Establishing optimal cutoff values for high-sensitivity cardiac troponin algorithms in risk stratification of acute myocardial infarction.

Acute myocardial infarction (AMI) is a leading cause of mortality globally, highlighting the need for timely and accurate diagnostic strategies. Cardiac troponin has been the biomarker of choice for detecting myocardial injury. A dynamic change in concentrations supports the diagnosis of AMI in the setting of evidence of acute myocardial ischemia. The new generation of high-sensitivity cardiac troponin (hs-cTn) assays has significantly improved analytical sensitivity but at the expense of decreased clinical specificity. As a result, sophisticated algorithms are required to differentiate AMI from non-AMI patients. Establishing optimal hs-cTn cutoffs for these algorithms to rule out and rule in AMI has been the subject of intensive investigations. These efforts have evolved from examining the utility of the hs-cTn 99th percentile upper reference limit, comparing the percentage versus absolute delta thresholds, and evaluating the performance of an early European Society of Cardiology-recommended 3 h algorithm, to the development of accelerated 1 h and 2 h algorithms that combine the admission hs-cTn concentrations and absolute delta cutoffs to rule out and rule in AMI. Specific cutoffs for individual confounding factors such as sex, age, and renal insufficiency have also been investigated. At the same time, concerns such as whether the small delta thresholds exceed the analytical and biological variations of hs-cTn assays and whether the algorithms developed in European study populations fit all other patient cohorts have been raised. In addition, the accelerated algorithms leave a substantial number of patients in a non-diagnostic observation zone. How to properly diagnose patients falling in this zone and those presenting with elevated baseline hs-cTn concentrations due to the presence of confounding factors or comorbidities remain open questions. Here we discuss the developments described above, focusing on criteria and underlying considerations for establishing optimal cutoffs. In-depth analyses are provided on the influence of biological variation, analytical imprecision, local AMI rate, and the timing of presentation on the performance metrics of the accelerated hs-cTn algorithms. Developing diagnostic strategies for patients who remain in the observation zone and those presenting with confounding factors are also reviewed.

Use of Routine Complete Blood Count Results to Rule Out Anaplasmosis Without the Need for Specific Diagnostic Testing.

BACKGROUND: Anaplasmosis presents with fever, headache, and laboratory abnormalities including leukopenia and thrombocytopenia. Polymerase chain reaction (PCR) is the preferred diagnostic but is overutilized. We determined if routine laboratory tests could exclude anaplasmosis, improving PCR utilization. METHODS: Anaplasma PCR results from a 3-year period, with associated complete blood count (CBC) and liver function test results, were retrospectively reviewed. PCR rejection criteria, based on white blood cell (WBC) and platelet (PLT) counts, were developed and prospectively applied in a mock stewardship program. If rejection criteria were met, a committee mock-refused PCR unless the patient was clinically unstable or immunocompromised. RESULTS: WBC and PLT counts were the most actionable routine tests for excluding anaplasmosis. Retrospective review demonstrated that rejection criteria of WBC ≥11 000 cells/µL or PLT ≥300 000 cells/µL would have led to PCR refusal in 428 of 1685 true-negative cases (25%) and 3 of 66 true-positive cases (5%) involving clinically unstable or immunocompromised patients. In the prospective phase, 155 of 663 PCR requests (23%) met rejection criteria and were reviewed by committee, which endorsed refusal in 110 of 155 cases (71%) and approval in 45 (29%), based on clinical criteria. PCR was negative in all 45 committee-approved cases. Only 1 of 110 mock-refused requests yielded a positive PCR result; this patient was already receiving doxycycline at the time of testing. CONCLUSIONS: A CBC-based stewardship algorithm would reduce unnecessary Anaplasma PCR testing, without missing active cases. Although the prospectively evaluated screening approach involved medical record review, this was unnecessary to prevent errors and could be replaced by a rejection comment specifying clinical situations that might warrant overriding the algorithm.

Reference interval evaluation of high-sensitivity troponin T and N-terminal B-type natriuretic peptide in Vietnam and the US: The North South East West Trial.

BACKGROUND: Reference intervals of high-sensitivity troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been determined from Western populations. No data are available regarding expected values in Asian populations. METHODS: A total of 1157 age- and sex-matched healthy individuals (mean age, 41.2 years; 48.0% male) were prospectively enrolled from the US (n = 565) and Vietnam (n = 592). Blood samples were analyzed for hs-cTnT and NT-proBNP. Median values were determined for each country and compared in unadjusted analyses and in analyses adjusted for age, sex, body mass index, study site, race, and vital signs. RESULTS: Median hs-cTnT concentrations were slightly higher for individuals from the US than for those from Vietnam, but both were below the limit of detection (3.7 vs 3.0 ng/L, respectively; P = 0.03). More US participants had an hs-cTnT concentration above the limit of detection (57.2% vs 47.3%; P = 0.001), but the 99th percentile concentration was slightly higher for Asians (US 15.1 vs Vietnam 19.0 ng/L). Concentrations for >98% of both populations were below the standard hs-cTnT 99th percentile of 14.0 ng/L (P = 0.54). Median NT-proBNP concentrations were slightly higher for US participants compared with Vietnamese participants (28 vs 16 ng/L, respectively; P < 0.001). Following adjustment, differences in concentrations of NT-proBNP between healthy US and Vietnamese populations remained significant, whereas for hs-cTnT the differences were no longer significant. Inclusion of hs-cTnT values down to the limit of blank did not change the result. CONCLUSIONS: The differences in hs-cTnT and NT-proBNP between healthy individuals from the US and Vietnam are small. Previously derived reference intervals for both analytes may be applied in Asian populations.

Clinical decision support to improve CBC and differential ordering.

OBJECTIVES: Complete blood count and differential (CBC diff) is a common laboratory test that may be overused or misordered, particularly in an inpatient setting. We assessed the ability of a clinical decision support (CDS) alert to decrease unnecessary orders for CBC diff and analyzed its impact in the laboratory. METHODS: We designed 3 CDS alerts to provide guidance to providers ordering CBC diff on inpatients at frequencies of daily, greater than once daily, or as needed. RESULTS: The 3 alerts were highly effective in reducing orders for CBC diff at the frequencies targeted by the alert. Overall, test volume for CBC diff decreased by 32% (mean of 5257 tests per month) after implementation of the alerts, with a corresponding decrease of 22% in manual differentials performed (mean of 898 per month). Turnaround time for manual differentials decreased by a mean of 41.5 minutes, with a mean decrease of up to 90 minutes during peak morning hours. CONCLUSIONS: The 3 CDS alerts successfully decreased inpatient orders for CBC diff and improved the quality of patient care by decreasing turnaround time for manual differentials.

Evaluation of the Rapid Quidel Sofia 2 Lyme Immunoassay as a First-Tier Test in a Two-Tier Testing Algorithm for Lyme Disease: Comparison to the Zeus ELISA Borrelia VlsE1/pepC10 IgG/IgM Assay Followed by Immunoblot.

OBJECTIVES: Two-tiered serologic testing for Lyme disease is usually performed using an enzyme-linked immunosorbent assay (ELISA) as the first-tier test. The Quidel Sofia 2 Lyme test is a relatively new lateral flow method to provide more rapid turnaround time. We evaluated its performance in comparison to an established ELISA method. The test can be performed on demand rather than batching assays in a central laboratory. METHODS: We compared the Sofia 2 assay to the Zeus VlsE1/pepC10 IgG/IgM test in a standard two-tiered testing algorithm. RESULTS: Comparison of the Sofia 2 to the Zeus VlsE1/pepC10 IgG/IgM showed an overall agreement of 89.9% (κ statistic of 0.750, indicating "substantial agreement"). When the tests were followed by immunoblot in a two-tier algorithm, the agreement was 98.9% (κ statistic of 0.973, indicating "almost perfect" agreement). CONCLUSIONS: The Sofia 2 Lyme test performs well when compared with the Zeus VlsE1/pepC10 IgG/IgM in a two-tiered testing algorithm.

Evaluation of the rapid Quidel Sofia Lyme fluorescent immunoassay as a first-tier test in a modified 2-tier testing algorithm for Lyme disease: A comparison with the Zeus ELISA Borrelia VlsE1/pepC10 lgG/IgM assay followed by the Zeus monovalent IgM/IgG confirmatory assay.

OBJECTIVES: Recently modified 2-tier testing (MTTT) algorithms using 2 enzyme immunoassays (EIAs) as opposed to an EIA followed by immunoblot have been approved by the US Food and Drug Administration (FDA) for the screening and confirmation of Lyme disease. The Quidel Sofia Lyme fluorescent immunoassay is a rapid lateral-flow method that can be performed in real time, permitting on-demand testing. We evaluated the performance of the Sofia assay as a first-tier test in an MTTT algorithm. METHODS: We compared the Sofia Lyme test with the Zeus ELISA Borrelia VlsE1/pepC10 lgG/IgM test, followed by the Zeus monovalent IgM/IgG EIA as the confirmatory test. RESULTS: When used as a first-tier test compared with a standard Zeus MTTT assay, the positive percentage agreement was 91.4%% (95% CI, 77.6%-97.0%). The negative percentage agreement was 100% (95% CI, 94.0%-100%). The overall agreement was 98.3% (95% CI, 94.2%-99.4%). κ = 0.945, indicating "almost perfect agreement." CONCLUSIONS: The Sofia Lyme test performs well compared with an FDA-approved MTTT.

