title: Defining normality in a European multinational cohort: Critical factors influencing the 99th percentile upper reference limit for high sensitivity cardiac troponin I.
abstract: OBJECTIVE
  To establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria.
  
  
  METHODS
  1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c] < 48 mmol/mol), myocardial (B-type natriuretic peptide [BNP] < 35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m(2)), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods.
  
  
  RESULTS
  The use of biomarker selection criteria resulted in a decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age-specific, differences at 99th percentile URL have been identified.
  
  
  CONCLUSIONS
  The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed.
authors.affiliation: Department of Laboratory Medicine, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Poland. Electronic address: krintus@wp.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Krintus
authors.affiliation: Department of Cardiology and Internal Medicine, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Kozinski
authors.affiliation: Department of Clinical Biology, CHR Mons-Hainaut, Mons, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Boudry
authors.affiliation: Laboratory Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Lackner
authors.affiliation: Department of Biochemistry and Hormonology, AP-HP, Hôpital Tenon, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lefèvre
authors.affiliation: Abbott Laboratories, Wiesbaden, Germany.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Lennartz
authors.affiliation: Laboratory Medicine, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Lotz
authors.affiliation: Department of Laboratory Medicine, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Poland.
authors.forename: Slawomir
authors.initials: S
authors.lastname: Manysiak
authors.affiliation: Abbott Laboratories, Abbott Park, IL, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Shih
authors.affiliation: Laboratory of Clinical Biochemistry, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Skadberg
authors.affiliation: Department of Biochemistry and Hormonology, AP-HP, Hôpital Tenon, Paris, France.
authors.forename: Ahmed Taoufik
authors.initials: AT
authors.lastname: Chargui
authors.affiliation: Department of Laboratory Medicine, Nicolaus Copernicus University, Collegium Medicum in Bydgoszcz, Poland.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Sypniewska
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D012016:Reference Values; D012680:Sensitivity and Specificity; D019210:Troponin I / Q000097:blood*
chemical_list: D015415:Biomarkers; D019210:Troponin I
keywords: 99th percentile URL; High-sensitivity troponin; Normality