Rank-based estimate of four-parameter logistic model.

During drug development, the calculation of inhibitory concentration that results in a response of 50% (IC50) is performed thousands of times every day. The nonlinear model most often used to perform this calculation is a four-parameter logistic, suitably parameterized to estimate the IC50 directly. When performing these calculations in a high-throughput mode, each and every curve cannot be studied in detail, and outliers in the responses are a common problem. A robust estimation procedure to perform this calculation is desirable. In this paper, a rank-based estimate of the four-parameter logistic model that is analogous to least squares is proposed. The rank-based estimate is based on the Wilcoxon norm. The robust procedure is illustrated with several examples from the pharmaceutical industry. When no outliers are present in the data, the robust estimate of IC50 is comparable with the least squares estimate, and when outliers are present in the data, the robust estimate is more accurate. A robust goodness-of-fit test is also proposed. To investigate the impact of outliers on the traditional and robust estimates, a small simulation study was conducted.

Reference regions for beat-to-beat ECG data.

The QT interval is regarded as an important biomarker for the assessment of arrhythmia liability, and evidence of QT prolongation has led to the withdrawal and relabeling of numerous compounds. Traditional methods of assessing QT prolongation correct the QT interval for the length of the RR interval (which varies inversely with heart-rate) in a variety of ways. These methods often disagree with each other and do not take into account changes in autonomic state. Correcting the QT interval for RR reduces a bivariate observation (RR, QT) to a univariate observation (QTc). The development of automatic electrocardiogram (ECG) signal acquisition systems has made it possible to collect continuous (so called 'beat-to-beat') ECG data. ECG data collected prior to administration of a compound allow us to define a region for (RR, QT) values that encompasses typical activity. Such reference regions are used in clinical applications to define the 'normal' region of clinical or laboratory measurements. This paper motivates the need for reference regions of (RR, QT) values from beat-to-beat ECG data, and describes a way of constructing these. We introduce a measure of agreement between two reference regions that points to the reliability of 12-lead digital Holter data. We discuss the use of reference regions in establishing baselines for ECG parameters to assist in the evaluation of cardiac risk and illustrate using data from two methodological studies.

Automated identification of postoperative complications within an electronic medical record using natural language processing.

CONTEXT: Currently most automated methods to identify patient safety occurrences rely on administrative data codes; however, free-text searches of electronic medical records could represent an additional surveillance approach. OBJECTIVE: To evaluate a natural language processing search-approach to identify postoperative surgical complications within a comprehensive electronic medical record. DESIGN, SETTING, AND PATIENTS: Cross-sectional study involving 2974 patients undergoing inpatient surgical procedures at 6 Veterans Health Administration (VHA) medical centers from 1999 to 2006. MAIN OUTCOME MEASURES: Postoperative occurrences of acute renal failure requiring dialysis, deep vein thrombosis, pulmonary embolism, sepsis, pneumonia, or myocardial infarction identified through medical record review as part of the VA Surgical Quality Improvement Program. We determined the sensitivity and specificity of the natural language processing approach to identify these complications and compared its performance with patient safety indicators that use discharge coding information. RESULTS: The proportion of postoperative events for each sample was 2% (39 of 1924) for acute renal failure requiring dialysis, 0.7% (18 of 2327) for pulmonary embolism, 1% (29 of 2327) for deep vein thrombosis, 7% (61 of 866) for sepsis, 16% (222 of 1405) for pneumonia, and 2% (35 of 1822) for myocardial infarction. Natural language processing correctly identified 82% (95% confidence interval [CI], 67%-91%) of acute renal failure cases compared with 38% (95% CI, 25%-54%) for patient safety indicators. Similar results were obtained for venous thromboembolism (59%, 95% CI, 44%-72% vs 46%, 95% CI, 32%-60%), pneumonia (64%, 95% CI, 58%-70% vs 5%, 95% CI, 3%-9%), sepsis (89%, 95% CI, 78%-94% vs 34%, 95% CI, 24%-47%), and postoperative myocardial infarction (91%, 95% CI, 78%-97%) vs 89%, 95% CI, 74%-96%). Both natural language processing and patient safety indicators were highly specific for these diagnoses. CONCLUSION: Among patients undergoing inpatient surgical procedures at VA medical centers, natural language processing analysis of electronic medical records to identify postoperative complications had higher sensitivity and lower specificity compared with patient safety indicators based on discharge coding.

Electrical alternans and hemodynamics in the anesthetized guinea pig can discriminate the cardiac safety of antidepressants.

