of the diagnostic pathway owing to poor sample quality; difficulties with transporting specimens; lack of sufficient resources; maintenance of low-complexity NAATs; increased workload; inefficient work and patient flows; over-reliance on low-complexity NAAT results in lieu of clinical judgement; and lack of data-driven and inclusive implementation processes. These challenges were reported to lead to underutilization.  Concerns for access and equity The reported concerns included sustainable funding and maintenance and equitable use of resources to access low-complexity NAATs, as well as conflicts of interest between donors and people implementing the tests. Also, lengthy diagnostic delays, underutilization of low-complexity NAATs, lack of tuberculosis diagnostic facilities in the community, and too many eligibility restrictions hampered access to prompt and accurate testing and treatment. This was particularly the case for vulnerable groups, such as children, people with MDR-TB, or people with limited ability to pay. We had high confidence in most of our findings. AUTHORS' CONCLUSIONS: Low-complexity diagnostics have been presented as a solution to overcome deficiencies in laboratory infrastructure and lack of skilled professionals. This review indicates this is misleading. The lack of infrastructure and human resources undermine the added value new diagnostics of low complexity have for recipients and providers. We had high confidence in the evidence contributing to these review findings. Implementation of new diagnostic technologies, like those considered in this review, will need to tackle the challenges identified in this review including weak infrastructure and systems, and insufficient data on ground level realities prior and during implementation, as well as problems of conflicts of interest in order to ensure equitable use of resources.

Point-of-care viral load tests to detect high HIV viral load in people living with HIV/AIDS attending health facilities.

BACKGROUND: Viral load (VL) testing in people living with HIV (PLHIV) helps to monitor antiretroviral therapy (ART). VL is still largely tested using central laboratory-based platforms, which have long test turnaround times and involve sophisticated equipment. VL tests with point-of-care (POC) platforms capable of being used near the patient are potentially easy to use, give quick results, are cost-effective, and could replace central or reference VL testing platforms. OBJECTIVES: To estimate the diagnostic accuracy of POC tests to detect high viral load levels in PLHIV attending healthcare facilities. SEARCH METHODS: We searched eight electronic databases using standard, extensive Cochrane search methods, and did not use any language, document type, or publication status limitations. We also searched the reference lists of included studies and relevant systematic reviews, and consulted an expert in the field from the World Health Organization (WHO) HIV Department for potentially relevant studies. The latest search was 23 November 2020. SELECTION CRITERIA: We included any primary study that compared the results of a VL test with a POC platform to that of a central laboratory-based reference test to detect high viral load in PLHIV on HIV/AIDS care or follow-up. We included all forms of POC tests for VL as defined by study authors, regardless of the healthcare facility in which the test was conducted. We excluded diagnostic case-control studies with healthy controls and studies that did not provide sufficient data to create the 2 × 2 tables to calculate sensitivity and specificity. We did not limit our study inclusion to age, gender, or geographical setting. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles, abstracts, and full texts of the search results to identify eligible articles. They also independently extracted data using a standardized data extraction form and conducted risk of bias assessment using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Using participants as the unit of analysis, we fitted simplified univariable models for sensitivity and specificity separately, employing a random-effects model to estimate the summary sensitivity and specificity at the current and commonly reported World Health Organization (WHO) threshold (≥ 1000 copies/mL). The bivariate models did not converge to give a model estimate. MAIN RESULTS: We identified 18 studies (24 evaluations, 10,034 participants) defining high viral loads at main thresholds ≥ 1000 copies/mL (n = 20), ≥ 5000 copies/mL (n = 1), and ≥ 40 copies/mL (n = 3). All evaluations were done on samples from PLHIV retrieved from routine HIV/AIDS care centres or health facilities. For clinical applicability, we included 14 studies (20 evaluations, 8659 participants) assessing high viral load at the clinical threshold of ≥ 1000 copies/mL in the meta-analyses. Of these, sub-Saharan Africa, Europe, and Asia contributed 16, three, and one evaluation respectively. All included participants were on ART in only nine evaluations; in the other 11 evaluations the proportion of participants on ART was either partial or not clearly stated. Thirteen evaluations included adults only (n = 13), five mixed populations of adults and children, whilst in the remaining two the age of included populations was not clearly stated. The majority of evaluations included commercially available tests (n = 18). Ten evaluations were POC VL tests conducted near the patient in a peripheral or onsite laboratory, whilst the other 10 were evaluations of POC VL tests in a central or reference laboratory setting. The test types evaluated as POC VL tests included Xpert HIV-1 Viral Load test (n = 8), SAMBA HIV-1 Semi-Q Test (n = 9), Alere Q NAT prototype assay for HIV-1 (n = 2) and m-PIMA HIV-1/2 Viral Load test (n = 1). The majority of evaluations (n = 17) used plasma samples, whilst the rest (n = 3) utilized whole blood samples. Pooled sensitivity (95% confidence interval (CI)) of POC VL at a threshold of ≥ 1000 copies/mL was 96.6% (94.8 to 97.8) (20 evaluations, 2522 participants), and pooled specificity (95% CI) was 95.7% (90.8 to 98.0) (20 evaluations, 6137 participants). Median prevalence for high viral load (≥ 1000 copies/mL) (n = 20) was 33.4% (range 6.9% to 88.5%). Limitations The risk of bias was mostly assessed as unclear across the four domains due to incomplete reporting. AUTHORS' CONCLUSIONS: We found POC VL to have high sensitivity and high specificity for the diagnosis of high HIV viral load in PLHIV attending healthcare facilities at a clinical threshold of ≥ 1000 copies/mL.

Point-of-care tests detecting HIV nucleic acids for diagnosis of HIV-1 or HIV-2 infection in infants and children aged 18 months or less.

