THE INFLUENCE OF THE REFERENCE MEAN PROTHROMBIN TIME ON THE INTERNATIONAL NORMALIZED RATIO

The International Normalized Ratio (INR) is a mathematical transformat ion of the prothrombin time (PT). The transformation requires a labora tory 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 l aboratory settings was determined. Because the variance of an individu al laboratory geometric mean is not directly determinable by simple pa rametric equations, its variance is estimated using bootstrap analysis . The geometric mean is compared to the computationally simpler arithm etic mean for effects on accuracy and precision of the resulting INR. The study shows mathematically and empirically that using the arithmet ic mean biases INR determinations so that patients tend to be over-ant icoagulated. However, in the laboratory settings examined, the amount of bias was both statistically and clinically insignificant. An analys is of the effect on the INR of errors in estimating the geometric mean reference PT also is performed. For large biases in estimating the re ference mean, the INR can be significantly affected and can trigger in appropriate clinical actions in patients. The authors demonstrate empi rically and mathematically that biases in the geometric mean reference PT do not affect the INR coefficient of variation. However, they prod uce significant differences in confidence intervals for INR determinat ions. Laboratories must exercise care in determining specific referenc e means to ensure that biases do not occur in geometric mean reference PT determinations. This can be achieved by circumspection in the sele ction of normal subjects for the reference population, carefully revie wing the data, and performing the proper calculations on the data.