A one-step approach to the analysis of the QT interval in conscious telemetrized dogs.
BACKGROUND
To account for heart rate-induced changes in the QT interval, correction formulas are generally applied to normalize the QT interval for heart rate. None of these formulas is entirely accurate because correction or normalization of any parameter in biology may introduce an additional source of variation in estimating the parameter. In this article, a one-step approach for the statistical analysis of the QT interval was proposed based on modeling the functional relationship between the QT interval and heart rate.


METHODS
The QT-HR relationship was incorporated into the statistical analysis to provide a model-based correction. This was accomplished by including HR as a covariate in the QT interval analysis. The approach was demonstrated using data generated from Lilly Research Laboratories. We compared the false positive rate and statistical power of QT, QTcF, and the proposed one-step method.


RESULTS
We found the one-step method demonstrated the greatest sensitivity in detecting a QT interval change without an increase in the false positive rate. It was shown that the one-step QT analysis could detect a 5%-6% increment of the QT interval. This is approximately equivalent to an increase of 11-13 ms in QT interval in beagle dogs.


CONCLUSIONS
Several advantages and unique features of the one-step method are discussed. These include evaluating treatment effect on QT without applying a heart rate correction formula and estimating QT difference flexibly at any selected heart rate. In addition to the linear QT-HR relationship, other functional relationships can be easily implemented to this approach.
Chiang
Alan Y
AY
Global Statistical Sciences and Toxicology, Lilly Research Laboratories, Eli Lilly and Company, P.O. Box 708, Greenfield, IN 46140, USA. chiangay@lilly.com
Holdsworth
David L
DL
Leishman
Derek J
DJ
D000465:Algorithms; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005189:False Positive Reactions; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology*; D013686:Telemetry