An Escalation for Bivariate Binary Endpoints Controlling the Risk of Overtoxicity (EBE-CRO): Managing Efficacy and Toxicity in Early Oncology Clinical Trials.

For about a decade, early clinical development in oncology is facing new challenges. This is due to two main reasons. The first one is linked to the developed molecular targeted agents (MTA) themselves for which the maximum tolerated dose (MTD) is no longer the only dose of interest. The second reason is related to the fact that costs and attrition rates are huge. When selecting a dose, evidence of early activity signal becomes required for future engagements. This implies the need to handle both toxicity and activity endpoints in the analysis and also in the dose escalation design of early-phase trials. We propose a model-based design taking into account both safety and activity for dose escalation. The proposed model involves a bivariate Gaussian latent variable depending on a monotonic toxicity curve and a quadratic activity curve. This model is fitted under the Bayesian framework that allows the incorporation of prior information. The predictive distributions of dose-response curves are used to lead the dose recommendation. Uncertainty in the dose-response relationship is taken into account to calculate the probability of being an over-toxic or a target dose. The proposed design is compared to two other widely used methods.

[Analysis of repeated binary data: sensitivity to missing data]. / Analyse de données binaires répétées: sensibilité aux données manquantes.

BACKGROUND: In longitudinal studies, it is extremely rare that all the planned measurements are actually performed. Missing data are often consecutive to drop-outs, but may also be intermittent. In both cases, the analysis of incomplete data necessarily requires assumptions that are generally unverifiable, and the need for sensitivity analyses has been advocated over the past few years. In this article, the attention will be given to longitudinal binary data. METHODS: A method is proposed, which is based on a log-linear model. A sensitivity parameter is introduced that represents the relationship between the response mechanism and the missing data mechanism. It is recommended not to estimate this parameter, but to consider a range of plausible values, and to estimate the parameters of interest conditionally on these plausible values. This allows to assess the sensitivity of the conclusion of a study to various assumptions regarding the missing data mechanism. RESULTS: This method was applied to a randomized clinical trial comparing the efficacy of two treatment regimens in patients with persistent asthma. The sensitivity analysis showed that the conclusion of this study was robust to missing data.

Large scale safety study of a liquid hexavalent vaccine (D-T-acP-IPV-PRP--T-HBs) administered at 2, 4, 6 and 12-14 months of age.

A study was conducted to assess the safety of a new, liquid hexavalent vaccine (Hexavac, Aventis Pasteur MSD, Lyon, France) in a large population of 1783 children in Germany vaccinated at 2, 4, 6 and 12-14 months of age. Immediate reactions, local and systemic reactions, and serious adverse events (SAEs) were monitored. The frequencies of redness > or = 2 cm and swelling > or = 2 cm were 6.7 and 7.1% after all doses of the primary series combined and 13.4 and 12.0% following the booster dose, respectively. Transient swelling of the entire thigh was reported in seven infants after all doses of the primary series (0.1%) and in four children after the booster dose (0.2%). The most frequent systemic adverse events within 3 days after vaccination were irritability (19.3% after primary series and 13.2% after booster) and fever > or = 38.0 degrees C (15.4% after primary series and 28.5% after booster). Fever above 40.0 degrees C was reported in 0.1% of the infants post-primary series and in 0.9% of the children after the booster immunization. Only 3 of 144 SAE were considered to be vaccine related and were seen to resolve spontaneously and without sequelae. The liquid hexavalent vaccine was generally well tolerated when given to children as a primary immunization series at 2, 4 and 6 months and as a booster dose at 12-14 months.

A practical method to statistically classify devices according to their relative accuracy.

Mathematical methods to statistically compare the relative accuracy of physiological monitoring devices to reference measurements are scarce. We developed such a method to compare any number of devices to each other as well as to reference values. This new statistical comparative procedure uses a combination of different known mathematical processes. The method allows the separation of the error of the devices into two components, the first, being systematic, can be easily amended, while the second, inherent to the technical limitations of the measuring device as well as to the physical properties of the explored phenomenon, cannot be corrected and will thus be used as the comparative criterion for statistics. That method, which is easy to implement should ease comparisons of the accuracy of any number of devices as well as comparison of other sets of physiological values, by giving an easy access to statistical results.

Relation between heart rate variability and training load in middle-distance runners.

PURPOSE: Monitoring physical performance is of major importance in competitive sports. Indices commonly used, like resting heart rate, VO2max, and hormones, cannot be easily used because of difficulties in routine use, of variations too small to be reliable, or of technical challenges in acquiring the data. METHODS: We chose to assess autonomic nervous system activity using heart rate variability in seven middle-distance runners, aged 24.6 +/- 4.8 yr, during their usual training cycle composed of 3 wk of heavy training periods, followed by a relative resting week. The electrocardiogram was recorded overnight twice a week and temporal and frequency indices of heart rate variability, using Fourier and Wavelet transforms, were calculated. Daily training loads and fatigue sensations were estimated with a questionnaire. Similar recordings were performed in a sedentary control group. RESULTS: The results demonstrated a significant and progressive decrease in parasympathetic indices of up to -41% (P < 0.05) during the 3 wk of heavy training, followed by a significant increase during the relative resting week of up to +46% (P < 0.05). The indices of sympathetic activity followed the opposite trend, first up to +31% and then -24% (P < 0.05), respectively. The percentage increasing mean nocturnal heart rate variation remained below 12% (P < 0.05). There was no significant variation in the control group. CONCLUSION: This study confirmed that heavy training shifted the cardiac autonomic balance toward a predominance of the sympathetic over the parasympathetic drive. When recorded during the night, heart rate variability appeared to be a better tool than resting heart rate to evaluate cumulated physical fatigue, as it magnified the induced changes in autonomic nervous system activity. These results could be of interest for optimizing individual training profiles.