Measurement of High Sensitivity Troponin T in Patients with Early Stage Lyme Disease: Preliminary Evidence for Possible Subclinical Cardiac Involvement.

OBJECTIVE: In patients with early Lyme disease (ELD), cardiac involvement is known to occur in approximately 1% of patients. We measured high-sensitivity troponin T (hsTnT) in patients with early Lyme disease to evaluate the possibility of subclinical cardiac involvement. METHODS: We measured hsTnT in 41 patients with well characterized ELD. RESULTS: A total of 6/41 (14.6%) of patients exhibited hsTnT values above either the gender specific or gender neutral 99th percentile cutoff for a normal hsTnT. One patient had a value greater than the cutoff used for acute myocardial infarction. CONCLUSIONS: There are many possible explanations for increased hsTnT values in different types of patients in the absence of acute cardiac damage. Nonetheless our results raise the possibility that subclinical cardiac involvement may be more common in ELD than previously recognized. Further studies will be necessary to elucidate the significance of this finding.

Glucose meter standardization across a large academic hospital system.

BACKGROUND: To select and standardize point-of-care (POC) glucose meters across a multi-hospital system. METHODS: We formed a multidisciplinary POC glucose standardization working group including key stakeholders from each site. A set of selection criteria: usability, clinical and laboratory performance, indications for use, interface connectivity, ease of implementation and ongoing operational costs were used to develop a scoring schemato facilitate a consensus-driven selection process. RESULTS: Method comparison and consensus error grid evaluation against the clinically validated reference methods demonstrated that the analytical performance for all candidate meters was comparable for both the laboratory and clinical evaluation. However, Meter 1 ranked highest in usability evaluations, implementation and streamlined interface connectivity. The meter selection process and implementation were staggered across sites due to complexity of transitioning to a new manufacturer's meter and limitations in vendor support for training and ongoing troubleshooting of interface connectivity. CONCLUSIONS: Standardization of POC glucose meters in a large multi-hospital system is a complex undertaking requiring robust, multidisciplinary organizational structure both system-wide and locally, development of consensus-driven selection tools, usability evaluation by end-users, laboratory and clinical evaluation of the analytical performance, and a strong vendor-laboratory partnership during the implementation process.

Detection and localization of early- and late-stage cancers using platelet RNA.

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.

Description of a point-of-care testing program in a large urban academic medical center: Technologies, management and program cost.

BACKGROUND: Point-of-care testing (POCT) is an important component of hospital-based and ambulatory laboratory testing. Despite its importance, there is relatively little in the peer reviewed literature describing the details of successful POCT programs. METHODS: Administrative records and test volumes from the Massachusetts General Hospital were compiled using POCT middleware (Telcor) and the hospital information system (Epic). Financial data was derived from vendor contracts and the hospital budget management system. RESULTS: Our POCT management team consists of 2.8 medical technologists and 0.1 medical director with an annual labor cost of $458,000 ($0.80/test). The team oversees quality and regulatory compliance for 143 testing sites. POCT constitutes 24 tests with an annual volume of over 573,000 tests (10.8% of all tests performed). Regular site inspections utilizing a compliance checklist with mandatory remedial action plans are employed. This approach has reduced inspection citations from 3.17 per testing site to 0.27 citations. The average cost of POCT tests is $1.89. CONCLUSIONS: POCT is widespread in our institution and comprises a significant percentage of the total test volume. A dedicated POCT team combined with regular site inspections using a comprehensive checklist facilitates regulatory compliance and quality testing.

The Impact of Point-of-Care Hemoglobin A1c Testing on Population Health-Based Onsite Testing Adherence: A Primary-Care Quality Improvement Study.