BACKGROUND: The standard method of diagnosing HIV in infants and children less than 18 months is with a nucleic acid amplification test reverse transcriptase polymerase chain reaction test (NAT RT-PCR) detecting viral ribonucleic acid (RNA). Laboratory testing using the RT-PCR platform for HIV infection is limited by poor access, logistical support, and delays in relaying test results and initiating therapy in low-resource settings. The use of rapid diagnostic tests at or near the point-of-care (POC) can increase access to early diagnosis of HIV infection in infants and children less than 18 months of age and timely initiation of antiretroviral therapy (ART). OBJECTIVES: To summarize the diagnostic accuracy of point-of-care nucleic acid-based testing (POC NAT) to detect HIV-1/HIV-2 infection in infants and children aged 18 months or less exposed to HIV infection. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (until 2 February 2021), MEDLINE and Embase (until 1 February 2021), and LILACS and Web of Science (until 2 February 2021) with no language or publication status restriction. We also searched conference websites and clinical trial registries, tracked reference lists of included studies and relevant systematic reviews, and consulted experts for potentially eligible studies. SELECTION CRITERIA: We defined POC tests as rapid diagnostic tests conducted at or near the patient site. We included any primary study that compared the results of a POC NAT to a reference standard of laboratory NAT RT-PCR or total nucleic acid testing to detect the presence or absence of HIV infection denoted by HIV viral nucleic acids in infants and children aged 18 months or less who were exposed to HIV-1/HIV-2 infection. We included cross-sectional, prospective, and retrospective study designs and those that provided sufficient data to create the 2 × 2 table to calculate sensitivity and specificity. We excluded diagnostic case control studies with healthy controls. DATA COLLECTION AND ANALYSIS: We extracted information on study characteristics using a pretested standardized data extraction form. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool to assess the risk of bias and applicability concerns of the included studies. Two review authors independently selected and assessed the included studies, resolving any disagreements by consensus. The unit of analysis was the participant. We first conducted preliminary exploratory analyses by plotting estimates of sensitivity and specificity from each study on forest plots and in receiver operating characteristic (ROC) space. For the overall meta-analyses, we pooled estimates of sensitivity and specificity using the bivariate meta-analysis model at a common threshold (presence or absence of infection). MAIN RESULTS: We identified a total of 12 studies (15 evaluations, 15,120 participants). All studies were conducted in sub-Saharan Africa. The ages of included infants and children in the evaluations were as follows: at birth (n = 6), ≤ 12 months (n = 3), ≤ 18 months (n = 5), and ≤ 24 months (n = 1). Ten evaluations were field evaluations of the POC NAT test at the point of care, and five were laboratory evaluations of the POC NAT tests.The POC NAT tests evaluated included Alere q HIV-1/2 Detect qualitative test (recently renamed m-PIMA q HIV-1/2 Detect qualitative test) (n = 6), Xpert HIV-1 qualitative test (n = 6), and SAMBA HIV-1 qualitative test (n = 3). POC NAT pooled sensitivity and specificity (95% confidence interval (CI)) against laboratory reference standard tests were 98.6% (96.1 to 99.5) (15 evaluations, 1728 participants) and 99.9% (99.7 to 99.9) (15 evaluations, 13,392 participants) in infants and children ≤ 18 months. Risk of bias in the included studies was mostly low or unclear due to poor reporting. Five evaluations had some concerns for applicability for the index test, as they were POC tests evaluated in a laboratory setting, but there was no difference detected between settings in sensitivity (-1.3% (95% CI -4.1 to 1.5)); and specificity results were similar. AUTHORS' CONCLUSIONS: For the diagnosis of HIV-1/HIV-2 infection, we found the sensitivity and specificity of POC NAT tests to be high in infants and children aged 18 months or less who were exposed to HIV infection.

Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis.

