Abstract
Fleming raises an interesting point about who has the responsibility to verify the analytical performance of cardiac troponin assays. 1 He questions whether routine diagnostic laboratories need to do an imprecision profile, or whether within- and between-day imprecision studies suffice, and whether laboratories should establish their own reference ranges, given the difficulties in confirming a reference individual is cardio-healthy and the large number of subjects required for establishing the 99th percentile of the troponin distribution?
Every laboratory has to take responsibility for the results it releases. Broadly we are offering a comment as to how normal or abnormal results are. For this reason we become mildly to moderately obsessive with reference intervals and imprecision testing. In the real world we find there are often differences between the analytical characteristics of troponin assays quoted in the manufacturer's package insert and those obtained by the routine laboratory. 2 Higher 10% coefficient of variation concentrations and lower 99th percentile upper reference limits (URLs) have been reported for some second-generation troponin I assays. 3,4 These findings may reflect that often assays perform better in a highly quality-controlled setting such as research and development laboratories than in the real-world environment and the reference populations may differ in sample size or their characteristics. 2,5 For troponin T, these issues have been less of a problem as a single manufacturer has produced the different generations of troponin T assays.
So what should a routine laboratory do? Clearly there is a need for meaningful input from diagnostic companies who provide kits. They have a regulatory requirement to have validated their assays and many of us pragmatically use the data they provide. In some countries governments may fund reference interval studies, but laboratories in Australia are not funded by the government to do research and development studies. Hence this work is done as an extra and in our own time, with outside funding required to support larger studies.
It is our opinion that as a minimum standard, laboratories should select a reference interval that is supported by findings in the peer-reviewed literature relating specifically to the assay they are using. Routine laboratories can verify that their assay measures ‘normal’ troponin concentrations that are below the 99th percentile URL by using blood samples from young males and females, e.g. medical students.
As a minimum standard for imprecision testing, routine laboratories should verify the within- and between-run precision capability of their assay over the troponin measuring range concentration, e.g. CLSI guideline EP15-A2. 6 The Study Group on Biomarkers in Cardiology of the European Society of Cardiology Working Group on Acute Cardiac Care recommends determination of at least one level close to the clinical decision limit for troponin, which may be the 99th percentile of a reference population value distribution. 5 This enables verification of the limit of quantitation that is clinically relevant. Adequate long-term monitoring of troponin imprecision is also essential to avoid wrong results in clinical samples and to confirm troponin transferability and accuracy across different reagent lots.
Ultimately it is buyer beware. A doctor using a pathology laboratory relies on them to produce quality results. When all is considered, it is the responsibility of each laboratory to put out meaningful, quality troponin data.
DECLARATIONS