Analytical validation of the Mindray CL1200i analyzer high sensitivity cardiac troponin I assay: MERITnI study.

OBJECTIVES: This study performed an analytical validation study of the Mindray high-sensitivity cardiac troponin I (hs-cTnI) assay addressing limit of blank (LoB), limit of detection (LoD), precision, linearity, analytical specificity and sex-specific 99th percentile upper reference limits. METHODS: LoB, LoD, precision, linearity and analytical specificity were studied according to Clinical and Laboratory Standards Institute. We used one reagent lot and one CL1200i analyzer. Skeletal troponin I and T, cardiac troponin T, troponin C, actin, tropomyosin, myosin light chain, myoglobin and creatine kinase (CK-MB) were studied for cross-reactivity. Interference with biotin was examined. Lithium heparin samples (one freeze thaw cycle) from healthy males and females were measured to determine the 99th percentiles by using the non-parametric method. Analyses were performed before and after excluding subjects with clinical conditions and/or increased surrogate biomarkers. RESULTS: The Mindray hs-cTnI assay met criteria to be considered as a hs-cTn assay. LoB and LoD was <0.1 ng/L and 0.1 ng/L, respectively. Repeatability had a coefficient of variation 1.2-3.8 %, and within-laboratory imprecision 1.7-5.0 %. The measuring interval ranged from 1.1 to 28,180 ng/L. The analytical specificity was clinically acceptable for the interferents studied. After exclusions, the 99th percentile URLs obtained were 10 ng/L overall, 5 ng/L for females and 12 ng/L for males. CONCLUSIONS: Analytical observations of the Mindray hs-cTnI assay demonstrated excellent LoB, LoD, precision, linearity and analytical specificity, that were in alignment with the manufacturer's claims and regulatory guidelines for hs-cTnI. The assay is suitable for clinical investigation for patient-oriented studies.

Sex-Specific 99th Percentile Upper Reference Limits for High Sensitivity Cardiac Troponin Assays Derived Using a Universal Sample Bank.

BACKGROUND: How to select healthy reference subjects in deriving 99th percentiles for cardiac troponin assays still needs to be clarified. To assist with global implementation of high sensitivity (hs)-cardiac troponin (cTn) I and hs-cTnT assays in clinical practice, we determined overall and sex-specific 99th percentiles in 9 hs-cTnI and 3 hs-cTnT assays using a universal sample bank (USB). METHODS: The Universal Sample Bank (USB) comprised healthy subjects, 426 men and 417 women, screened using a health questionnaire. Hemoglobin A1c (>URL 6.5%), NT-proBNP (>URL 125 ng/L) and eGFR (<60 mL/min), were used as surrogate biomarker exclusion criteria along with statin use. 99th percentiles were determined by nonparametric, Harrell--Davis bootstrap, and robust methods. RESULTS: Subjects were ages 19 to 91 years, Caucasian 58%, African American 27%, Pacific Islander/Asian 11%, other 4%, Hispanic 8%, and non-Hispanic 92%. The overall and sex-specific 99th percentiles for all assays, before and after exclusions (n = 694), were influenced by the statistical method used, with substantial differences noted between and within both hs-cTnI and hs-cTnT assays. Men had higher 99th percentiles (ng/L) than women. The Roche cTnT and Beckman and Abbott cTnI assays (after exclusions) did not measure cTn values at ≥ the limit of detection in ≥50% women. CONCLUSIONS: Our findings have important clinical implications in that sex-specific 99th percentiles varied according to the statistical method and hs-cTn assay used, not all assays provided a high enough percentage of measurable concentrations in women to qualify as a hs-assay, and the surrogate exclusion criteria used to define normality tended to lower the 99th percentiles.

