title: Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction.
abstract: OBJECTIVE
  To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies.
  
  
  METHODS
  Twenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT-RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation.
  
  
  RESULTS
  Moxifloxacin prolonged the QTc by 10.6 ± 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ± 0.13 vs. 0.82 ± 0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ± 0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7 ± 1.1 ms vs. 8.8 ± 1.2 ms for Fridericia).
  
  
  CONCLUSIONS
  The ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.
authors.affiliation: Hôpital du Sacré-Cœur de Montréal, Centre de Recherche, Montréal, QC, Canada.
authors.forename: Raymundo
authors.initials: R
authors.lastname: Cassani González
authors.forename: Elien B
authors.initials: EB
authors.lastname: Engels
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubé
authors.forename: Réginald
authors.initials: R
authors.lastname: Nadeau
authors.forename: Alain
authors.initials: A
authors.lastname: Vinet
authors.forename: A Robert
authors.initials: AR
authors.lastname: LeBlanc
authors.forename: Marcio
authors.initials: M
authors.lastname: Sturmer
authors.forename: Giuliano
authors.initials: G
authors.lastname: Becker
authors.forename: Teresa
authors.initials: T
authors.lastname: Kus
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacquemet
mesh_terms: D000465:Algorithms; D001372:Aza Compounds / Q000008:administration & dosage*; D003936:Diagnosis, Computer-Assisted / Q000379:methods*; D015716:Electrocardiography, Ambulatory / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage*; D012372:ROC Curve; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin