Evidence Synthesis and Linkage for Modelling the Cost-Effectiveness of Diagnostic Tests: Preliminary Good Practice Recommendations.

OBJECTIVES: To develop preliminary good practice recommendations for synthesising and linking evidence of treatment effectiveness when modelling the cost-effectiveness of diagnostic tests. METHODS: We conducted a targeted review of guidance from key Health Technology Assessment (HTA) bodies to summarise current recommendations on synthesis and linkage of treatment effectiveness evidence within economic evaluations of diagnostic tests. We then focused on a specific case study, the cost-effectiveness of troponin for the diagnosis of myocardial infarction, and reviewed the approach taken to synthesise and link treatment effectiveness evidence in different modelling studies. RESULTS: The Australian and UK HTA bodies provided advice for synthesising and linking treatment effectiveness in diagnostic models, acknowledging that linking test results to treatment options and their outcomes is common. Across all reviewed models for the case study, uniform test-directed treatment decision making was assumed, i.e., all those who tested positive were treated. Treatment outcome data from a variety of sources, including expert opinion, were utilised for linked clinical outcomes. Preliminary good practice recommendations for data identification, integration and description are proposed. CONCLUSION: Modelling the cost-effectiveness of diagnostic tests poses unique challenges in linking evidence on test accuracy to treatment effectiveness data to understand how a test impacts patient outcomes and costs. Upfront consideration of how a test and its results will likely be incorporated into patient diagnostic pathways is key to exploring the optimal design of such models. We propose some preliminary good practice recommendations to improve the quality of cost-effectiveness evaluations of diagnostics tests going forward.

Assessing the potential cost-effectiveness of centralised versus point-of-care testing for hepatitis C virus in Pakistan: a model-based comparison.

OBJECTIVES: Pakistan has a hepatitis C virus (HCV) infection prevalence of 6%-9% and aims to achieve World Health Organisation (WHO) targets for elimination of HCV by the year 2030. We aim to evaluate the potential cost-effectiveness of a reference laboratory-based (centralised laboratory testing; CEN) confirmatory testing approach versus a molecular near-patient point-of-care (POC) confirmatory approach to screen the general population for HCV in Pakistan. STUDY DESIGN: We used a decision tree-analytic model from a governmental (formal healthcare sector) perspective. STUDY SETTING: Individuals were assumed to be initially screened with an anti-HCV test at home, followed by POC nucleic acid test (NAT) at nearby district hospitals or followed by NAT at centralised laboratories. PARTICIPANTS: We included the general testing population for chronic HCV in Pakistan. INTERVENTION: Screening with an anti-HCV antibody test (Anti-HCV) followed by either POC NAT (Anti-HCV-POC), or reference laboratory NAT (Anti-HCV-CEN), was compared, using data from published literature and the Pakistan Ministry of Health. MEASURES: Outcome measures included: number of HCV infections identified per year, percentage of individuals correctly classified, total costs, average costs per individual tested, and cost-effectiveness (assessed as cost per additional HCV infection identified). Sensitivity analysis was also performed. RESULTS: At a national level (25 million annual screening tests), the Anti-HCV-CEN strategy would identify 142 406 more HCV infections in 1 year and increase correct classification of individuals by 0.57% compared with the Anti-HCV-POC strategy. The total annual cost of HCV testing was reduced using the Anti-HCV-CEN strategy by US$7.68 million (US$0.31/person). Thus, incrementally, the Anti-HCV-CEN strategy costs less and identifies more HCV infections than Anti-HCV-POC. The incremental difference in HCV infections identified was most sensitive to the probability of loss to follow-up (for POC confirmatory NAT). CONCLUSIONS: Anti-HCV-CEN would provide the best value for money when scaling up HCV testing in Pakistan.

Outpatient Antibiotic and Antiviral Utilization Patterns in Patients Tested for Respiratory Pathogens in the United States: A Real-World Database Study.

This retrospective observational study evaluated outpatient treatment patterns among patients with molecular-based viral diagnostic testing for suspected upper respiratory tract infections in the United States. Patients with a respiratory viral test were identified from 1 August 2016 to 1 July 2019 in a large national reference laboratory database linked to IQVIA's prescription and medical claims databases. Antibiotic and influenza antiviral treatment patterns were reported up to 7 days post-test result. Predictors of antibiotic utilization were assessed using multivariable logistic regression. Among 9561 patients included in the study, 24.6% had evidence of ≥1 filled antibiotic prescription. Antibiotic utilization was higher in patients who tested negative for all viral targets (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.17-1.50) and patients positive for non-influenza viruses (OR, 1.28; 95% CI, 1.09-1.51) compared with those influenza-positive only. Age ≥ 50 years and location outside of the northeast United States also predicted antibiotic utilization. Influenza antivirals were more common in influenza-positive patients compared with patients with other test results (32.5% vs. 3.6-9.0%). Thus, in this real-world study, antibiotic utilization was elevated in patients positive for non-influenza viruses, although antibiotics would generally not be indicated. Further research on pairing diagnostic tools with outpatient antibiotic stewardship programs is needed.