BACKGROUND: Xpert MTB/RIF and Xpert MTB/RIF Ultra (Xpert Ultra) are World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in people with signs and symptoms of tuberculosis. This review builds on our recent extensive Cochrane Review of Xpert MTB/RIF accuracy. OBJECTIVES: To compare the diagnostic accuracy of Xpert Ultra and Xpert MTB/RIF for the detection of pulmonary tuberculosis and detection of rifampicin resistance in adults with presumptive pulmonary tuberculosis. For pulmonary tuberculosis and rifampicin resistance, we also investigated potential sources of heterogeneity. We also summarized the frequency of Xpert Ultra trace-positive results, and estimated the accuracy of Xpert Ultra after repeat testing in those with trace-positive results. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, LILACS, Scopus, the WHO ICTRP, the ISRCTN registry, and ProQuest to 28 January 2020 with no language restriction. SELECTION CRITERIA: We included diagnostic accuracy studies using respiratory specimens in adults with presumptive pulmonary tuberculosis that directly compared the index tests. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based drug susceptibility testing and line probe assays. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardized form, including data by smear and HIV status. We assessed risk of bias using QUADAS-2 and QUADAS-C. We performed meta-analyses comparing pooled sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection, and separately by reference standard. Most analyses used a bivariate random-effects model. For tuberculosis detection, we estimated accuracy in studies in participants who were not selected based on prior microscopy testing or history of tuberculosis. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarized Xpert Ultra trace results. MAIN RESULTS: We identified nine studies (3500 participants): seven had unselected participants (2834 participants). All compared Xpert Ultra and Xpert MTB/RIF for pulmonary tuberculosis detection; seven studies used a paired comparative accuracy design, and two studies used a randomized design. Five studies compared Xpert Ultra and Xpert MTB/RIF for rifampicin resistance detection; four studies used a paired design, and one study used a randomized design. Of the nine included studies, seven (78%) were mainly or exclusively in high tuberculosis burden countries. For pulmonary tuberculosis detection, most studies had low risk of bias in all domains. Pulmonary tuberculosis detection Xpert Ultra pooled sensitivity and specificity (95% credible interval) against culture were 90.9% (86.2 to 94.7) and 95.6% (93.0 to 97.4) (7 studies, 2834 participants; high-certainty evidence) versus Xpert MTB/RIF pooled sensitivity and specificity of 84.7% (78.6 to 89.9) and 98.4% (97.0 to 99.3) (7 studies, 2835 participants; high-certainty evidence). The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at 6.3% (0.1 to 12.8) for sensitivity and -2.7% (-5.7 to -0.5) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss 9 cases, and Xpert MTB/RIF will miss 15 cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 40 with Xpert Ultra and 14 with Xpert MTB/RIF. In smear-negative, culture-positive participants, pooled sensitivity was 77.5% (67.6 to 85.6) for Xpert Ultra versus 60.6% (48.4 to 71.7) for Xpert MTB/RIF; pooled specificity was 95.8% (92.9 to 97.7) for Xpert Ultra versus 98.8% (97.7 to 99.5) for Xpert MTB/RIF (6 studies). In people living with HIV, pooled sensitivity was 87.6% (75.4 to 94.1) for Xpert Ultra versus 74.9% (58.7 to 86.2) for Xpert MTB/RIF; pooled specificity was 92.8% (82.3 to 97.0) for Xpert Ultra versus 99.7% (98.6 to 100.0) for Xpert MTB/RIF (3 studies). In participants with a history of tuberculosis, pooled sensitivity was 84.2% (72.5 to 91.7) for Xpert Ultra versus 81.8% (68.7 to 90.0) for Xpert MTB/RIF; pooled specificity was 88.2% (70.5 to 96.6) for Xpert Ultra versus 97.4% (91.7 to 99.5) for Xpert MTB/RIF (4 studies). The proportion of Ultra trace-positive results ranged from 3.0% to 30.4%. Data were insufficient to estimate the accuracy of Xpert Ultra repeat testing in individuals with initial trace-positive results. Rifampicin resistance detection Pooled sensitivity and specificity were 94.9% (88.9 to 97.9) and 99.1% (97.7 to 99.8) (5 studies, 921 participants; high-certainty evidence) for Xpert Ultra versus 95.3% (90.0 to 98.1) and 98.8% (97.2 to 99.6) (5 studies, 930 participants; high-certainty evidence) for Xpert MTB/RIF. The difference in the accuracy of Xpert Ultra minus Xpert MTB/RIF was estimated at -0.3% (-6.9 to 5.7) for sensitivity and 0.3% (-1.2 to 2.0) for specificity. If the point estimates for Xpert Ultra and Xpert MTB/RIF are applied to a hypothetical cohort of 1000 patients, where 10% of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss 5 cases, and Xpert MTB/RIF will miss 5 cases. The number of people wrongly diagnosed with rifampicin resistance would be 8 with Xpert Ultra and 11 with Xpert MTB/RIF. We identified a higher number of rifampicin resistance indeterminate results with Xpert Ultra, pooled proportion 7.6% (2.4 to 21.0) compared to Xpert MTB/RIF pooled proportion 0.8% (0.2 to 2.4). The estimated difference in the pooled proportion of indeterminate rifampicin resistance results for Xpert Ultra versus Xpert MTB/RIF was 6.7% (1.4 to 20.1). AUTHORS' CONCLUSIONS: Xpert Ultra has higher sensitivity and lower specificity than Xpert MTB/RIF for pulmonary tuberculosis, especially in smear-negative participants and people living with HIV. Xpert Ultra specificity was lower than that of Xpert MTB/RIF in participants with a history of tuberculosis. The sensitivity and specificity trade-off would be expected to vary by setting. For detection of rifampicin resistance, Xpert Ultra and Xpert MTB/RIF had similar sensitivity and specificity. Ultra trace-positive results were common. Xpert Ultra and Xpert MTB/RIF provide accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multidrug-resistant tuberculosis.

Routine laboratory testing to determine if a patient has COVID-19.