Outcomes Following Ischemic Stroke in Older Patients With CKD Stages 4 and 5: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: The associations between ischemic stroke and time to dialysis initiation and/or death in adults with late-stage chronic kidney disease (CKD) have not been explored. We sought to measure the rate and factors associated with stroke in CKD stages 4 and 5 (CKD4-5) and assess the association of stroke with initiation of dialysis and death. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: Patients with CKD4-5 in Medicare 2007 to 2014. EXPOSURE OR PREDICTOR: Ischemic stroke in CKD4-5. OUTCOMES: Initiation of maintenance dialysis or death. ANALYTICAL APPROACH: Cox proportional hazard modeling assessed factors associated with ischemic stroke. A matched analysis (stroke/no stroke) estimated the cumulative incidence of incident kidney failure and death, treated as competing events. Simulations using a state transition model determined differences in expected time to kidney failure or death and death alone for patients with and without stroke with CKD5. RESULTS: 123,251 patients with CKD4 and 22,054 with CKD5 were identified. Mean ages were 81.0 and 79.2 years, respectively. Female sex (HRs of 1.21 [95% CI, 1.12-1.31] and 1.39 [95% CI, 1.04-1.86] for CKD4 and CKD5, respectively) and black race (HRs of 1.25 [95% CI, 1.12-1.39] and 1.12 [95% CI, 0.80-1.58] for CKD4 and CKD5, respectively) were factors associated with ischemic stroke. Rates for 30-day mortality were 13.3% and 18.8%, and for 1-year mortality, 40.0% and 38.2%. For patients with CKD5, kidney failure or death occurred an average of 3.6 months sooner for patients with an ischemic stroke, and death (irrespective of kidney failure), a mean of 24.3 months sooner. LIMITATIONS: Study design cannot determine causality; lack of data for stroke severity. CONCLUSIONS: Female sex and black race were associated with increased risk for stroke in CKD4 and CKD5. In CKD5, stroke was associated with a shorter time to kidney failure or death by nearly 4 months, and to death, by more than 2 years.

Exposure to Racism and Other Adverse Childhood Experiences Among Perinatal Women with Moderate to Severe Mental Illness.

We sought to determine the prevalence and correlates of conventional and expanded adverse childhood experiences (ACEs), including exposure to violence and racism, in perinatal women with mental illness. 133 perinatal women with mental illness completed the original ACEs (conventional ACEs) survey and the 6-question adverse environmental experiences (expanded ACEs) survey from the Philadelphia ACEs study. Associations between racial groups and ACE scores, mental health and psychosocial variables were evaluated. Subjects were predominantly white (68%) and married/partnered (66%), and 57% had at least 4 conventional ACEs. Compared to White women, Black women were significantly more likely to report conventional and expanded ACEs including experiencing racism and witnessing violence. Early life adversity was exceedingly common among pregnant and postpartum women with moderate to severe mental illness. Childhood exposure to racism and environmental trauma are important risk categories for perinatal mental illness.

Renal Dysfunction Influences the Diagnostic and Prognostic Performance of High-Sensitivity Cardiac Troponin I.

Measures of cardiac troponin (cTn) may have lower specificity for myocardial infarction in patients with CKD. We examined the diagnostic accuracy of baseline and serial high-sensitivity cTnI (hs-cTnI) measurements for myocardial infarction and 30- and 180-day mortality according to renal function. hs-cTnI was measured (Abbott assay) using sex-specific 99th percentiles (women, 16 ng/L; men, 34 ng/L) in 1555 adults presenting to the emergency department with symptoms suggesting ischemia (NCT02060760). Myocardial infarction was adjudicated along universal definition classification. Renal function did not significantly affect sensitivity or negative predictive values. Specificity decreased with impaired renal function from 93%-95% with normal function (eGFR≥90 ml/min per 1.73 m2; n=722) to 57%-61% with severely impaired renal function (eGFR<30 ml/min per 1.73 m2; n=81) and 40%-41% on dialysis (n=78). Positive predictive values decreased with decreasing renal function from 51%-57% with normal function to 27%-42% with severely impaired function and 15%-32% on dialysis. Receiver operating characteristic curve areas trended lower at baseline and 3 hours with renal impairment. Mortality increased significantly with increasing hs-cTnI tertile (1.3%, 6.0%, and 10.4%, respectively). Patients with hs-cTnI concentration exceeding concentrations in the 99th percentiles had a mortality rate (11.7%) significantly higher than that of patients with concentrations between 99th percentile concentrations and limit of detection (6.2%) or below limit of detection (1.1%). Renal dysfunction and dialysis reduced the rule-in performance but not the rule-out performance of hs-cTnI for myocardial infarction, and mortality increased in patients with higher hs-cTnI concentrations and any level of renal dysfunction.

