Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study.
Abstract
Background:High-sensitivity cardiac troponin I (hs-cTnI) assays have been developed
that quantify lower cTnI concentrations with better precision versus earlier generation
assays. hs-cTnI assays allow improved clinical utility for diagnosis and risk stratification
in patients presenting to the emergency department with suspected acute myocardial
infarction. We describe the High-Sensitivity Cardiac Troponin I Assays in the United
States (HIGH-US) study design used to conduct studies for characterizing the analytical
and clinical performance of hs-cTnI assays, as required by the US Food and Drug Administration
for a 510(k) clearance application. This study was non-interventional and therefore
it was not registered at clinicaltrials.gov. Methods:We conducted analytic studies
utilizing Clinical and Laboratory Standards Institute guidance that included limit
of blank, limit of detection, limit of quantitation, linearity, within-run and between
run imprecision and reproducibility as well as potential interferences and high dose
hook effect. A sample set collected from healthy females and males was used to determine
the overall and sex-specific cTnI 99th percentile upper reference limits (URL). The
total coefficient of variation at the female 99th percentile URL and a universally
available American Association for Clinical Chemistry sample set (AACC Universal Sample
Bank) from healthy females and males was used to examine high-sensitivity (hs) performance
of the cTnI assays. Clinical diagnosis of enrolled subjects was adjudicated by expert
cardiologists and emergency medicine physicians. Assessment of temporal diagnostic
accuracy including sensitivity, specificity, positive predictive value, and negative
predictive value were determined at presentation and collection times thereafter.
The prognostic performance at one-year after presentation to the emergency department
was also performed. This design is appropriate to describe analytical characterization
and clinical performance, and allows for acute myocardial infarction diagnosis and
risk assessment.
Type
Journal articleSubject
99th percentileACS, acute coronary syndrome
AMI, acute myocardial infarction
Analytical characteristics
CLSI, Clinical and Laboratory Standards Institute
Clinical performance
High-sensitivity cardiac troponin
IM, immunoassay
Immunoassay
Li-Hep, lithium heparin
LoB, Limit of Blank
LoD, Limit of Detection
LoQ, Limit of Quantitation
MDP, Medical Decision Pools
NPV, negative predictive value
PPV, positive predictive value
Sex-specific 99th percentile cutoffs
URL, upper reference limit
cTn, cardiac troponin
cTnI, cardiac troponin I
hs-cTn, high-sensitivity cardiac troponin
hs-cTnI, High-Sensitivity Troponin I
Permalink
https://hdl.handle.net/10161/20601Published Version (Please cite this version)
10.1016/j.conctc.2019.100337Publication Info
Christenson, RH; Peacock, WF; Apple, FS; Limkakeng, AT; Nowak, RM; McCord, J; & deFilippi,
CR (2019). Trial design for assessing analytical and clinical performance of high-sensitivity
cardiac troponin I assays in the United States: The HIGH-US study. Contemporary clinical trials communications, 14. pp. 100337. 10.1016/j.conctc.2019.100337. Retrieved from https://hdl.handle.net/10161/20601.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Alexander Tan Limkakeng Jr.
Professor of Surgery
My personal research interest is finding new ways to diagnose acute coronary syndrome.
In particular, I am interested in novel biomarkers and precision medicine approaches
to this problem. I also have an interest in sepsis and empirical bioethics. As Vice
Chief of Research for the Duke Division of Emergency Medicine, I also work with researchers
from many fields spanning global health, innovation, clinical trials, basic discovery,
and translational research. The

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