Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study

R. H. Christenson; W. F. Peacock; F. S. Apple; A. T. Limkakeng; R. M. Nowak; J. McCord; C. R. deFilippi

doi:10.1016/j.conctc.2019.100337

Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study

R. H. Christenson, W. F. Peacock, F. S. Apple, A. T. Limkakeng, R. M. Nowak, J. McCord, C. R. deFilippi

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	100337
Journal	Contemporary Clinical Trials Communications
Volume	14
DOIs	https://doi.org/10.1016/j.conctc.2019.100337
State	Published - Jun 2019

Bibliographical note

Funding Information:
The HIGH-US study was supported/funded by Siemens Healthineers, 511 Benedict Avenue, Tarrytown, NY 10591, USA. This research did not receive any specific grant from funding agencies in the public, or not-for-profit sectors.This work is funded/supported by Siemens Healthineers Laboratory Diagnostics Inc.Dr. R.H. Christenson has received fees from Siemens Healthineers for consultancy work on design and conduct of high-sensitivity cardiac troponin I clinical trials, and is a consultant for Siemens Healthineers, Roche Diagnostics, Quidel Diagnostics, and Beckman Coulter.Dr. F. Peacock has received research Grants from Abbott, Braincheck, Immunarray, Janssen, Ortho Clinical Diagnostics, Relypsa, Roche. He has served as a consultant to Abbott, Astra-Zeneca, Bayer, Beckman, Boehrhinger-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens Healthineers. He has provided expert testimony for Johnson and Johnson, and has stock/ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC.Dr. A.T. Limkakeng has received grant funding from Roche Diagnostics, Inc., Abbott Laboratories, Bristol Meyers Squibb, Ischemia Care, LTD., GE, and Astrazeneca. He has served as a consultant to Biomerieux and ZS Pharma.Dr. R.M. Nowak has received fees from Siemens Healthineers as a consultant for the design and conduct of this high-sensitivity cardiac troponin I trial. Additionally, he has been or is a consultant for Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Ortho Diagnostics, and Abbott.Dr. J. McCord has received research support from Roche, Siemens Healthineers, Abbott, and Beckman, and has served as a consultant for Roche and Siemens Healthineers.Dr. C. deFilippi has received research support through his institution Inova. In addition, he consults for Abbott Diagnostics, FujiRebio, Metabolomics, Ortho Diagnostics, Roche Diagnostics, and Siemens Healthineers. He has received honorarium from WebMD and Royalties from UpToDate.

Funding Information:
Dr. A.T. Limkakeng has received grant funding from Roche Diagnostics, Inc ., Abbott Laboratories , Bristol Meyers Squibb , Ischemia Care, LTD ., GE , and Astrazeneca . He has served as a consultant to Biomerieux and ZS Pharma.

Publisher Copyright:
© 2019

Keywords

99th percentile
Analytical characteristics
Clinical performance
High-sensitivity cardiac troponin
Immunoassay
Sex-specific 99th percentile cutoffs

PubMed: MeSH publication types

Journal Article

Publisher link

10.1016/j.conctc.2019.100337

Find It

Find It at U of M Libraries

Cite this

Christenson, R. H., Peacock, W. F., Apple, F. S., Limkakeng, A. T., Nowak, R. M., McCord, J., & deFilippi, C. R. (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, Article 100337. https://doi.org/10.1016/j.conctc.2019.100337

@article{61c99d091cf441358734e28f51298713,

title = "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.",

keywords = "99th percentile, Analytical characteristics, Clinical performance, High-sensitivity cardiac troponin, Immunoassay, Sex-specific 99th percentile cutoffs",

author = "Christenson, {R. H.} and Peacock, {W. F.} and Apple, {F. S.} and Limkakeng, {A. T.} and Nowak, {R. M.} and J. McCord and deFilippi, {C. R.}",

note = "Funding Information: The HIGH-US study was supported/funded by Siemens Healthineers, 511 Benedict Avenue, Tarrytown, NY 10591, USA. This research did not receive any specific grant from funding agencies in the public, or not-for-profit sectors.This work is funded/supported by Siemens Healthineers Laboratory Diagnostics Inc.Dr. R.H. Christenson has received fees from Siemens Healthineers for consultancy work on design and conduct of high-sensitivity cardiac troponin I clinical trials, and is a consultant for Siemens Healthineers, Roche Diagnostics, Quidel Diagnostics, and Beckman Coulter.Dr. F. Peacock has received research Grants from Abbott, Braincheck, Immunarray, Janssen, Ortho Clinical Diagnostics, Relypsa, Roche. He has served as a consultant to Abbott, Astra-Zeneca, Bayer, Beckman, Boehrhinger-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens Healthineers. He has provided expert testimony for Johnson and Johnson, and has stock/ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC.Dr. A.T. Limkakeng has received grant funding from Roche Diagnostics, Inc., Abbott Laboratories, Bristol Meyers Squibb, Ischemia Care, LTD., GE, and Astrazeneca. He has served as a consultant to Biomerieux and ZS Pharma.Dr. R.M. Nowak has received fees from Siemens Healthineers as a consultant for the design and conduct of this high-sensitivity cardiac troponin I trial. Additionally, he has been or is a consultant for Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Ortho Diagnostics, and Abbott.Dr. J. McCord has received research support from Roche, Siemens Healthineers, Abbott, and Beckman, and has served as a consultant for Roche and Siemens Healthineers.Dr. C. deFilippi has received research support through his institution Inova. In addition, he consults for Abbott Diagnostics, FujiRebio, Metabolomics, Ortho Diagnostics, Roche Diagnostics, and Siemens Healthineers. He has received honorarium from WebMD and Royalties from UpToDate. Funding Information: Dr. A.T. Limkakeng has received grant funding from Roche Diagnostics, Inc ., Abbott Laboratories , Bristol Meyers Squibb , Ischemia Care, LTD ., GE , and Astrazeneca . He has served as a consultant to Biomerieux and ZS Pharma. Publisher Copyright: {\textcopyright} 2019",