BACKGROUND: The hemoglobin A1c (HbA1c) is a gold-standard test to diagnose and monitor diabetes mellitus and has been incorporated into population health performance metrics for quality care. However, patients and practices remain challenged in completing timely HbA1c tests. Point-of-care testing (POCT) for HbA1c provides a quick, easy, reliable method for monitoring diabetes in the primary care office setting. The objectives of this quality improvement study were to evaluate the impact of HbA1c POCT on onsite HbA1c testing frequency as a component of population health performance, as well as to measure the utility of HbA1c POCT in identifying clinically meaningful change in disease. METHOD: Prospective quality improvement cohort study among sequentially scheduled adult patients with diabetes due for HbA1c testing across three primary care practices. RESULTS: Practices with HbA1c POCT were 3.7 times less likely to miss HbA1c testing at the time of the visit compared with practices in which HbA1c POCT was not available (P < .001). Nearly one in four patients in each group were found to have clinically worsening diabetes (defined by an increase in HbA1c of ≥0.5% or 5.5 mmol/mol). Nearly half of those patients in the intervention group were identified by POCT. CONCLUSIONS: HbA1c POCT can improve population health-driven HbA1c testing adherence at office visits in primary care and may enable more timely intervention of diabetes management for patients with worsening disease.

Clinical uncertainty, diagnostic accuracy, and outcomes in emergency department patients presenting with dyspnea.

BACKGROUND: Dyspnea is a common complaint in the emergency department (ED) and may be a diagnostic challenge. We hypothesized that diagnostic uncertainty in this setting is associated with adverse outcomes, and amino-terminal pro-B-type natriuretic peptide (NT-proBNP) testing would improve diagnostic accuracy and reduce diagnostic uncertainty. METHODS: A total of 592 dyspneic patients were evaluated from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Managing physicians were asked to provide estimates from 0% to 100%of the likelihood of acutely destabilized heart failure (ADHF). A certainty estimate of either 20% or lower or 80% or higher was classified as clinical certainty, while estimates between 21% and 79% were defined as clinical uncertainty. Associations between clinical uncertainty,hospital length of stay, morbidity, and mortality were examined. The diagnostic value of clinical judgment vs NT-proBNP measurement was compared across categories of clinical certainty. RESULTS: Clinical uncertainty was present in 185 patients (31%), 103 (56%) of whom had ADHF. Patients judged with clinical uncertainty had longer hospital length of stay and increased morbidity and mortality,especially those with ADHF. Receiver operating characteristic analysis of clinical judgment yielded an area under the curve (AUC) of 0.88 in the clinical certainty group and 0.76 in the uncertainty group (P<.001); NT-proBNP testing alone in these same groups had AUCs of 0.96 and 0.91, respectively. The combination of clinical judgment with NT-proBNP testing yielded improvements in AUC. CONCLUSIONS: Among dyspneic patients in the ED, clinical uncertainty is associated with increased morbidity and mortality, especially in those with ADHF.The addition of NT-proBNP testing to clinical judgment may reduce diagnostic uncertainty in this setting.

Integrating Decision Support into a Laboratory Utilization Management Program.

Overuse of clinical laboratory testing increases costs, contributes to iatrogenic anemia, and results in downstream costs, including unnecessary work-ups and treatments. Physicians order unnecessary laboratory tests because of lack of knowledge, the practice of defensive medicine and adherence to historical test ordering. Utilization management is increasingly important to control costs and ensure patients receive appropriate tests for diagnosis and management. Clinical decision support is essential for a successful utilization management program. Successful programs rely on clinical informatics to identify misutilization, implement interventions, and track effectiveness. We describe the role of clinical decision support in a laboratory utilization management program.

Effect of laboratory testing guidelines on the utilization of tests and order entries in a surgical intensive care unit.

OBJECTIVE: Diagnostic testing is frequently overused in the intensive care unit. We devised guidelines to optimize blood tests utilization, and designed this study to quantify their efficacy over time, their safety, and their possible benefits. DESIGN: Laboratory testing guidelines were created by consensus and implemented through repeated staff education. The guidelines included: a) the tests to be obtained daily: complete blood count, serum electrolytes, urea nitrogen, creatinine, and blood glucose concentration; b) the need to discuss laboratory testing at daily patient's rounds; c) the need to provide a written order for all tests. The number of tests performed, corresponding physician orders, and various outcome measures were collected for two 6-month study periods, before and after the first day of implementation of the guidelines. SETTING: Twenty-bed surgical intensive care unit in a tertiary care teaching hospital. PATIENTS: All patients admitted during the two study periods. METHODS: Laboratory tests and related physician orders, demographics, blood products transfusion, and outcomes were collected from hospital databases. In prospectively defined subgroups, additional outcome measures were obtained by ad-hoc chart review. RESULTS: One thousand one hundred seventeen patients were enrolled. After the institution of the guidelines, the number of laboratory tests decreased by 37% (from 64,305 to 40,877), and the number of respective physician orders increased by 38% (from 20,940 to 35,472), p < 0.001. These results were manifest within 1 month, sustained through the study period, and still present at 1 yr. No changes in outcomes or in the rates of selected complications were detected. Red blood cells utilization correlated linearly (r .47) with the number of blood tests performed in both study periods. CONCLUSIONS: Guidelines designed to optimize laboratory tests use in an intensive care unit can produce rapid and long-lasting effects, can be safe, and may affect the number of red blood cell units transfused.