BACKGROUND: Specific diagnostic tests to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and resulting COVID-19 disease are not always available and take time to obtain results. Routine laboratory markers such as white blood cell count, measures of anticoagulation, C-reactive protein (CRP) and procalcitonin, are used to assess the clinical status of a patient. These laboratory tests may be useful for the triage of people with potential COVID-19 to prioritize them for different levels of treatment, especially in situations where time and resources are limited. OBJECTIVES: To assess the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. SEARCH METHODS: On 4 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. SELECTION CRITERIA: We included both case-control designs and consecutive series of patients that assessed the diagnostic accuracy of routine laboratory testing as a triage test to determine if a person has COVID-19. The reference standard could be reverse transcriptase polymerase chain reaction (RT-PCR) alone; RT-PCR plus clinical expertise or and imaging; repeated RT-PCR several days apart or from different samples; WHO and other case definitions; and any other reference standard used by the study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each included study. They also assessed the methodological quality of the studies, using QUADAS-2. We used the 'NLMIXED' procedure in SAS 9.4 for the hierarchical summary receiver operating characteristic (HSROC) meta-analyses of tests for which we included four or more studies. To facilitate interpretation of results, for each meta-analysis we estimated summary sensitivity at the points on the SROC curve that corresponded to the median and interquartile range boundaries of specificities in the included studies. MAIN RESULTS: We included 21 studies in this review, including 14,126 COVID-19 patients and 56,585 non-COVID-19 patients in total. Studies evaluated a total of 67 different laboratory tests. Although we were interested in the diagnotic accuracy of routine tests for COVID-19, the included studies used detection of SARS-CoV-2 infection through RT-PCR as reference standard. There was considerable heterogeneity between tests, threshold values and the settings in which they were applied. For some tests a positive result was defined as a decrease compared to normal vaues, for other tests a positive result was defined as an increase, and for some tests both increase and decrease may have indicated test positivity. None of the studies had either low risk of bias on all domains or low concerns for applicability for all domains. Only three of the tests evaluated had a summary sensitivity and specificity over 50%. These were: increase in interleukin-6, increase in C-reactive protein and lymphocyte count decrease. Blood count Eleven studies evaluated a decrease in white blood cell count, with a median specificity of 93% and a summary sensitivity of 25% (95% CI 8.0% to 27%; very low-certainty evidence). The 15 studies that evaluated an increase in white blood cell count had a lower median specificity and a lower corresponding sensitivity. Four studies evaluated a decrease in neutrophil count. Their median specificity was 93%, corresponding to a summary sensitivity of 10% (95% CI 1.0% to 56%; low-certainty evidence). The 11 studies that evaluated an increase in neutrophil count had a lower median specificity and a lower corresponding sensitivity. The summary sensitivity of an increase in neutrophil percentage (4 studies) was 59% (95% CI 1.0% to 100%) at median specificity (38%; very low-certainty evidence). The summary sensitivity of an increase in monocyte count (4 studies) was 13% (95% CI 6.0% to 26%) at median specificity (73%; very low-certainty evidence). The summary sensitivity of a decrease in lymphocyte count (13 studies) was 64% (95% CI 28% to 89%) at median specificity (53%; low-certainty evidence). Four studies that evaluated a decrease in lymphocyte percentage showed a lower median specificity and lower corresponding sensitivity. The summary sensitivity of a decrease in platelets (4 studies) was 19% (95% CI 10% to 32%) at median specificity (88%; low-certainty evidence). Liver function tests The summary sensitivity of an increase in alanine aminotransferase (9 studies) was 12% (95% CI 3% to 34%) at median specificity (92%; low-certainty evidence). The summary sensitivity of an increase in aspartate aminotransferase (7 studies) was 29% (95% CI 17% to 45%) at median specificity (81%) (low-certainty evidence). The summary sensitivity of a decrease in albumin (4 studies) was 21% (95% CI 3% to 67%) at median specificity (66%; low-certainty evidence). The summary sensitivity of an increase in total bilirubin (4 studies) was 12% (95% CI 3.0% to 34%) at median specificity (92%; very low-certainty evidence). Markers of inflammation The summary sensitivity of an increase in CRP (14 studies) was 66% (95% CI 55% to 75%) at median specificity (44%; very low-certainty evidence). The summary sensitivity of an increase in procalcitonin (6 studies) was 3% (95% CI 1% to 19%) at median specificity (86%; very low-certainty evidence). The summary sensitivity of an increase in IL-6 (four studies) was 73% (95% CI 36% to 93%) at median specificity (58%) (very low-certainty evidence). Other biomarkers The summary sensitivity of an increase in creatine kinase (5 studies) was 11% (95% CI 6% to 19%) at median specificity (94%) (low-certainty evidence). The summary sensitivity of an increase in serum creatinine (four studies) was 7% (95% CI 1% to 37%) at median specificity (91%; low-certainty evidence). The summary sensitivity of an increase in lactate dehydrogenase (4 studies) was 25% (95% CI 15% to 38%) at median specificity (72%; very low-certainty evidence). AUTHORS' CONCLUSIONS: Although these tests give an indication about the general health status of patients and some tests may be specific indicators for inflammatory processes, none of the tests we investigated are useful for accurately ruling in or ruling out COVID-19 on their own. Studies were done in specific hospitalized populations, and future studies should consider non-hospital settings to evaluate how these tests would perform in people with milder symptoms.

Abdominal ultrasound for diagnosing abdominal tuberculosis or disseminated tuberculosis with abdominal involvement in HIV-positive individuals.

BACKGROUND: Accurate diagnosis of tuberculosis in people living with HIV is difficult. HIV-positive individuals have higher rates of extrapulmonary tuberculosis and the diagnosis of tuberculosis is often limited to imaging results. Ultrasound is such an imaging test that is widely used as a diagnostic tool (including point-of-care) in people suspected of having abdominal tuberculosis or disseminated tuberculosis with abdominal involvement. OBJECTIVES: To determine the diagnostic accuracy of abdominal ultrasound for detecting abdominal tuberculosis or disseminated tuberculosis with abdominal involvement in HIV-positive individuals.To investigate potential sources of heterogeneity in test accuracy, including clinical setting, ultrasound training level, and type of reference standard. SEARCH METHODS: We searched for publications in any language up to 4 April 2019 in the following databases: MEDLINE, Embase, BIOSIS, Science Citation Index Expanded (SCI-EXPANDED), Social Sciences Citation Index (SSCI), Conference Proceedings Citation Index- Science (CPCI-S), and also ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform to identify ongoing trials. SELECTION CRITERIA: We included cross-sectional, cohort, and diagnostic case-control studies (prospective and retrospective) that compared the result of the index test (abdominal ultrasound) with one of the reference standards. We only included studies that allowed for extraction of numbers of true positives (TPs), true negatives (TNs), false positives (FPs), and false negatives (FNs). Participants were HIV-positive individuals aged 15 years and older. A higher-quality reference standard was the bacteriological confirmation of Mycobacterium tuberculosis from any clinical specimen, and a lower-quality reference standard was a clinical diagnosis of tuberculosis without microbiological confirmation. We excluded genitourinary tuberculosis. DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted data using a standardized form. We assessed the quality of studies using a tailored Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. We used the bivariate model to estimate pooled sensitivity and specificity. When studies were few we simplified the bivariate model to separate univariate random-effects logistic regression models for sensitivity and specificity. We explored the influence of the type of reference standard on the accuracy estimates by conducting separate analyses for each type of reference standard. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 11 studies. The risks of bias and concern about applicability were often high or unclear in all domains. We included six studies in the main analyses of any abnormal finding on abdominal ultrasound; five studies reported only individual lesions.The six studies of any abnormal finding were cross-sectional or cohort studies. Five of these (83%) were conducted in low- or middle-income countries, and one in a high-income country. The proportion of participants on antiretroviral therapy was none (1 study), fewer then 50% (4 studies), more than 50% (1 study), and not reported (5 studies). The first main analysis, studies using a higher-quality reference standard (bacteriological confirmation), had a pooled sensitivity of 63% (95% confidence interval (CI) 43% to 79%; 5 studies, 368 participants; very low-certainty evidence) and a pooled specificity of 68% (95% CI 42% to 87%; 5 studies, 511 participants; very low-certainty evidence). If the results were to be applied to a hypothetical cohort of 1000 people with HIV where 200 (20%) have tuberculosis then:- About 382 individuals would have an ultrasound result indicating tuberculosis; of these, 256 (67%) would be incorrectly classified as having tuberculosis (false positives).- Of the 618 individuals with a result indicating that tuberculosis is not present, 74 (12%) would be incorrectly classified as not having tuberculosis (false negatives).In the second main analysis involving studies using a lower-quality reference standard (clinical diagnosis), the pooled sensitivity was 68% (95% CI 45% to 85%; 4 studies, 195 participants; very low-certainty evidence) and the pooled specificity was 73% (95% CI 41% to 91%; 4 studies, 202 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: In HIV-positive individuals thought to have abdominal tuberculosis or disseminated tuberculosis with abdominal involvement, abdominal ultrasound appears to have 63% sensitivity and 68% specificity when tuberculosis was bacteriologically confirmed. These estimates are based on data that is limited, varied, and low-certainty.The low sensitivity of abdominal ultrasound means clinicians should not use a negative test result to rule out the disease, but rather consider the result in combination with other diagnostic strategies (including clinical signs, chest x-ray, lateral flow urine lipoarabinomannan assay (LF-LAM), and Xpert MTB/RIF). Research incorporating the test into tuberculosis diagnostic algorithms will help in delineating more precisely its value in diagnosing abdominal tuberculosis or disseminated tuberculosis with abdominal involvement.

Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults.

BACKGROUND: Xpert MTB/RIF (Xpert MTB/RIF) and Xpert MTB/RIF Ultra (Xpert Ultra), the newest version, are the only World Health Organization (WHO)-recommended rapid tests that simultaneously detect tuberculosis and rifampicin resistance in persons with signs and symptoms of tuberculosis, at lower health system levels. A previous Cochrane Review found Xpert MTB/RIF sensitive and specific for tuberculosis (Steingart 2014). Since the previous review, new studies have been published. We performed a review update for an upcoming WHO policy review. OBJECTIVES: To determine diagnostic accuracy of Xpert MTB/RIF and Xpert Ultra for tuberculosis in adults with presumptive pulmonary tuberculosis (PTB) and for rifampicin resistance in adults with presumptive rifampicin-resistant tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, to 11 October 2018, without language restriction. SELECTION CRITERIA: Randomized trials, cross-sectional, and cohort studies using respiratory specimens that evaluated Xpert MTB/RIF, Xpert Ultra, or both against the reference standard, culture for tuberculosis and culture-based drug susceptibility testing or MTBDRplus for rifampicin resistance. DATA COLLECTION AND ANALYSIS: Four review authors independently extracted data using a standardized form. When possible, we also extracted data by smear and HIV status. We assessed study quality using QUADAS-2 and performed meta-analyses to estimate pooled sensitivity and specificity separately for tuberculosis and rifampicin resistance. We investigated potential sources of heterogeneity. Most analyses used a bivariate random-effects model. For tuberculosis detection, we first estimated accuracy using all included studies and then only the subset of studies where participants were unselected, i.e. not selected based on prior microscopy testing. MAIN RESULTS: We identified in total 95 studies (77 new studies since the previous review): 86 studies (42,091 participants) evaluated Xpert MTB/RIF for tuberculosis and 57 studies (8287 participants) for rifampicin resistance. One study compared Xpert MTB/RIF and Xpert Ultra on the same participant specimen.Tuberculosis detectionOf the total 86 studies, 45 took place in high tuberculosis burden and 50 in high TB/HIV burden countries. Most studies had low risk of bias.Xpert MTB/RIF pooled sensitivity and specificity (95% credible Interval (CrI)) were 85% (82% to 88%) and 98% (97% to 98%), (70 studies, 37,237 unselected participants; high-certainty evidence). We found similar accuracy when we included all studies.For a population of 1000 people where 100 have tuberculosis on culture, 103 would be Xpert MTB/RIF-positive and 18 (17%) would not have tuberculosis (false-positives); 897 would be Xpert MTB/RIF-negative and 15 (2%) would have tuberculosis (false-negatives).Xpert Ultra sensitivity (95% confidence interval (CI)) was 88% (85% to 91%) versus Xpert MTB/RIF 83% (79% to 86%); Xpert Ultra specificity was 96% (94% to 97%) versus Xpert MTB/RIF 98% (97% to 99%), (1 study, 1439 participants; moderate-certainty evidence).Xpert MTB/RIF pooled sensitivity was 98% (97% to 98%) in smear-positive and 67% (62% to 72%) in smear-negative, culture-positive participants, (45 studies). Xpert MTB/RIF pooled sensitivity was 88% (83% to 92%) in HIV-negative and 81% (75% to 86%) in HIV-positive participants; specificities were similar 98% (97% to 99%), (14 studies).Rifampicin resistance detectionXpert MTB/RIF pooled sensitivity and specificity (95% Crl) were 96% (94% to 97%) and 98% (98% to 99%), (48 studies, 8020 participants; high-certainty evidence).For a population of 1000 people where 100 have rifampicin-resistant tuberculosis, 114 would be positive for rifampicin-resistant tuberculosis and 18 (16%) would not have rifampicin resistance (false-positives); 886 would be would be negative for rifampicin-resistant tuberculosis and four (0.4%) would have rifampicin resistance (false-negatives).Xpert Ultra sensitivity (95% CI) was 95% (90% to 98%) versus Xpert MTB/RIF 95% (91% to 98%); Xpert Ultra specificity was 98% (97% to 99%) versus Xpert MTB/RIF 98% (96% to 99%), (1 study, 551 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: We found Xpert MTB/RIF to be sensitive and specific for diagnosing PTB and rifampicin resistance, consistent with findings reported previously. Xpert MTB/RIF was more sensitive for tuberculosis in smear-positive than smear-negative participants and HIV-negative than HIV-positive participants. Compared with Xpert MTB/RIF, Xpert Ultra had higher sensitivity and lower specificity for tuberculosis and similar sensitivity and specificity for rifampicin resistance (1 study). Xpert MTB/RIF and Xpert Ultra provide accurate results and can allow rapid initiation of treatment for multidrug-resistant tuberculosis.

Improving the design of studies evaluating the impact of diagnostic tests for tuberculosis on health outcomes: a qualitative study of perspectives of diverse stakeholders.