year = "2019",

month = jun,

doi = "10.1016/j.conctc.2019.100337",

language = "English (US)",

volume = "14",

journal = "Contemporary Clinical Trials Communications",

issn = "2451-8654",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States

T2 - The HIGH-US study

AU - Christenson, R. H.

AU - Peacock, W. F.

AU - Apple, F. S.

AU - Limkakeng, A. T.

AU - Nowak, R. M.

AU - McCord, J.

AU - deFilippi, C. R.

N1 - Funding Information: The HIGH-US study was supported/funded by Siemens Healthineers, 511 Benedict Avenue, Tarrytown, NY 10591, USA. This research did not receive any specific grant from funding agencies in the public, or not-for-profit sectors.This work is funded/supported by Siemens Healthineers Laboratory Diagnostics Inc.Dr. R.H. Christenson has received fees from Siemens Healthineers for consultancy work on design and conduct of high-sensitivity cardiac troponin I clinical trials, and is a consultant for Siemens Healthineers, Roche Diagnostics, Quidel Diagnostics, and Beckman Coulter.Dr. F. Peacock has received research Grants from Abbott, Braincheck, Immunarray, Janssen, Ortho Clinical Diagnostics, Relypsa, Roche. He has served as a consultant to Abbott, Astra-Zeneca, Bayer, Beckman, Boehrhinger-Ingelheim, Ischemia Care, Dx, Immunarray, Instrument Labs, Janssen, Nabriva, Ortho Clinical Diagnostics, Relypsa, Roche, Quidel, and Siemens Healthineers. He has provided expert testimony for Johnson and Johnson, and has stock/ownership interests in AseptiScope Inc, Brainbox Inc, Comprehensive Research Associates LLC, Emergencies in Medicine LLC, and Ischemia DX LLC.Dr. A.T. Limkakeng has received grant funding from Roche Diagnostics, Inc., Abbott Laboratories, Bristol Meyers Squibb, Ischemia Care, LTD., GE, and Astrazeneca. He has served as a consultant to Biomerieux and ZS Pharma.Dr. R.M. Nowak has received fees from Siemens Healthineers as a consultant for the design and conduct of this high-sensitivity cardiac troponin I trial. Additionally, he has been or is a consultant for Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Ortho Diagnostics, and Abbott.Dr. J. McCord has received research support from Roche, Siemens Healthineers, Abbott, and Beckman, and has served as a consultant for Roche and Siemens Healthineers.Dr. C. deFilippi has received research support through his institution Inova. In addition, he consults for Abbott Diagnostics, FujiRebio, Metabolomics, Ortho Diagnostics, Roche Diagnostics, and Siemens Healthineers. He has received honorarium from WebMD and Royalties from UpToDate. Funding Information: Dr. A.T. Limkakeng has received grant funding from Roche Diagnostics, Inc ., Abbott Laboratories , Bristol Meyers Squibb , Ischemia Care, LTD ., GE , and Astrazeneca . He has served as a consultant to Biomerieux and ZS Pharma. Publisher Copyright: © 2019

PY - 2019/6

Y1 - 2019/6

N2 - 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.

AB - 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.

KW - 99th percentile

KW - Analytical characteristics

KW - Clinical performance

KW - High-sensitivity cardiac troponin

KW - Immunoassay

KW - Sex-specific 99th percentile cutoffs

UR - http://www.scopus.com/inward/record.url?scp=85061806373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061806373&partnerID=8YFLogxK

U2 - 10.1016/j.conctc.2019.100337

DO - 10.1016/j.conctc.2019.100337

M3 - Article

C2 - 30834354

AN - SCOPUS:85061806373

SN - 2451-8654

VL - 14

JO - Contemporary Clinical Trials Communications

JF - Contemporary Clinical Trials Communications

M1 - 100337

ER -

Trial design for assessing analytical and clinical performance of high-sensitivity cardiac troponin I assays in the United States: The HIGH-US study

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

Publisher link

Find It

Other files and links

Fingerprint

Cite this