Cardiac biomarkers, electrolytes, and other analytes in collapsed marathon runners: implications for the evaluation of runners following competition.

We measured analytes in collapsed Boston Marathon runners to compare with changes in asymptomatic runners. Of collapsed runners at the 2007 marathon, 18.2% had a measurable cardiac troponin T (cTnT) value with a mean postrace level of 0.017 ng/mL (0.017 microg/L; SD, 0.02 ng/mL [0.02 microg/L]). Three subjects had cTnT values above the cutoff (0.10 ng/mL [0.10 microg/L]) typically used for the diagnosis of acute myocardial infarction. The mean and median N-terminal pro-B-type natriuretic peptide levels were 73 ng/L (SD, 77.3 ng/L) and 54.3 ng/L (interquartile range, 22.8-87.3 ng/L), respectively, in collapsed runners. Only 4.9% had values more than the age-specific normal value (<125 ng/L for subjects younger than 75 years). In collapsed subjects at the 2006 marathon, 18.0% had an abnormal sodium value, including 18 cases of hypernatremia and 7 cases of hyponatremia. The ionized calcium level was low in 49% of subjects, and the ionized magnesium level was low in 19.5% and elevated in 1 subject. The blood lactate level was elevated in 95% of subjects. The frequency of elevated postrace cTnT levels in collapsed athletes after endurance exercise is similar to that in asymptomatic runners. Other metabolic abnormalities, including hypernatremia, hyponatremia, low ionized calcium and magnesium levels, and lactic acidosis may contribute to muscle fatigue and collapse.

Implementation of point-of-care rapid urine testing for drugs of abuse in the emergency department of an academic medical center: impact on test utilization and ED length of stay.

We evaluated the impact of implementing a point-of-care (POC) rapid urine test panel for drugs of abuse on turnaround time (TAT), emergency department length of stay (LOS), and laboratory test utilization patterns. The mean TAT from sample collection to results reporting decreased by 69.4%, from 108 to 33 minutes, the mean LOS from 11.1 to 8.1 hours (27% P < .0001), and the median LOS from 8.0 to 7.0 hours (13% P = .0017). A method crossover between the POC and central laboratory methods revealed differences in sensitivity and specificity. Overall, there was no clear preference for either method. Differences in performance for individual drug classes were reconciled by providing interpretive comments with POC results. Following implementation, use of urine testing for drugs of abuse increased by 30%, which was offset by fewer requests for extended toxicology testing in the central laboratory and more selective ordering of toxicology tests not on the POC panel (alcohols and analgesics). The implementation of a POC urine test panel for drugs of abuse decreased LOS and TAT and essentially replaced central laboratory testing for drugs of abuse. Differences in sensitivity and specificity between POC and central laboratory results require provision of interpretive comments with results.

Analytical and clinical performance of the Ortho-Clinical Diagnostics VITROS amino-terminal pro-B type natriuretic peptide assay.

BACKGROUND: Measurement of amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is useful for evaluating patients with heart failure (HF). METHODS: We evaluated the performance of a new automated NT-proBNP assay. RESULTS: The VITROS NT-proBNP assay had mean within-run and total imprecision of 1.0% and 3.4% at NT-proBNP concentrations from 67-27,500 ng/l. Acceptable linearity, functional/analytical sensitivity were demonstrated. Anticoagulant/tube types had no effect on results. Excellent sample stability and no high-dose hook were observed. High correlation between the VITROS and Elecsys methods was demonstrated (r=0.995; P<.001), with 98.3% clinical concordance. VITROS NT-proBNP concentrations were significantly higher in HF subjects than those without (1210 versus 68 ng/l; P<.001) and associated with HF symptom severity (P<.001). The VITROS assay had AUC for HF of 0.95 (P<.001), and had excellent NPV for excluding HF. CONCLUSIONS: The automated VITROS NT-proBNP assay demonstrates excellent analytical and clinical performance for evaluating the presence and severity of HF.