Background: Studies evaluating the impact of Xpert MTB/RIF testing for tuberculosis (TB) have demonstrated varied effects on health outcomes with many studies showing inconclusive results. We explored perceptions among diverse stakeholders about studies evaluating the impact of TB diagnostic tests, and identified suggestions for improving these studies. Methods: We used purposive sampling with consideration for differing expertise and geographical balance and conducted in depth semi-structured interviews. We interviewed English-speaking participants, including TB patients, and others involved in research, care or decision-making about TB diagnostics. We used the thematic approach to code and analyse the interview transcripts. Results: We interviewed 31 participants. Our study showed that stakeholders had different expectations with regard to test impact and how it is measured. TB test impact studies were perceived to be important for supporting implementation of tests but there were concerns about the unrealistic expectations placed on tests to improve outcomes in health systems with many influencing factors. To improve TB test impact studies, respondents suggested conducting health system assessments prior to the study; developing clear guidance on the study methodology and interpretation; improving study design by describing questions and interventions that consider the influences of the health-care ecosystem on the diagnostic test; selecting the target population at the health-care level most likely to benefit from the test; setting realistic targets for effect sizes in the sample size calculations; and interpreting study results carefully and avoiding categorisation and interpretation of results based on statistical significance alone. Researchers should involve multiple stakeholders in the design of studies. Advocating for more funding to support robust studies is essential. Conclusion: TB test impact studies were perceived to be important to support implementation of tests but there were concerns about their complexity. Process evaluations of their health system context and guidance for their design and interpretation are recommended.

Variation in the observed effect of Xpert MTB/RIF testing for tuberculosis on mortality: A systematic review and analysis of trial design considerations.

Background: Most studies evaluating the effect of Xpert MTB/RIF testing for tuberculosis (TB) concluded that it did not reduce overall mortality compared to usual care. We conducted a systematic review to assess whether key study design and execution features contributed to earlier identification of patients with TB and decreased pre-treatment loss to follow-up, thereby reducing the potential impact of Xpert MTB/RIF testing. Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Scopus for literature published from 1 st January 2009 to February 2019. We included all primary intervention studies that had evaluated the effect of Xpert MTB/RIF on mortality compared to usual care in participants with presumptive pulmonary TB. We critically reviewed features of included studies across: Study setting and context, Study population, Participant recruitment and enrolment, Study procedures, and Study follow-up. Results: We included seven randomised and one non-randomised study.  All included studies demonstrated relative reductions in overall mortality in the Xpert MTB/RIF arm ranging from 6% to 40%. However, mortality reduction was reported to be statistically significant in two studies. Study features that could explain the lack of observed effect on mortality included: the higher quality of care at study sites; inclusion of patients with a higher pre-test probability of TB leading to higher than expected empirical rates; performance of additional diagnostic testing not done in usual care leading to increased TB diagnosis or empiric treatment initiation; the recruitment of participants likely to return for follow-up; and involvement of study staff in ensuring adherence with care and follow-up. Conclusion: Most studies of Xpert MTB/RIF were designed and conducted in a manner that resulted in more patients being diagnosed and treated for TB, minimising the potential difference in mortality Xpert MTB/RIF testing could have achieved compared to usual care.

Standard echocardiography versus handheld echocardiography for the detection of subclinical rheumatic heart disease: protocol for a systematic review.

INTRODUCTION: Rheumatic heart disease (RHD) is a preventable and treatable chronic condition which persists in many developing countries largely affecting impoverished populations. Handheld echocardiography presents an opportunity to address the need for more cost-effective methods of diagnosing RHD in developing countries, where the disease continues to carry high rates of morbidity and mortality. Preliminary studies have demonstrated moderate sensitivity as well as high specificity and diagnostic odds for detecting RHD in asymptomatic patients. We describe a protocol for a systematic review on the diagnostic performance of handheld echocardiography compared to standard echocardiography using the 2012 World Heart Federation criteria for diagnosing subclinical RHD. METHODS AND ANALYSIS: Electronic databases including PubMed, Scopus, Web of Science and EBSCOhost as well as reference lists and citations of relevant articles will be searched from 2012 to date using a predefined strategy incorporating a combination of Medical Subject Heading terms and keywords. The methodological validity and quality of studies deemed eligible for inclusion will be assessed against review specific Quality Assessment of Diagnostic Accuracy Studies 2 criteria and information on metrics of diagnostic accuracy and demographics extracted. Forest plots of sensitivity and specificity as well as scatter plots in receiver operating characteristic (ROC) space will be used to investigate heterogeneity. If possible, a meta-analysis will be conducted to produce summary results of sensitivity and specificity using the Hierarchical Summary ROC method. In addition, a sensitivity analysis will be conducted to investigate the effect of studies with a high risk of bias. ETHICS AND DISSEMINATION: Ethics approval is not required for this systematic review of previously published literature. The planned review will provide a summary of the diagnostic accuracy of handheld echocardiography. Results may feed into evidence-based guidelines and should the findings of this review warrant a change in clinical practice, a summary report will be disseminated among leading clinicians and healthcare professionals in the field. PROSPERO REGISTRATION NUMBER: CRD42016051261.

A systematic review of the efficacy and safety of intrapericardial fibrinolysis in patients with pericardial effusion.

Pericardial effusion is the abnormal accumulation of fluid in the pericardial space. The complications of pericardial effusion can either be acute (e.g., cardiac tamponade) or chronic (e.g., constrictive pericarditis). We have conducted a systematic review of the scientific literature to evaluate the efficacy and safety of intrapericardial fibrinolysis in preventing complications of pericardial effusion. We searched for both published and unpublished studies. 29 studies, with a total of 109 patients were included in this review; 17 case reports, 11 case series, and one randomised controlled trial (RCT). All included studies had a high risk of bias. The most common causes of pericardial effusion were Staphylococcus aureus (12 studies with 23 cases) and Mycobacterium tuberculosis (2 studies with 19 cases). The most common fibrinolytic agents used were streptokinase (15 studies) and urokinase (5 studies). Intrapericardial fibrinolysis prevented complications in 94 (86.2%) patients. Non-fatal procedure-related complications were reported 21 (19.2%) patients. No patient died following intrapericardial fibrinolysis. There is very low certainty of the efficiency and safety of intrapericardial fibrinolysis in preventing the complications of pericardial effusion. High quality RCTs are required to address this question.

