Statistical models for heart rate correction of the QT interval. 2010

Arne Ring
Boehringer Ingelheim Pharma GmbH & Co. KG, Phase I/IIa Biostatistics, Biberach, Germany. arne.ring@boehringer-ingelheim.com

The analysis of QT interval data is now an essential part of the assessment of drug safety. As the QT interval is inversely associated with heart rate, an appropriate correction must be applied in order to evaluate QT data in clinical trials. The aim is to characterize changes in QT interval at a standard heart rate, taking into account the correlation between these two variables to adjust for heart rate changes during the course of the trial. It has been shown that the relationship between the RR interval (=1/heart rate) and the QT interval is highly variable between individuals but stable over time within each individual.Many mathematical models have been developed to describe the QT-RR relationship. However, there has been less emphasis on the derivation of suitable statistical models that account for the multilevel structure of the ECG data.An important example is the interpretation of the so-called population-specific heart rate corrections, which are based on data pooled from different subjects. Often, simple regression techniques are used to quantify the population correction, disregarding the subject level and leading to biased parameter estimates. Instead, population-based corrections that account for individual intercepts should be used, in order to distinguish within-subject-effects from between-subject effects. Therefore, population-specific corrections cannot be derived solely from the cross-sectional data. The impact of the different statistical models is illustrated by data from the baseline periods of six clinical QT studies.

UI MeSH Term Description Entries
D008955 Models, Cardiovascular Theoretical representations that simulate the behavior or activity of the cardiovascular system, processes, or phenomena; includes the use of mathematical equations, computers and other electronic equipment. Cardiovascular Model,Cardiovascular Models,Model, Cardiovascular
D002986 Clinical Trials as Topic Works about pre-planned studies of the safety, efficacy, or optimum dosage schedule (if appropriate) of one or more diagnostic, therapeutic, or prophylactic drugs, devices, or techniques selected according to predetermined criteria of eligibility and observed for predefined evidence of favorable and unfavorable effects. This concept includes clinical trials conducted both in the U.S. and in other countries. Clinical Trial as Topic
D004562 Electrocardiography Recording of the moment-to-moment electromotive forces of the HEART as projected onto various sites on the body's surface, delineated as a scalar function of time. The recording is monitored by a tracing on slow moving chart paper or by observing it on a cardioscope, which is a CATHODE RAY TUBE DISPLAY. 12-Lead ECG,12-Lead EKG,12-Lead Electrocardiography,Cardiography,ECG,EKG,Electrocardiogram,Electrocardiograph,12 Lead ECG,12 Lead EKG,12 Lead Electrocardiography,12-Lead ECGs,12-Lead EKGs,12-Lead Electrocardiographies,Cardiographies,ECG, 12-Lead,EKG, 12-Lead,Electrocardiograms,Electrocardiographies, 12-Lead,Electrocardiographs,Electrocardiography, 12-Lead
D006339 Heart Rate The number of times the HEART VENTRICLES contract per unit of time, usually per minute. Cardiac Rate,Chronotropism, Cardiac,Heart Rate Control,Heartbeat,Pulse Rate,Cardiac Chronotropy,Cardiac Chronotropism,Cardiac Rates,Chronotropy, Cardiac,Control, Heart Rate,Heart Rates,Heartbeats,Pulse Rates,Rate Control, Heart,Rate, Cardiac,Rate, Heart,Rate, Pulse
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000465 Algorithms A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. Algorithm
D056808 Biostatistics The application of STATISTICS to biological systems and organisms involving the retrieval or collection, analysis, reduction, and interpretation of qualitative and quantitative data. Biological Statistics,Biological Statistic,Statistic, Biological,Statistics, Biological
D018592 Cross-Over Studies Studies comparing two or more treatments or interventions in which the subjects or patients, upon completion of the course of one treatment, are switched to another. In the case of two treatments, A and B, half the subjects are randomly allocated to receive these in the order A, B and half to receive them in the order B, A. A criticism of this design is that effects of the first treatment may carry over into the period when the second is given. (Last, A Dictionary of Epidemiology, 2d ed) Cross-Over Design,Cross-Over Trials,Crossover Design,Crossover Studies,Crossover Trials,Cross Over Design,Cross Over Studies,Cross Over Trials,Cross-Over Designs,Cross-Over Study,Crossover Designs,Crossover Study,Design, Cross-Over,Design, Crossover,Designs, Cross-Over,Designs, Crossover,Studies, Cross-Over,Studies, Crossover,Study, Cross-Over,Study, Crossover,Trial, Cross-Over,Trial, Crossover,Trials, Cross-Over,Trials, Crossover

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