Performance of MPO-ANCA and PR3-ANCA immunoassays for the stratification of specific ANCA-associated vasculitis: A systematic review and meta-analysis.

OBJECTIVE: To determine the impact of myeloperoxidase (MPO) and proteinase 3 (PR3) antigen-specific immunoassays in the stratification of patients at-risk for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) at diagnosis. METHODS: A Medline search was conducted to identify diagnostic accuracy studies using PR3-ANCA or MPO-ANCA for the evaluation of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Studies estimates were pooled using the bivariate method. RESULTS: Diagnostic accuracy varied by analyte and AAV subtype. PR3-ANCA had greater sensitivity than MPO-ANCA for GPA (74% vs 11%, p < 0.001) and MPO-ANCA greater sensitivity for MPA (73% vs 7%, p < 0.001). Specificities of both MPO-ANCA and PR3-ANCA were consistently high (mean 97%, range: 93-99%) for both AAV subtypes. There was insufficient data to perform meta-analysis for the diagnostic accuracy of EPGA. CONCLUSION: These results validate the use of high quality MPO-ANCA and PR3-ANCA immunoassays to screen patients at-risk for AAV as well as to categorize disease as GPA or MPA subtype. However, caution must be exercised in doing so, since some assays may not have optimal performance. Each laboratory should validate appropriate algorithms based on the tests used and testing population.

(1→3)-ß-D-glucan testing for the detection of invasive fungal infections in immunocompromised or critically ill people.

BACKGROUND: Invasive fungal infections (IFIs) are life-threatening opportunistic infections that occur in immunocompromised or critically ill people. Early detection and treatment of IFIs is essential to reduce morbidity and mortality in these populations. (1→3)-ß-D-glucan (BDG) is a component of the fungal cell wall that can be detected in the serum of infected individuals. The serum BDG test is a way to quickly detect these infections and initiate treatment before they become life-threatening. Five different versions of the BDG test are commercially available: Fungitell, Glucatell, Wako, Fungitec-G, and Dynamiker Fungus. OBJECTIVES: To compare the diagnostic accuracy of commercially available tests for serum BDG to detect selected invasive fungal infections (IFIs) among immunocompromised or critically ill people. SEARCH METHODS: We searched MEDLINE (via Ovid) and Embase (via Ovid) up to 26 June 2019. We used SCOPUS to perform a forward and backward citation search of relevant articles. We placed no restriction on language or study design. SELECTION CRITERIA: We included all references published on or after 1995, which is when the first commercial BDG assays became available. We considered published, peer-reviewed studies on the diagnostic test accuracy of BDG for diagnosis of fungal infections in immunocompromised people or people in intensive care that used the European Organization for Research and Treatment of Cancer (EORTC) criteria or equivalent as a reference standard. We considered all study designs (case-control, prospective consecutive cohort, and retrospective cohort studies). We excluded case studies and studies with fewer than ten participants. We also excluded animal and laboratory studies. We excluded meeting abstracts because they provided insufficient information. DATA COLLECTION AND ANALYSIS: We followed the standard procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened studies, extracted data, and performed a quality assessment for each study. For each study, we created a 2 × 2 matrix and calculated sensitivity and specificity, as well as a 95% confidence interval (CI). We evaluated the quality of included studies using the Quality Assessment of Studies of Diagnostic Accuracy-Revised (QUADAS-2). We were unable to perform a meta-analysis due to considerable variation between studies, with the exception of Candida, so we have provided descriptive statistics such as receiver operating characteristics (ROCs) and forest plots by test brand to show variation in study results. MAIN RESULTS: We included in the review 49 studies with a total of 6244 participants. About half of these studies (24/49; 49%) were conducted with people who had cancer or hematologic malignancies. Most studies (36/49; 73%) focused on the Fungitell BDG test. This was followed by Glucatell (5 studies; 10%), Wako (3 studies; 6%), Fungitec-G (3 studies; 6%), and Dynamiker (2 studies; 4%). About three-quarters of studies (79%) utilized either a prospective or a retrospective consecutive study design; the remainder used a case-control design. Based on the manufacturer's recommended cut-off levels for the Fungitell test, sensitivity ranged from 27% to 100%, and specificity from 0% to 100%. For the Glucatell assay, sensitivity ranged from 50% to 92%, and specificity ranged from 41% to 94%. Limited studies have used the Dynamiker, Wako, and Fungitec-G assays, but individual sensitivities and specificities ranged from 50% to 88%, and from 60% to 100%, respectively. Results show considerable differences between studies, even by manufacturer, which prevented a formal meta-analysis. Most studies (32/49; 65%) had no reported high risk of bias in any of the QUADAS-2 domains. The QUADAS-2 domains that had higher risk of bias included participant selection and flow and timing. AUTHORS' CONCLUSIONS: We noted considerable heterogeneity between studies, and these differences precluded a formal meta-analysis. Because of wide variation in the results, it is not possible to estimate the diagnostic accuracy of the BDG test in specific settings. Future studies estimating the accuracy of BDG tests should be linked to the way the test is used in clinical practice and should clearly describe the sampling protocol and the relationship of time of testing to time of diagnosis.