The efficacy and safety of complete pericardial drainage by means of intrapericardial fibrinolysis for the prevention of complications of pericardial effusion: a systematic review protocol.

INTRODUCTION: Intrapericardial fibrinolysis has been proposed as a means of preventing complications of pericardial effusion such as cardiac tamponade, persistent and recurrent pericardial effusion, and pericardial constriction. There is a need to understand the efficacy and safety of this procedure because it shows promise. METHODS AND ANALYSIS: We aim to assess the effects of intrapericardial fibrinolysis in the treatment of pericardial effusion. We will search PubMed, the Cochrane Library, African Journals online, Cumulative Index to Nursing and Allied Health Literature, Trip database, Clinical trials.gov and the WHO International Clinical Trials Registry Platform for studies that evaluate the efficacy and/or safety of complete pericardial fluid drainage by intrapericardial fibrinolysis irrespective of study design, geographical location, language, age of participants, aetiology of pericarditis or types of fibrinolytics. Two authors will do the search independently, screen the search outputs for potentially eligible studies and assess whether the studies meet the inclusion criteria. Discrepancies between the two authors will be resolved through discussion and arbitration by a third author. Data from the selected studies shall be extracted using a standardised data collection form which will be piloted before use. The methodological quality of studies will be assessed using the Cochrane Collaboration's tools for assessing risk of bias for experimental studies and non-randomised studies, respectively. The primary meta-analysis will use random effects models due to expected interstudy heterogeneity. Dichotomous data will be analysed using relative risk and continuous with data mean differences, both with 95% CIs. ETHICS AND DISSEMINATION: Approval by an ethics committee is not required for this study as it is a protocol for a systematic review of published studies. The results will be disseminated through a conference presentation and peer-reviewed publication. REVIEW REGISTRATION NUMBER: PROSPERO, CRD42014015238.

Assessing variability in results in systematic reviews of diagnostic studies.

BACKGROUND: To describe approaches used in systematic reviews of diagnostic test accuracy studies for assessing variability in estimates of accuracy between studies and to provide guidance in this area. METHODS: Meta-analyses of diagnostic test accuracy studies published between May and September 2012 were systematically identified. Information on how the variability in results was investigated was extracted. RESULTS: Of the 53 meta-analyses included in the review, most (n=48; 91%) presented variability in diagnostic accuracy estimates visually either through forest plots or ROC plots and the majority (n=40; 75%) presented a test or statistical measure for the variability. Twenty-eight reviews (53%) tested for variability beyond chance using Cochran's Q test and 31 (58%) reviews quantified it with I(2). 7 reviews (13%) presented between-study variance estimates (τ(2)) from random effects models and 3 of these presented a prediction interval or ellipse to facilitate interpretation. Half of all the meta-analyses specified what was considered a significant amount of variability (n=24; 49%). CONCLUSIONS: Approaches to assessing variability in estimates of accuracy varied widely between diagnostic test accuracy reviews and there is room for improvement. We provide initial guidance, complemented by an overview of the currently available approaches.

Small-study effects and time trends in diagnostic test accuracy meta-analyses: a meta-epidemiological study.

BACKGROUND: Small-study effects and time trends have been identified in meta-analyses of randomized trials. We evaluated whether these effects are also present in meta-analyses of diagnostic test accuracy studies. METHODS: A systematic search identified test accuracy meta-analyses published between May and September 2012. In each meta-analysis, the strength of the associations between estimated accuracy of the test (diagnostic odds ratio (DOR), sensitivity, and specificity) and sample size and between accuracy estimates and time since first publication were evaluated using meta-regression models. The regression coefficients over all meta-analyses were summarized using random effects meta-analysis. RESULTS: Forty-six meta-analyses and their corresponding primary studies (N = 859) were included. There was a non-significant relative change in the DOR of 1.01 per 100 additional participants (95% CI 1.00 to 1.03; P = 0.07). In the subgroup of imaging studies, there was a relative increase in sensitivity of 1.13 per 100 additional diseased subjects (95% CI 1.05 to 1.22; P = 0.002). The relative change in DOR with time since first publication was 0.94 per 5 years (95% CI 0.80 to 1.10; P = 0.42). Sensitivity was lower in studies published later (relative change 0.89, 95% CI 0.80 to 0.99; P = 0.04). CONCLUSIONS: Small-study effects and time trends do not seem to be as pronounced in meta-analyses of test accuracy studies as they are in meta-analyses of randomized trials. Small-study effects seem to be reversed in imaging, where larger studies tend to report higher sensitivity.

Circulating antigen tests and urine reagent strips for diagnosis of active schistosomiasis in endemic areas.