Real-world HIV diagnostic testing patterns in the United States.

OBJECTIVES: To understand real-world implementation of the updated CDC HIV diagnostic testing algorithm. STUDY DESIGN: Retrospective database analysis. METHODS: Using data from Quest Diagnostics, we identified patients with at least 1 HIV-1/HIV-2 antibody differentiation test (BioRad Geenius HIV 1/2 Supplemental Assay [Geenius]) between January 1 and December 31, 2017. Study measures included Health Insurance Portability and Accountability Act-compliant patient demographics, test results, test frequency, and sequence relative to the CDC HIV diagnostic algorithm, including HIV-1 RNA Qualitative Assay (Aptima) or HIV-2 nucleic acid test (NAT). RESULTS: A total of 26,319 patients were identified (mean [SD] age, 40.7 [14.3] years; 66.4% male), with 28,954 Geenius tests, 7234 Aptima tests, and 298 HIV-2 NATs. In 26.4% of test sequences, the Geenius results were indeterminate or negative and required subsequent confirmatory NATs. A total of 8.5% of patients had more than 1 Geenius test in 2017, and 11.2% of the time, results of the first and second tests differed. A total of 74.2% of test sequences matched the CDC-recommended algorithm. CONCLUSIONS: Our study findings suggest that the CDC HIV diagnostic algorithm is complex and may pose suboptimal testing efficiency. Opportunities to improve diagnostic efficiency by reducing indeterminate results and repeat tests are warranted.

US cost-effectiveness and budget impact of point-of-care NAAT for streptococcus.

OBJECTIVES: In the United States, approximately 12 million individuals seek medical care for pharyngitis each year, accounting for about 2% of ambulatory care visits. Although the gold standard for diagnosing group A streptococcus (GAS) is culture, it is time intensive. Rapid antigen detection tests (RADT) with or without culture confirmation are commonly used instead. Although RADT provide results quickly, they generally have lower test sensitivity. Recently, point-of-care nucleic acid amplification tests (POC NAAT) have emerged. This study evaluates the cost-effectiveness and budget impact to the US payer of adopting POC NAAT. STUDY DESIGN: This study was a cost-effectiveness analysis, with costs and outcomes calculated via a decision tree. METHODS: A decision-tree model quantified costs and outcomes associated with a GAS diagnostic strategy using POC NAAT compared with RADT + culture confirmation. Model inputs were derived from the published literature. Model outputs included costs and clinical effects: quality-adjusted life-days lost, GAS and antibiotic complications, number of patients appropriately treated, and antibiotic utilization. Sensitivity and scenario analyses were performed. RESULTS: Base-case analysis projected that a POC NAAT strategy would cost $44 per patient compared with $78 for RADT + culture. Compared with RADT + culture, POC NAAT would increase the number of appropriately treated patients and avert unnecessary use of antibiotics. The budget impact of POC NAAT was -0.4% relative to current budget over 5 years. Findings were robust in sensitivity analyses. CONCLUSIONS: Our results suggest that POC NAAT would be less costly and more effective than RADT + culture; POC NAAT adoption may yield cost savings to US third-party payers. Access to POC NAAT is important to optimize GAS diagnosis and treatment decisions in the United States.

Rapid Replacement of Acinetobacter baumannii Strains Accompanied by Changes in Lipooligosaccharide Loci and Resistance Gene Repertoire.