INTRODUCTION: The arrhythmogenic risk of fluoxetine, citalopram, and venlafaxine were evaluated through preclinical assays measuring hERG, blood pressure and electrical alternans over their respective clinical unbound concentration ranges. METHODS: Anesthetized guinea pigs were instrumented with jugular and carotid cannulae for drug infusion and blood pressure monitoring respectively; a thoracotomy was performed for placement of a monophasic action potential probe on the left ventricle and for placement of pacing wires on the left ventricular apex. Drugs were infused as a 5-min loading dose immediately followed by a 10-min maintenance dose to achieve clinically relevant plasma concentrations; blood samples were taken at the end of each maintenance dose. Ventricular pacing was performed twice at baseline and at each dose level as follows: 50 preconditioning-beats at S1=220 (or 240) ms immediately followed by 30 test-beats at S2=200 ms. This S1-S2 protocol was repeated for S2=190 to 140 ms. HERG and calcium current measurements were recorded in HEK-293 cells stably expressing hERG potassium currents and freshly isolated guinea pig cardiac myocytes using the whole-cell configuration of the patch clamp technique. RESULTS: Physiologically relevant inhibition (IC(20)) of hERG occurred at concentrations 22-fold (fluoxetine), 9-fold (citalopram), and 11-fold (venlafaxine) beyond their respective clinically effective concentration (C(eff)). At the highest achievable levels, fluoxetine (20-fold C(eff)) and citalopram (28-fold C(eff)) significantly decreased heart rate and/or blood pressure as well as increasing electrical alternans by 5 and 18 ms respectively. Venlafaxine increased blood pressure at only 1.3-fold C(eff), but did not increase electrical alternans at the highest achievable dose (3.1-fold C(eff)). DISCUSSION: These data suggest that evaluating other dose limiting side effects in relation to a drug's therapeutic range may be crucial for accurate assessment of arrhythmia liability.

Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat.

The relationship of rotatable bond count (N(rot)) and polar surface area (PSA) with oral bioavailability in rats was examined for 434 Pharmacia compounds and compared with an earlier report from Veber et al. (J. Med. Chem. 2002, 45, 2615). N(rot) and PSA were calculated with QikProp or Cerius2. The resulting correlations depended on the calculation method and the therapeutic class within the data superset. These results underscore that such generalizations must be used with caution.

Operating room clinicians' ratings of workload: a vignette simulation study.

OBJECTIVES: Increased clinician workload is associated with medical errors and patient harm. The Quality and Workload Assessment Tool (QWAT) measures anticipated (pre-case) and perceived (post-case) clinical workload during actual surgical procedures using ratings of individual and team case difficulty from every operating room (OR) team member. The purpose of this study was to examine the QWAT ratings of OR clinicians who were not present in the OR but who read vignettes compiled from actual case documentation to assess interrater reliability and agreement with ratings made by clinicians involved in the actual cases. METHODS: Thirty-six OR clinicians (13 anesthesia providers, 11 surgeons, and 12 nurses) used the QWAT to rate 6 cases varying from easy to moderately difficult based on actual ratings made by clinicians involved with the cases. Cases were presented and rated in random order. Before rating anticipated individual and team difficulty, the raters read prepared clinical vignettes containing case synopses and much of the same written case information that was available to the actual clinicians before the onset of each case. Then, before rating perceived individual and team difficulty, they read part 2 of the vignette consisting of detailed role-specific intraoperative data regarding the anesthetic and surgical course, unusual events, and other relevant contextual factors. RESULTS: Surgeons had higher interrater reliability on the QWAT than did OR nurses or anesthesia providers. For the anticipated individual and team workload ratings, there were no statistically significant differences between the actual ratings and the ratings obtained from the vignettes. There were differences for the 3 provider types in perceived individual workload for the median difficulty cases and in the perceived team workload for the median and more difficult cases. CONCLUSIONS: The case difficulty items on the QWAT seem to be sufficiently reliable and valid to be used in other studies of anticipated and perceived clinical workload of surgeons. Perhaps because of the limitations of the clinical documentation shown to anesthesia providers and OR nurses in the current vignette study, more evidence needs to be gathered to demonstrate the criterion-related validity of the QWAT difficulty items for assessing the workload of nonsurgeon OR clinicians.

Analyses of dynamic beat-to-beat QT-TQ interval (ECG restitution) changes in humans under normal sinus rhythm and prior to an event of torsades de pointes during QT prolongation caused by sotalol.

BACKGROUND: Restitution through intracardiac pacing has been used to assess arrhythmia vulnerability. We examined whether analyses of sequential beat-to-beat QT and TQ interval measures can be used to quantify ECG restitution changes under normal sinus rhythm. METHODS: The QT, R-R and TQ intervals were examined 22.5 hour Holter monitoring before and after oral sotalol in normal male and female volunteers. Additionally, comparisons were made to those observed in the time-matched dataset prior to torsades de pointes in a heart diseased patient that received a single dose of sotalol. RESULTS: Sotalol increased QT, R-R and TQ intervals 71, 101, and 125 ms after 160 mg (n = 38) and 194, 235, and 135 ms after 320 mg (n = 19) during maximum plasma concentrations, respectively. The percentage of beats with a QT/TQ ratio >1 was reduced 25% over the entire 22.5 hours after sotalol and the lower TQ interval boundary (5th quantile) was increased 22-30%. In contrast, 99% of the beats prior to torsades de pointes had a QT/TQ ratio > 1 and the median TQ interval was below the lower 98% confidence bounds of normals before and after sotalol. CONCLUSIONS: ECG restitution changes are quantifiable under varying states (nocturnally, beta-adrenergic blockade, QT prolongation) in healthy subjects.