Diagnostic Performance of High Sensitivity Compared with Contemporary Cardiac Troponin I for the Diagnosis of Acute Myocardial Infarction.

BACKGROUND: We examined the diagnostic performance of high-sensitivity cardiac troponin I (hs-cTnI) vs contemporary cTnI with use of the 99th percentile alone and with a normal electrocardiogram (ECG) to rule out acute myocardial infarction (MI) and serial changes (deltas) to rule in MI. METHODS: We included consecutive patients presenting to a US emergency department with serial cTnI onclinical indication. Diagnostic performance for acute MI, including MI subtypes, and 30-day outcomes were examined. RESULTS: Among 1631 patients, MI was diagnosed in 12.9% using the contemporary cTnI assay and in 10.4% using the hs-cTnI assay. For ruling out MI, contemporary cTnI ≤99th percentile at 0, 3, and 6 h and a normal ECG had a negative predictive value (NPV) of 99.5% (95% CI, 98.6-100) and a sensitivity of 99.1% (95% CI, 97.4-100) for diagnostic and safety outcomes. Serial hs-cTnI measurements ≤99th percentile at 0 and 3 h and a normal ECG had an NPV and sensitivity of 100% (95% CI, 100-100) for diagnostic and safety outcomes. For ruling in MI, contemporary cTnI measurements had specificities of 84.4% (95% CI, 82.5-86.3) at presentation and 78.7% (95% CI, 75.4-82.0) with serial testing at 0, 3, and 6 h, improving to 89.2% (95% CI, 87.1-91.3) by using serial cTnI changes (delta, 0 and 6 h) >150%. hs-cTnI had specificities of 86.9% (95% CI, 85.1-88.6) at presentation and 85.7% (95% CI, 83.5-87.9) with serial testing at 0 and 3 h, improving to 89.3% (95% CI, 87.3-91.2) using a delta hs-cTnI (0 and 3 h) >5 ng/L. CONCLUSIONS: hs-cTnI and contemporary cTnI assays are excellent in ruling out MI following recommendations predicated on serial testing and the 99th percentile with a normal ECG. For ruling in MI, deltas improve the specificity. ClinicalTrials.gov Identifier: NCT02060760.

Use of objective evidence of myocardial ischemia to facilitate the diagnostic and prognostic distinction between type 2 myocardial infarction and myocardial injury.

AIMS: First, describe how acute myocardial infarction criteria are used to diagnose type 1 (T1MI) and 2 (T2MI) myocardial infarction. Second, determine whether subjective or objective criteria are used for T2MI. Third, examine outcomes for T2MI based on the presence or absence of objective evidence of myocardial ischemia compared with myocardial injury. METHODS AND RESULTS: Post-hoc analysis of UTROPIA (NCT02060760), a prospective, observational, cohort study involving 1640 consecutive emergency department patients with serial high-sensitivity cardiac troponin I among whom 74 (4.5%) had T1MI, 103 (6.3%) T2MI, and 245 (15%) myocardial injury. Compared with T1MI, patients with T2MI were less likely to have ischemic symptoms (97% vs. 83%), Q waves (24% vs. 1%), new ST-T wave changes (74% vs. 51%), new regional wall motion abnormality (64% vs. 11%), and a culprit lesion on coronary angiography (59% vs. 0%) (all p <0.05). T2MIs were more likely to be diagnosed using subjective criteria (symptoms alone) than T1MI (42% vs. 12%, p <0.0001). Patients with objective T2MI, but not subjective T2MI, had a two-fold increase in early mortality compared with myocardial injury, with 30- and 60-day hazard ratios (95% confidence interval) of 2.3 (0.9, 6.2) and 2.0 (0.9, 4.7) respectively. CONCLUSIONS: Among patients with T2MI, many cases are diagnosed using subjective criteria. The presence of objective evidence of myocardial ischemia may identify a higher-risk group of T2MI patients in whom early outcomes are worse than myocardial injury. Emphasis on using objective evidence of myocardial ischemia to diagnose T2MI may result in a more precise and specific disease definition.