The population structure of health care-associated pathogens reflects patterns of diversification, selection, and dispersal over time. Empirical data detailing the long-term population dynamics of nosocomial pathogens provide information about how pathogens adapt in the face of exposure to diverse antimicrobial agents and other host and environmental pressures and can inform infection control priorities. Extensive sequencing of clinical isolates from one hospital spanning a decade and a second hospital in the Cleveland, OH, metropolitan area over a 3-year time period provided high-resolution genomic analysis of the Acinetobacter baumannii metapopulation. Genomic analysis demonstrated an almost complete replacement of the predominant strain groups with a new, genetically distinct strain group during the study period. The new group, termed clade F, differs from other global clone 2 (GC2) strains of A. baumannii in several ways, including its antibiotic resistance and lipooligosaccharide biosynthesis genes. Clade F strains are part of a large phylogenetic group with broad geographic representation. Phylogenetic analysis of single-nucleotide variants in core genome regions showed that although the Cleveland strains are phylogenetically distinct from those isolated from other locations, extensive intermixing of strains from the two hospital systems was apparent, suggesting either substantial exchange of strains or a shared, but geographically restricted, external pool from which infectious isolates were drawn. These findings document the rapid evolution of A. baumannii strains in two hospitals, with replacement of the predominant clade by a new clade with altered lipooligosaccharide loci and resistance gene repertoires.IMPORTANCE Multidrug-resistant (MDR) A. baumannii is a difficult-to-treat health care-associated pathogen. Knowing the resistance genes present in isolates causing infection aids in empirical treatment selection. Furthermore, knowledge of the genetic background can assist in tracking patterns of transmission to limit the spread of infections in hospitals. The appearance of a new genetic background in A. baumannii strains with a different set of resistance genes and cell surface structures suggests that strong selective pressures exist, even in highly MDR pathogens. Because the new strains have levels of antimicrobial resistance similar to those of the strains that were displaced, we hypothesize that other features, including host colonization and infection, may confer additional selective advantages and contribute to their increased prevalence.

Evaluation of Sensititre Broth Microdilution Plate for determining the susceptibility of carbapenem-resistant Klebsiella pneumoniae to polymyxins.

Colistin and polymyxin B MICs were determined for 106 carbapenem-resistant Klebsiella pneumoniae (CR-Kp) isolates using Sensititre Research Use Only GNX2F plates (Thermo Fisher) and compared to CLSI broth macrodilution (BMD) as the reference method. For colistin, EUCAST breakpoints were applied and testing of isolates with very major (VM) errors was repeated in duplicate by both methods to determine a majority result. Essential agreement (MIC ± one dilution) of GNX2F with the reference method was 97.1% for polymyxin B and 92.5% for colistin (7 VM errors, 22.6%). After discrepancy testing, there were 28 colistin resistant isolates by BMD and essential agreement was 94.3% with 4 VM errors (14.3%). Colistin and polymyxin B GNX2F results showed acceptable essential agreement with BMD for MICS without interpretation. Colistin VM errors with EUCAST breakpoints were due to MIC variability in the 2 to 4 µg/mL range that could be addressed by establishing an intermediate category.

Hemolytic strains of Propionibacterium acnes do not demonstrate greater pathogenicity in periprosthetic shoulder infections.

BACKGROUND: Hemolysis has been suggested as a feature conferring increased pathogenicity to certain Propionibacterium acnes strains in the setting of shoulder infection. The purpose of this study was to compare the virulence of hemolytic and nonhemolytic P acnes strains in patients undergoing revision shoulder arthroplasty. METHODS: Thirty-nine patients with at least 1 positive culture growth for P acnes at the time of revision surgery were identified with P acnes isolates available for hemolysis testing. Patients were grouped into those with P acnes isolates positive (n = 20) and negative (n = 19) for hemolysis. The groups were retrospectively compared based on objective perioperative findings around the time of revision surgery and the postoperative clinical course, including the need for revision surgery. All cases were classified into categories of infection (definite infection, probable infection, and probable contaminant) based on objective perioperative criteria. RESULTS: The presence of hemolysis was not significantly associated with an increased likelihood of infection (P = .968). Hemolysis demonstrated a 75% sensitivity and 26% specificity for determining infection (definite infection and probable infection categories). The hemolytic and nonhemolytic groups showed no difference regarding preoperative serum erythrocyte sedimentation rate and/or C-reactive protein level (P = .70), number of positive cultures (P = .395), time to positive culture (P = .302), and presence of positive frozen section findings (P = .501). Postoperatively, clindamycin resistance, shoulder function, and the rate of reoperation were not significantly different between the hemolytic and nonhemolytic groups. CONCLUSION: The presence of hemolysis was not associated with increased pathogenicity in patients with P acnes-positive cultures following revision shoulder arthroplasty, when assessed by objective perioperative criteria and the postoperative clinical course.

Accuracy of Cardiovascular Risk Prediction Varies by Neighborhood Socioeconomic Position: A Retrospective Cohort Study.