BACKGROUND: Point-of-care (POC) tests for diagnosing schistosomiasis include tests based on circulating antigen detection and urine reagent strip tests. If they had sufficient diagnostic accuracy they could replace conventional microscopy as they provide a quicker answer and are easier to use. OBJECTIVES: To summarise the diagnostic accuracy of: a) urine reagent strip tests in detecting active Schistosoma haematobium infection, with microscopy as the reference standard; and b) circulating antigen tests for detecting active Schistosoma infection in geographical regions endemic for Schistosoma mansoni or S. haematobium or both, with microscopy as the reference standard. SEARCH METHODS: We searched the electronic databases MEDLINE, EMBASE, BIOSIS, MEDION, and Health Technology Assessment (HTA) without language restriction up to 30 June 2014. SELECTION CRITERIA: We included studies that used microscopy as the reference standard: for S. haematobium, microscopy of urine prepared by filtration, centrifugation, or sedimentation methods; and for S. mansoni, microscopy of stool by Kato-Katz thick smear. We included studies on participants residing in endemic areas only. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed quality of the data using QUADAS-2, and performed meta-analysis where appropriate. Using the variability of test thresholds, we used the hierarchical summary receiver operating characteristic (HSROC) model for all eligible tests (except the circulating cathodic antigen (CCA) POC for S. mansoni, where the bivariate random-effects model was more appropriate). We investigated heterogeneity, and carried out indirect comparisons where data were sufficient. Results for sensitivity and specificity are presented as percentages with 95% confidence intervals (CI). MAIN RESULTS: We included 90 studies; 88 from field settings in Africa. The median S. haematobium infection prevalence was 41% (range 1% to 89%) and 36% for S. mansoni (range 8% to 95%). Study design and conduct were poorly reported against current standards. Tests for S. haematobium Urine reagent test strips versus microscopyCompared to microscopy, the detection of microhaematuria on test strips had the highest sensitivity and specificity (sensitivity 75%, 95% CI 71% to 79%; specificity 87%, 95% CI 84% to 90%; 74 studies, 102,447 participants). For proteinuria, sensitivity was 61% and specificity was 82% (82,113 participants); and for leukocyturia, sensitivity was 58% and specificity 61% (1532 participants). However, the difference in overall test accuracy between the urine reagent strips for microhaematuria and proteinuria was not found to be different when we compared separate populations (P = 0.25), or when direct comparisons within the same individuals were performed (paired studies; P = 0.21).When tests were evaluated against the higher quality reference standard (when multiple samples were analysed), sensitivity was marginally lower for microhaematuria (71% vs 75%) and for proteinuria (49% vs 61%). The specificity of these tests was comparable. Antigen assayCompared to microscopy, the CCA test showed considerable heterogeneity; meta-analytic sensitivity estimate was 39%, 95% CI 6% to 73%; specificity 78%, 95% CI 55% to 100% (four studies, 901 participants). Tests for S. mansoni Compared to microscopy, the CCA test meta-analytic estimates for detecting S. mansoni at a single threshold of trace positive were: sensitivity 89% (95% CI 86% to 92%); and specificity 55% (95% CI 46% to 65%; 15 studies, 6091 participants) Against a higher quality reference standard, the sensitivity results were comparable (89% vs 88%) but specificity was higher (66% vs 55%). For the CAA test, sensitivity ranged from 47% to 94%, and specificity from 8% to 100% (4 studies, 1583 participants). AUTHORS' CONCLUSIONS: Among the evaluated tests for S. haematobium infection, microhaematuria correctly detected the largest proportions of infections and non-infections identified by microscopy.The CCA POC test for S. mansoni detects a very large proportion of infections identified by microscopy, but it misclassifies a large proportion of microscopy negatives as positives in endemic areas with a moderate to high prevalence of infection, possibly because the test is potentially more sensitive than microscopy.

Systematic overview finds variation in approaches to investigating and reporting on sources of heterogeneity in systematic reviews of diagnostic studies.

OBJECTIVES: To examine how authors explore and report on sources of heterogeneity in systematic reviews of diagnostic accuracy studies. STUDY DESIGN AND SETTING: A cohort of systematic reviews of diagnostic tests was systematically identified. Data were extracted on whether an exploration of the sources of heterogeneity was undertaken, how this was done, the number and type of potential sources explored, and how results and conclusions were reported. RESULTS: Of the 65 systematic reviews, 12 did not perform a meta-analysis and eight of these gave heterogeneity between studies as a reason. Of the 53 reviews containing a meta-analysis, 40 explored potential sources of heterogeneity in a formal manner and 27 identified at least one source of heterogeneity. The reviews not investigating heterogeneity were smaller than those that did (median [interquartile range {IQR}], 8 [5-15] vs. 14 [11-19] primary studies). Twelve reviews performed a sensitivity analysis, 25 stratified analyses, and 19 metaregression. Many sources of heterogeneity were explored compared with the number of primary studies in a meta-analysis (median ratio, 1:5). Review authors placed importance on the exploration of sources of heterogeneity; 37 mentioned the exploration or the findings thereof in the abstract or conclusion of the main text.results CONCLUSION: Methods for investigating sources of heterogeneity varied widely between reviews. Based on our findings of the review, we made suggestions on what to consider and report on when exploring sources of heterogeneity in systematic reviews of diagnostic studies.

Incorporating quality assessments of primary studies in the conclusions of diagnostic accuracy reviews: a cross-sectional study.

BACKGROUND: Drawing conclusions from systematic reviews of test accuracy studies without considering the methodological quality (risk of bias) of included studies may lead to unwarranted optimism about the value of the test(s) under study. We sought to identify to what extent the results of quality assessment of included studies are incorporated in the conclusions of diagnostic accuracy reviews. METHODS: We searched MEDLINE and EMBASE for test accuracy reviews published between May and September 2012. We examined the abstracts and main texts of these reviews to see whether and how the results of quality assessment were linked to the accuracy estimates when drawing conclusions. RESULTS: We included 65 reviews of which 53 contained a meta-analysis. Sixty articles (92%) had formally assessed the methodological quality of included studies, most often using the original QUADAS tool (n = 44, 68%). Quality assessment was mentioned in 28 abstracts (43%); with a majority (n = 21) mentioning it in the methods section. In only 5 abstracts (8%) were results of quality assessment incorporated in the conclusions. Thirteen reviews (20%) presented results of quality assessment in the main text only, without further discussion. Forty-seven reviews (72%) discussed results of quality assessment; the most frequent form was as limitations in assessing quality (n = 28). Only 6 reviews (9%) further linked the results of quality assessment to their conclusions, 3 of which did not conduct a meta-analysis due to limitations in the quality of included studies. In the reviews with a meta-analysis, 19 (36%) incorporated quality in the analysis. Eight reported significant effects of quality on the pooled estimates; in none of them these effects were factored in the conclusions. CONCLUSION: While almost all recent diagnostic accuracy reviews evaluate the quality of included studies, very few consider results of quality assessment when drawing conclusions. The practice of reporting systematic reviews of test accuracy should improve if readers not only want to be informed about the limitations in the available evidence, but also on the associated implications for the performance of the evaluated tests.