Cost effectiveness of therapeutic drug monitoring for imatinib administration in chronic myeloid leukemia.

BACKGROUND: Imatinib mesylate (IM) is a first-line treatment option for patients with chronic myeloid leukemia (CML). Patients who fail or are intolerant to IM therapy are treated with more expensive second and third-generation tyrosine kinase inhibitors. Patients show wide variation in trough concentrations in response to standard dosing. Thus, many patients receive subtherapeutic or supratherapeutic doses. Therapeutic drug monitoring (TDM) may improve dose management that, in turn, may reduce costs and improve outcomes. However, TDM also adds to the cost of patient care. The objective of this study was to determine the cost-effectiveness of TDM for generic IM therapy. METHODS: We developed a microsimulation model for the trough plasma concentration of IM which is related to a cytogenetic or molecular response. We compared two cohorts: one with TDM and one without TDM (NTDM). The lifetime incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life years (QALYs) as the effectiveness measure. One-way and probabilistic sensitivity analyses were performed. RESULTS: The lifetime cost and QALY of treatment with TDM were $2,137K [95% Ci: 2,079K; 2,174K] and 12.37 [95% CI: 12.07; 12.55], respectively. The cost and QALY of NTDM were $2,132K [95% CI: 2,091K; 2,197K] and 12.23 [95% CI: 11.96; 12.50], respectively. The incremental cost and QALY for TDM relative to NTDM was $4,417 [95% CI: -52,582; 32,097]) and 0.15 [95% CI: -0.13; 0.28]. The ICER for TDM relative to NTDM was $30,450/QALY. Probabilistic sensitivity analysis showed that TDM was cost-effective relative to NTDM in 90% of the tested scenarios at a willingness-to-pay threshold of $100,000/QALY. CONCLUSIONS: Although the impact of TDM is modest, the cost-effectiveness over a lifetime horizon (societal perspective, ($30,450/QALY) falls within the acceptable range (< $100k/QALY).

Cost-effectiveness of antifungal prophylaxis, preemptive therapy, or empiric treatment following allogeneic hematopoietic stem cell transplant.

BACKGROUND: Invasive fungal infection (IFI) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is also associated with excess healthcare costs. Current approaches include universal antifungal prophylaxis, preemptive therapy based on biomarker surveillance, and empiric treatment initiated in response to clinical signs/symptoms. However, no study has directly compared the cost-effectiveness of these treatment strategies for an allogeneic HSCT patient population. METHODS: We developed a state transition model to study the impact of treatment strategies on outcomes associated with IFIs in the first 100 days following myeloablative allogeneic HSCT. We compared three treatment strategies: empiric voriconazole, preemptive voriconazole (200 mg), or prophylactic posaconazole (300 mg) for the management of IFIs. Preemptive treatment was guided by scheduled laboratory surveillance with galactomannan (GM) testing. Endpoints were cost and survival at 100 days post-HSCT. RESULTS: Empiric treatment was the least costly ($147 482) and was equally effective (85.2% survival at 100 days) as the preemptive treatment strategies. Preemptive treatments were slightly more costly than empiric treatment (GM cutoff ≥ 1.0 $147 910 and GM cutoff ≥ 0.5 $148 108). Preemptive therapy with GM cutoff ≥ 1.0 reduced anti-mold therapy by 5% when compared to empiric therapy. Posaconazole prophylaxis was the most effective (86.6% survival at 100 days) and costly ($152 240) treatment strategy with a cost of $352 415 per life saved when compared to empiric therapy. CONCLUSIONS: One preemptive treatment strategy reduced overall anti-mold drug exposure but did not reduce overall costs. Prevention of IFI using posaconazole prophylaxis was the most effective treatment strategy and may be cost-effective, depending upon the willingness to pay per life saved.