BACKGROUND: Inequality in health outcomes in relation to Americans' socioeconomic position is rising. OBJECTIVE: First, to evaluate the spatial relationship between neighborhood disadvantage and major atherosclerotic cardiovascular disease (ASCVD)-related events; second, to evaluate the relative extent to which neighborhood disadvantage and physiologic risk account for neighborhood-level variation in ASCVD event rates. DESIGN: Observational cohort analysis of geocoded longitudinal electronic health records. SETTING: A single academic health center and surrounding neighborhoods in northeastern Ohio. PATIENTS: 109 793 patients from the Cleveland Clinic Health System (CCHS) who had an outpatient lipid panel drawn between 2007 and 2010. The date of the first qualifying lipid panel served as the study baseline. MEASUREMENTS: Time from baseline to the first occurrence of a major ASCVD event (myocardial infarction, stroke, or cardiovascular death) within 5 years, modeled as a function of a locally derived neighborhood disadvantage index (NDI) and the predicted 5-year ASCVD event rate from the Pooled Cohort Equations Risk Model (PCERM) of the American College of Cardiology and American Heart Association. Outcome data were censored if no CCHS encounters occurred for 2 consecutive years or when state death data were no longer available (that is, from 2014 onward). RESULTS: The PCERM systematically underpredicted ASCVD event risk among patients from disadvantaged communities. Model discrimination was poorer among these patients (concordance index [C], 0.70 [95% CI, 0.67 to 0.74]) than those from the most affluent communities (C, 0.80 [CI, 0.78 to 0.81]). The NDI alone accounted for 32.0% of census tract-level variation in ASCVD event rates, compared with 10.0% accounted for by the PCERM. LIMITATIONS: Patients from affluent communities were overrepresented. Outcomes of patients who received treatment for cardiovascular disease at Cleveland Clinic were assumed to be independent of whether the patients came from a disadvantaged or an affluent neighborhood. CONCLUSION: Neighborhood disadvantage may be a powerful regulator of ASCVD event risk. In addition to supplemental risk models and clinical screening criteria, population-based solutions are needed to ameliorate the deleterious effects of neighborhood disadvantage on health outcomes. PRIMARY FUNDING SOURCE: The Clinical and Translational Science Collaborative of Cleveland and National Institutes of Health.

Multicenter Evaluation of a Modified Cefoxitin Disk Diffusion Method and PBP2a Testing To Predict mecA-Mediated Oxacillin Resistance in Atypical Staphylococcus aureus.

Phenotypic variants of Staphylococcus aureus that display small colonies, reduced pigmentation, and decreased hemolysis and/or coagulase activity are periodically isolated by the clinical laboratory. Antimicrobial susceptibility testing (AST) of these isolates is complicated, because many do not grow on routine AST media, including Mueller-Hinton agar (MHA) and cation-adjusted Mueller-Hinton broth. This multicenter study evaluated cefoxitin disk diffusion for 37 atypical S. aureus isolates (156 readings) with MHA supplemented with 5% sheep's blood (BMHA), using mecA PCR as the reference standard. The correlation of two commercial PBP2a assays with mecA PCR was also assessed. Ten isolates were negative and 27 positive for mecA No major errors for cefoxitin were observed, but 19.5% very major errors (VMEs) were observed at 24 h of incubation, and 17.2% VMEs were observed at 48 h. The proportions of VMEs ranged from 14.7 to 23.0% at 24 h, and from 13.3 to 17.6% at 48 h, across three testing laboratories. PBP2a tests were performed from growth on BMHA and blood agar plates (BAP), with and without cefoxitin disk induction. The Alere PBP2a SA culture colony test sensitivities for mecA were 90.0% with uninduced growth and 97.4% with induced growth from BMHA. On BAP, sensitivity was 96.0% with induced growth. The sensitivities of the Oxoid PBP2' latex agglutination test were 85.7% with uninduced growth and 93.9% with induced growth from BMHA and 95.9% with induced growth on BAP. On the basis of these data, we recommend that laboratories perform only mecA PCR and/or PBP2a tests when requested to perform AST on atypical isolates of S. aureus.

The presence of a single MALDI-TOF mass spectral peak predicts methicillin resistance in staphylococci.

The class A mec gene complex also carries the psm-mec gene. The psm-mec gene product can be detected as a peak near 2415m/z using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The correlation of a 2415m/z peak with methicillin resistance (mecA carriage) in consecutive staphylococcal blood culture isolates was evaluated. A 2415±2.00m/z peak was observed in 37% (51/137) of methicillin-resistant Staphylococcus aureus, in none (0/146) of the methicillin-susceptible S. aureus, in 6% (10/180) of methicillin-resistant S. epidermidis, and in 2% (1/63) of methicillin-susceptible S. epidermidis isolates. Although the sensitivity of the 2415m/z peak for mecA carriage in S. aureus and S. epidermidis was low (37% and 6%, respectively), the specificity was high (≥98%). This peak can be identified during routine MALDI-TOF MS clinical testing, and the analysis adds no reagent cost and requires minimal time expenditure.