Screening of obstructive sleep apnea syndrome by heart rate variability analysis.

BACKGROUND: Enhanced nocturnal heart rate variability (HRV) has been evoked in sleep-related breathing disorders. However, its capacity to detect obstructive sleep apnea syndrome (OSAS) has not been systematically determined. Thus, we evaluated the discriminant power of HRV parameters in a first group of patients (G1) and validated their discriminant capacity in a second group (G2). METHODS AND RESULTS: In G1, 39 of 91 patients (42.8%) were identified as diseased by polysomnography, as were 24 of 52 patients (46%) in G2. Time-domain HRV variables (SD of NN intervals [SDNN], mean of the standard deviations of all NN intervals for all consecutive 5-minute segments of the recording [SDNN index], square root of the mean of the sum of the squares of differences between adjacent normal RR intervals [r-MSSD], and SD of the averages of NN intervals in all 5-minute segments of the recording [SDANN]) were calculated for daytime and nighttime periods, as well as the differences between daytime and nighttime values (Delta[D/N]). Correlations between HRV variables and OSAS status were analyzed in G1 by use of receiver-operating characteristic (ROC) curves and logistic regression analysis. By ROC curve analysis, 7 variables were significantly associated with OSAS. After adjustment for other variables through multiple logistic regression analysis, Delta[D/N]SDNN index and Delta[D/N] r-MSSD remained significant independent predictors of OSAS, with ORs of 8.22 (95% CI, 3.16 to 21.4) and 2.86 (95% CI, 1.21 to 6.75), respectively. The classification and regression tree methodology demonstrated a sensitivity reaching 89.7% (95% CI, 73.7 to 97.7) with Delta[D/N] SDNN index and a specificity of 98.1% (95% CI, 86.4 to 100) with Delta[D/N] SDNN using appropriate thresholds. These thresholds, applied to G2, yielded a sensitivity of 83% using Delta[D/N] SDNN index and a specificity of 96.5% using Delta[D/N] SDNN. CONCLUSIONS: Time-domain HRV analysis may represent an accurate and inexpensive screening tool in clinically suspected OSAS patients and may help focus resources on those at the highest risk.

Maximal blood lactate level acts as a major discriminant variable in exercise testing for coronary artery disease detection in men.

BACKGROUND: The interpretation of exercise stress testing for coronary artery disease detection is affected by the many differences in chosen variables and mathematical methods. We conducted a prospective trial to evaluate a global muscle fatigue parameter--the blood lactate level achieved at maximal exercise--as a method of distinguishing between diseased and nondiseased coronary status. METHODS AND RESULTS: We evaluated 236 consecutive male patients without previous myocardial infarction who had been referred for the diagnosis of coronary artery disease. None of the patients had cardiomyopathy, severe cardiac heart failure, or valvular heart disease. Blood lactate concentration at maximal exercise was measured as well as other classic variables. Correlations between variables and coronary status as assessed by coronary arteriography were described using receiver operating characteristic (ROC) curves and logistic regression analysis. The first four most powerful variables (lactate level, maximal power output, exercise duration, and percentage of maximal predicted heart rate), which are directly representative of the global functional capacity, showed values of 0.777, 0.775, 0.760, and 0.740, respectively, by ROC curve analysis. Mean +/- SD blood lactate level at peak exercise reached 7.68 +/- 2.70 mmol/L in the 153 diseased and 10.56 +/- 2.75 mmol/L in the 83 nondiseased patients (P < .0001). After adjustment for other variables, blood lactate level remained a significant predictor of coronary artery disease by logistic regression analysis (adjusted odds ratio, 1.2; confidence interval, 1.04 to 1.4). CONCLUSIONS: Global muscle fatigue as assessed by lactate levels in the blood at maximal exercise appears to be a powerful distinguisher of diseased and nondiseased coronary status.

Elevated nocturnal blood pressure assessed by ambulatory automatic monitoring during a stay at high altitude.

The aim of this study was to explore, in healthy children, the arterial blood pressure response to a 3-week stay at high altitude (4200 m). An auscultatory automatic ambulatory pressuremeter was used to avoid undue environmental influence on the measurement. The blood pressure was monitored three times in a group of ten boys, aged 10.5 (CI 0.9 years): at sea level (control values), at an altitude of 2100 m after at least 24 h of acclimatization and after at least 24 h at 4200 m altitude. Each period of monitoring extended over 24 h with 10-min intervals between successive measurements. Arterial blood pressure was evaluated separately for the night and day periods. Nocturnal recordings revealed an increase with altitude in systolic as well as in the diastolic blood pressure. Because of the technique used to gather data, this is thought to have represented an independent effect of altitude without interference from the medical environment or diurnal activity.