The influence of the reference mean prothrombin time on the international normalized ratio

The International Normalized Ratio (INR) is a mathematical transformation of the prothrombin time (PT). The transformation requires a laboratory to compute the geometric mean of its own reference population. In this paper, the authors examine how the reference mean PT influences the INR accuracy and precision using a validated probabilistic model. The variance of the geometric mean of reference populations in three laboratory settings was determined. Because the variance of an individual laboratory geometric mean is not directly determinable by simple parametric equations, its variance is estimated using bootstrap analysis. The geometric mean is compared to the computationally simpler arithmetic mean for effects on accuracy and precision of the resulting INR. The study shows mathematically and empirically that using the arithmetic mean biases INR determinations so that patients tend to be over-anticoagulated. However, in the laboratory settings examined, the amount of bias was both statistically and clinically insignificant. An analysis of the effect on the INR of errors in estimating the geometric mean reference PT also is performed. For large biases in estimating the reference mean, the INR can be significantly affected and can trigger inappropriate clinical actions in patients. The authors demonstrate empirically and mathematically that biases in the geometric mean reference PT do not affect the INR coefficient of variation. However, they produce significant differences in confidence intervals for INR determinations. Laboratories must exercise care in determining specific reference means to ensure that biases do not occur in geometric mean reference PT determinations. This can be achieved by circumspection in the selection of normal subjects for the reference population, carefully reviewing the data, and performing the proper calculations on the data.