Differences between study-specific and subject-specific heart rate corrections of the QT interval in investigations of drug induced QTc prolongation

A computational study was designed to investigate the differences between the so-called Study-specific and subject-specific heart rate corrections of QT interval. In 53 healthy subjects (25 women, mean age 26.7 +/- 8.7 years), serial 10-second electrocardiograms (ECG) were obtained during daytime hours. In each subject, 200 ECGs were selected representative of the individual QT/RR relationship, Of the Population of 53 subjects, 30,000 different subgroups of 16 Subjects were considered and their data used to model drug induced QT interval prolongation by 0, 5, 10, and 20 ms combined with drug induced heart rate acceleration and deceleration. In each modeled Study, QTc changes were assessed by: (1) Six study-specific heart rate corrections designed by regression modeling of the baseline QT/RR data pooled from all subjects; (2) Six subject-specific heart rate corrections designed by the some regression modeling of the baseline QT/RR data in each subject separately; (3) Subject optimized correction that selected the best fitting regression model for each individual and (4) by Bazett and Fridericia Corrections. In each modeled study, the errors of the correction approaches were estimated and statistically Summarized over all modeled studies. The subject-specific corrections led to maximum errors in single milliseconds (error range of 2.4, 5.7, and 2.6 ms with linear, log/log linear, and exponential models, respectively) while the study-specific corrections led to substantially greater errors (error range of 17.8, 19.4, and 16.9 ms with linear, log/log linear, and exponential models, respectively). Both Bazett and Fridericia corrections led not only to substantial errors (error range of 28.3 and 16.9 ms) but also to regular bias with systematically false negative and false positive conclusions dependent on modeled heart rate acceleration and deceleration. Thus, subjects-specific corrections should be used in the intensive and definite studies aimed at providing the final answer on the ability of a drug to prolong the QT interval.