QT prolongation modifies dynamic restitution and hysteresis of the beat-to-beat QT-TQ interval relationship during normal sinus rhythm under varying states of repolarization.

The analysis of cardiac electrical restitution (the relationship between an action potential duration and its preceding diastolic interval) has been used to predict arrhythmia liability. However, the procedure to measure restitution is invasive and disrupts normal physiological autonomic balance. Dynamic analysis of sequential beat-to-beat ECG data was used to study restitution under normal sinus rhythm and to quantify changes in temporal hysteresis with heart rate acceleration/deceleration during QT prolongation. Congenital long QT (LQT) 1 and LQT2 syndromes during sympathetic stimulation were modeled because of their association with increased risk of ventricular arrhythmia. Temporal heterogeneity and hysteresis of restitution were examined in the conscious dog under varying conditions of delayed repolarization using either the selective inhibitors of the slowly activating delayed rectifier potassium current (R)-2-(4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide (L-768,673); the rapidly activating delayed rectifier potassium current (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methyl-sulfonylaminobenzoyl)-piperidine (E-4031); or a combination of both at rest and during heart rate acceleration with sympathetic stimulation using isoproterenol challenges. Impaired repolarization with the combination of E-4031 and L-768,673 increased heterogeneity of restitution at rest 55 to 91%, increased hysteresis during heart rate acceleration after isoproterenol challenge by approximately 40 to 60%, and dramatically reduced the minimum TQ interval by 72% to only 28 ms. Impaired repolarization alters restitution during normal sinus rhythm and increases hysteresis/heterogeneity during heart rate acceleration following sympathetic stimulation. Thus, dynamic beat-to-beat measurements of restitution could lead to clinically applicable ECG obtained biomarkers for assessment of changes associated with arrhythmogenic risk.

Differentiation of arrhythmia risk of the antibacterials moxifloxacin, erythromycin, and telithromycin based on analysis of monophasic action potential duration alternans and cardiac instability.

Antibacterial drugs are known to have varying degrees of cardiovascular liability associated with QT prolongation that can lead to the ventricular arrhythmia torsade de pointes. The purpose of these studies was to compare the assessment for the arrhythmogenic risk of moxifloxacin, erythromycin, and telithromycin. Each drug caused dose-dependent inhibition of the rapidly activating delayed rectifier potassium current encoded by the human ether-á-go-go-related gene (hERG) with IC20 concentrations of 31 microM (moxifloxacin), 21 microM (erythromycin), and 11 microM (telithromycin). These drugs were also evaluated in an anesthetized guinea pig model to measure changes in monophasic action potential duration (MAPD) and to quantify beat-to-beat alternations in MAPD during rapid ventricular pacing. Moxifloxacin dose dependently increased MAPD and caused a rate-dependent increase in alternans at the highest achieved free drug concentration (41 microM). Erythromycin also increased MAPD at its highest free drug concentration (58 microM), but alternans occurred at a relatively lower therapeutic multiple (13.9 microM), and the magnitude of alternans at higher concentrations was independent of pacing rate. Further analysis of the data showed that the beat-to-beat pattern of alternans with erythromycin was less stable than that with moxifloxacin and suggestive of greater arrhythmogenic liability. In contrast to erythromycin and moxifloxacin, telithromycin decreased both MAPD and alternans at the highest achievable drug concentration (7.9 microM). The relative risk at therapeutic concentrations is erythromycin>moxifloxacin>telithromycin and appears to be consistent with clinical observations of torsade de pointes in patients.

Dynamic beat-to-beat modeling of the QT-RR interval relationship: analysis of QT prolongation during alterations of autonomic state versus human ether a-go-go-related gene inhibition.

Methods to correct the QT interval for heart rate are often in disagreement and may be further confounded by changes in autonomic state. This can be problematic when trying to distinguish the changes in QT interval by either drug-induced delayed repolarization or from autonomic-mediated physiological responses. Assessment of the canine dynamic QT-RR interval relationship was visualized by novel programming of the dynamic beat-to-beat confluence of data or "clouds". To represent the nonuniformity of the clouds, a bootstrap sampling method that computes the mathematical center of the uncorrected beat-to-beat QT value (QTbtb) with upper 95% confidence bounds was adopted and compared with corrected QT (QTc) using standard correction factors. Nitroprusside-induced reflex tachycardia reduced QTbtb by 43 ms, whereas an increase of 55 and 16 ms was obtained using the Bazett (QTcB) and Fridericia (QTcF) formulae, respectively. Phenylephrine-induced reflex bradycardia increased QTbtb by 3 ms but decreased QTcB by 20 ms and QTcF by 12 ms. Delayed repolarization with E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methylsulfonylaminobenzoyl)-piperidine), an inhibitor of rectifier potassium current, increased QTbtb by 26 ms but QT prolongation calculations using QTcF and QTcB were between 12 and 52% less, respectively, when small decreases in heart rate (5-8 beats per minute) were apparent. Dynamic assessment of beat-to-beat data, using the bootstrap method, allows quantification of QT interval changes under varying conditions of heart rate, autonomic tone, and direct repolarization that may not be distinguishable with use of standard correction factors.