Diagnostic Accuracy of ß-d-Glucan (Fungitell) Testing Among Patients With Hematologic Malignancies or Solid Organ Tumors: A Systematic Review and Meta-Analysis.

Objectives: To determine the accuracy of Fungitell, a ß-d-glucan (BDG) test, for the diagnosis of invasive fungal infection (IFI) among cancer patients. Methods: For this meta-analysis, MEDLINE and EMBASE were searched for references related to BDG testing. Study quality was evaluated using QUADAS-2. Statistical analysis was performed using Stata 14. Results: We screened 12,426 references and identified 189 studies for full-text review. Nineteen studies were included in the final meta-analysis. There was moderate heterogeneity between studies. Nine studies had a high risk of bias, which significantly elevated the overall specificity estimate. Restricting to only low-bias studies, the sensitivity and specificity were 80% and 63%, respectively. Conclusions: The overall sensitivity and specificity of Fungitell as a diagnostic test for IFI is moderate, and there is substantial heterogeneity between studies. Limiting studies to only low-bias risk reduced heterogeneity but also lowered the overall specificity estimate.

Diagnostic Accuracy of Fine-Needle Aspiration Cytology for Discrimination of Squamous Cell Carcinoma from Adenocarcinoma in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: To determine the accuracy with which morphology alone can distinguish adenocarcinoma and squamous cell carcinoma in non-small cell lung cancer. METHODS: We performed a systematic review and meta-analysis. Three data bases (MEDLINE, EMBASE, Scopus) were searched for studies on the diagnostic accuracy of subtyping non-small cell lung cancer. Accuracy data was abstracted and synthesized using bivariate mixed effects logistic regression as implemented in the midas package in Stata 14. Heterogeneity was assessed using the Higgins I2. RESULTS: We included 17 studies (2,235 cases). Most studies had a low risk of bias. The pooled diagnostic accuracy for cytological diagnosis of adenocarcinoma resulted in a sensitivity of 63% (48-76%) and specificity of 95% (87-98%). The I2 values were 93 and 88% for sensitivity and specificity, respectively. The pooled diagnostic accuracy for the cytological diagnosis of squamous cell carcinoma resulted in a sensitivity of 84% (79-88%) and a specificity of 90% (84-94%). The I2 values were 69 and 86% for sensitivity and specificity, respectively. CONCLUSION: Accuracy varies widely by study and summary estimates do not provide a useful representation of accuracy. Squamous cell carcinoma was diagnosed more accurately than adenocarcinoma.

Rapid On-Site Evaluation of Fine-Needle Aspiration by Non-Cytopathologists: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies for Adequacy Assessment.

OBJECTIVE: Rapid on-site evaluation (ROSE) has been shown to improve adequacy rates and reduce needle passes. ROSE is often performed by cytopathologists who have limited availability and may be costlier than alternatives. Several recent studies examined the use of alternative evaluators (AEs) for ROSE. A summary of this information could help inform guidelines regarding the use of AEs. The objective was to assess the accuracy of AEs compared to cytopathologists in assessing the adequacy of specimens during ROSE. STUDY DESIGN: This was a systematic review and meta-analysis. Reporting and study quality were assessed using the STARD guidelines and QUADAS-2. All steps were performed independently by two evaluators. Summary estimates were obtained using the hierarchal method in Stata v14. Heterogeneity was evaluated using Higgins' I2 statistic. RESULTS: The systematic review identified 13 studies that were included in the meta-analysis. Summary estimates of sensitivity and specificity for AEs were 97% (95% CI: 92-99%) and 83% (95% CI: 68-92%). There was wide variation in accuracy statistics between studies (I2 = 0.99). CONCLUSIONS: AEs sometimes have accuracy that is close to cytopathologists. However, there is wide variability between studies, so it is not possible to provide a broad guideline regarding the use of AEs.

Benchmarking to Identify Practice Variation in Test Ordering: A Potential Tool for Utilization Management.

BACKGROUND: Appropriate test utilization is usually evaluated by adherence to published guidelines. In many cases, medical guidelines are not available. Benchmarking has been proposed as a method to identify practice variations that may represent inappropriate testing. This study investigated the use of benchmarking to identify sites with inappropriate utilization of testing for a particular analyte. METHODS: We used a Web-based survey to compare 2 measures of vitamin D utilization: overall testing intensity (ratio of total vitamin D orders to blood-count orders) and relative testing intensity (ratio of 1,25(OH)2D to 25(OH)D test orders). RESULTS: A total of 81 facilities contributed data. The average overall testing intensity index was 0.165, or approximately 1 vitamin D test for every 6 blood-count tests. The average relative testing intensity index was 0.055, or one 1,25(OH)2D test for every 18 of the 25(OH)D tests. Both indexes varied considerably. CONCLUSIONS: Benchmarking can be used as a screening tool to identify outliers that may be associated with inappropriate test utilization.

When Is Rapid On-Site Evaluation Cost-Effective for Fine-Needle Aspiration Biopsy?

BACKGROUND: Rapid on-site evaluation (ROSE) can improve adequacy rates of fine-needle aspiration biopsy (FNAB) but increases operational costs. The performance of ROSE relative to fixed sampling depends on many factors. It is not clear when ROSE is less costly than sampling with a fixed number of needle passes. The objective of this study was to determine the conditions under which ROSE is less costly than fixed sampling. METHODS: Cost comparison of sampling with and without ROSE using mathematical modeling. Models were based on a societal perspective and used a mechanistic, micro-costing approach. Sampling policies (ROSE, fixed) were compared using the difference in total expected costs per case. Scenarios were based on procedure complexity (palpation-guided or image-guided), adequacy rates (low, high) and sampling protocols (stopping criteria for ROSE and fixed sampling). One-way, probabilistic, and scenario-based sensitivity analysis was performed to determine which variables had the greatest influence on the cost difference. RESULTS: ROSE is favored relative to fixed sampling under the following conditions: (1) the cytologist is accurate, (2) the total variable cost ($/hr) is low, (3) fixed costs ($/procedure) are high, (4) the setup time is long, (5) the time between needle passes for ROSE is low, (6) when the per-pass adequacy rate is low, and (7) ROSE stops after observing one adequate sample. The model is most sensitive to variation in the fixed cost, the per-pass adequacy rate, and the time per needle pass with ROSE. CONCLUSIONS: Mathematical modeling can be used to predict the difference in cost between sampling with and without ROSE.

Verification and classification bias interactions in diagnostic test accuracy studies for fine-needle aspiration biopsy.

BACKGROUND: Reliable estimates of accuracy are important for any diagnostic test. Diagnostic accuracy studies are subject to unique sources of bias. Verification bias and classification bias are 2 sources of bias that commonly occur in diagnostic accuracy studies. Statistical methods are available to estimate the impact of these sources of bias when they occur alone. The impact of interactions when these types of bias occur together has not been investigated. METHODS: We developed mathematical relationships to show the combined effect of verification bias and classification bias. A wide range of case scenarios were generated to assess the impact of bias components and interactions on total bias. RESULTS: Interactions between verification bias and classification bias caused overestimation of sensitivity and underestimation of specificity. Interactions had more effect on sensitivity than specificity. Sensitivity was overestimated by at least 7% in approximately 6% of the tested scenarios. Specificity was underestimated by at least 7% in less than 0.1% of the scenarios. CONCLUSIONS: Interactions between verification bias and classification bias create distortions in accuracy estimates that are greater than would be predicted from each source of bias acting independently.

Rapid on-site evaluation reduces needle passes in endoscopic ultrasound-guided fine-needle aspiration for solid pancreatic lesions: a risk-benefit analysis.

BACKGROUND: The effectiveness of endoscopic ultrasound-guided fine-needle aspiration increases with the number of needle passes but needle passes are also associated with increased risk of adverse events. The trade-off between needle passes and adequacy has not been well-characterized. AIMS: The purpose of this study was to compare the risk-benefit tradeoff of different sampling protocols with and without rapid onsite evaluation (ROSE). PATIENTS AND METHODS: We used a discrete-event simulation model to compare eight different sampling protocols. Each sampling protocol was simulated 10,000 times to obtain the average performance for each scenario. The per-pass adequacy rates, ROSE, accuracy of the assessor and sampling limits were varied to determine the impact of these factors on the number of needle passes and adequacy rates. RESULTS: Increasing per-class adequacy can be achieved at a cost of increased needle passes. Sampling with ROSE achieved higher adequacy with fewer needle passes than policies using a fixed number of needle passes without ROSE. CONCLUSIONS: Variable sampling policies using ROSE generally achieve greater per-case adequacy with fewer needle passes than non-ROSE sampling policies using a fixed number of passes.