title: Improving the inter-laboratory harmonization of the international normalized ratio (INR): utilizing the concept of transference to estimate and/or validate international sensitivity index (ISI) and mean normal prothrombin time (MNPT) values and/or to eliminate measurement bias.
abstract: BACKGROUND
  The Prothrombin Time (PT) assay is clinically the most often requested coagulation test, as used primarily for monitoring of Vitamin K antagonist therapy where results are typically expressed as an International Normalized Ratio (INR). The INR reflects the patient's PT adjusted for the specific test reagent and instrument combination used by applying two correction factors, namely the International Sensitivity Index (ISI) and the Mean Normal Prothrombin Time (MNPT), according to the formula: INR = (patient PT/MNPT)ISI. When the manufacturer provides an ISI, laboratories are encumbered to check or locally validate the assigned value. Where a manufacturer does not provide an ISI, the laboratory needs to define its own (local ISI) value. The MNPT typically has to be locally defined, based on the population being tested. The main current CLSI recommendation for defining ISI values comprises use of commercial reference ('certified') plasma calibration sets, but FDA cleared material is limited, and different results may arise using different products. The MNPT can be defined using a WHO/CLSI recommended procedure requiring 20 normal individuals or with some calibration sets. Overall, there is limited data to validate the performance of these processes in laboratory practice, and ongoing evidence from external quality assurance (proficiency testing) programs indicates continued failure in INR harmonization, suggesting that ISI and MNPT values used by laboratories (and presumably assessed using current recommended processes) continue to be inaccurate.
  
  
  OBJECTIVE
  To assess some novel approaches to the laboratory estimation and/or validation of ISI and MNPT values for use in the INR calculation, and including the process of 'transference', normally used to assess the comparability of analytical systems or to transfer reference intervals between comparable systems.
  
  
  RESULTS
  We have successfully adapted these comparative procedures, including 'transference', to permit ongoing estimation and/or validation of ISI and MNPT values for use in INR calculations for a range of instrumentation, which has led to improved harmonization of INR values obtained in our pathology network. These processes do not require the use of any normal individual plasmas or calibrator sets and greatly simplifies the INR process. Evidence for validation of the processes used is provided by ongoing satisfactory performance in external quality assurance (proficiency testing).
authors.affiliation: Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead. emmanuel.favaloro@swahs.halth.nsw.gov.au
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Favaloro
authors.forename: Wendy
authors.initials: W
authors.lastname: McVicker
authors.forename: Yifang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sayed
authors.initials: S
authors.lastname: Hamdam
authors.forename: Michelle
authors.initials: M
authors.lastname: Huynh
authors.forename: Padmini
authors.initials: P
authors.lastname: Peris
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Neal
authors.forename: Naomi
authors.initials: N
authors.lastname: Hocker
mesh_terms: D015982:Bias; D006801:Humans; D019934:International Normalized Ratio / Q000592:standards*; D007753:Laboratories / Q000592:standards*; D011517:Prothrombin Time / Q000592:standards*; D012015:Reference Standards; D012016:Reference Values; D015203:Reproducibility of Results