Biological quality control for cardiopulmonary exercise testing in multicenter clinical trials.
ABSTRACT: Precision and accuracy assurance in cardiopulmonary exercise testing (CPET) facilitates multicenter clinical trials by maximizing statistical power and minimizing participant risk. Current guidelines recommend quality control that is largely based on precision at individual testing centers (minimizing test-retest variability). The aim of this study was to establish a multicenter biological quality control (BioQC) method that considers both precision and accuracy in CPET.BioQC testing was 6-min treadmill walking at 20 W and 70 W (below the lactate threshold) with healthy non-smoking laboratory staff (15 centers; ~16 months). Measurements were made twice within the initial 4 weeks and quarterly thereafter. Quality control was based on: 1) within-center precision (coefficient of variation [CV] for oxygen uptake [V?O2], carbon dioxide output [V?CO2], and minute ventilation [V?E] within ±10%); and 2) a criterion that V?O2 at 20 W and 70 W, and ?V?O2/?WR were each within ±10 % predicted. "Failed" BioQC tests (i.e., those outside the predetermined criterion) prompted troubleshooting and repeated measurements. An additional retrospective analysis, using a composite z-score combining both BioQC precision and accuracy of V?O2 at 70 W and ?V?O2/?WR, was compared with the other methods.Of 129 tests (5 to 8 per center), 98 (76%) were accepted by within-center precision alone. Within-center CV was <9%, but between-center CV remained high (9.6 to 12.5%). Only 43 (33%) tests had all V?O2 measurements within the ±10% predicted criterion. However, a composite z-score of 0.67 identified 67 (52%) non-normal outlying tests, exclusion of which coincided with the minimum CV for CPET variables.Study-wide BioQC using a composite z-score can increase study-wide precision and accuracy, and optimize the design and conduct of multicenter clinical trials involving CPET.ClinicalTrials.gov identifier: NCT01072396; February 19, 2010.
Project description:PURPOSE:Clinical use of cardiopulmonary exercise tests (CPETs) is increasing in elderly patients with cardiovascular (CV) diseases. However, data on Korean populations are limited. In this study, we aimed to examine the characteristics and safety of CPET in an elderly Korean population with CV disease. MATERIALS AND METHODS:We retrospectively analyzed records of 1485 patients (older than 65 years in age, with various underlying CV diseases) who underwent CPET. All CPET was performed using the modified Bruce ramp protocol. RESULTS:The mean age of patients was 71.6±4.7 years with 63.9% being men, 567 patients aged 60-65 years, 818 patients aged 70-79 years, and 100 patients aged 80-89 years. The mean respiratory exchange ratio was 1.09±0.14. During CPET, three adverse cardiovascular events occurred (total 0.20%), all ventricular tachycardia. All subjects showed an average exercise capacity of 21.3±5.5 mL/kg/min at peak VO₂ and 6.1±1.6 metabolic equivalents of task, and men showed better exercise capacity than women on most CEPT parameters. A significant difference was seen in peak oxygen uptake according to age group (65-69 years, 22.9±5.8; 70-79 years, 20.7±5.1; 80-89 years, 17.0±4.5 mL/kg/min, p<0.001). The most common causes for CPET termination were dyspnea (64.8%) and leg pain (24.3%), with higher incidence of leg pain in octogenarians compared to other age groups (65-69 years, 22.4%; 70-79 years, 24.6%; 80-89 years, 32.0%, p<0.001). CONCLUSION:CPET was relatively a safe and useful modality to assess exercise capacity, even in an elderly Korean population with underlying CV diseases.
Project description:BACKGROUND:Body composition assessment, measured using single-slice computed tomography (CT) image at L3 level, and aerobic physical fitness, objectively measured using cardiopulmonary exercise testing (CPET), are each independently used for perioperative risk assessment. Sarcopenia (i.e. low skeletal muscle mass), myosteatosis [i.e. low skeletal muscle radiation attenuation (SM-RA)], and impaired objectively measured aerobic fitness (reduced oxygen uptake) have been associated with poor post-operative outcomes and survival in various cancer types. However, the association between CT body composition and physical fitness has not been explored. In this study, we assessed the association of CT body composition with selected CPET variables in patients undergoing hepatobiliary and pancreatic surgery. METHODS:A pragmatic prospective cohort of 123 patients undergoing hepatobiliary and pancreatic surgery were recruited. All patients underwent preoperative CPET. Preoperative CT scans were analysed using a single-slice CT image at L3 level to assess skeletal muscle mass, adipose tissue mass, and muscle radiation attenuation. Multivariate linear regression was used to test the association between CPET variables and body composition. Main outcomes were oxygen uptake at anaerobic threshold ( V? O2 at AT), oxygen uptake at peak exercise ( V? O2 peak), skeletal muscle mass, and SM-RA. RESULTS:Of 123 patients recruited [77 men (63%), median age 66.9 ± 11.7, median body mass index 27.3 ± 5.2], 113 patients had good-quality abdominal CT scans available and were included. Of the CT body composition variables, SM-RA had the strongest correlation with V? O2 peak (r = 0.57, P < 0.001) and V? O2 at AT (r = 0.45, P < 0.001) while skeletal muscle mass was only weakly associated with V? O2 peak (r = 0.24, P < 0.010). In the multivariate analysis, only SM-RA was associated with V? O2 peak (B = 0.25, 95% CI 0.15-0.34, P < 0.001, R2 = 0.42) and V? O2 at AT (B = 0.13, 95% CI 0.06-0.18, P < 0.001, R2 = 0.26). CONCLUSIONS:There is a positive association between preoperative CT SM-RA and preoperative physical fitness ( V? O2 at AT and at peak). This study demonstrates that myosteatosis, and not sarcopenia, is associated with reduced aerobic physical fitness. Combining both myosteatosis and physical fitness variables may provide additive risk stratification accuracy and guide interventions during the perioperative period.
Project description:Purpose: This study aimed to investigate the physiological factors affected by rifle carriage during biathlon skiing performance, as well as the sex differences associated with rifle carriage. Methods: Seventeen national- and international-level biathletes (nine females and eight males; age 23.0 ± 3.3 years, V. O2 max 59.4 ± 7.6 mL.kg-1.min-1) performed a submaximal incremental test and a maximal time-trial (TT) using treadmill roller-skiing (gear 3, skating technique) on two occasions separated by at least 48 h. One condition involved carrying the rifle on the back (WR) and the other condition no rifle (NR) and the tests were randomized. Submaximal V. O2, skiing speed at 4 mmol.L-1 of blood lactate (speed@ 4 mmol), gross efficiency (GE), aerobic (MRae), and anaerobic (MRan) metabolic rates, and V. O2 max were determined. Results: Submaximal V. O2 (at all intensities) and GE (16.7 ± 0.9 vs. 16.5 ± 1.1%) were higher for WR compared to NR (p < 0.05), while speed@ 4 mmol was lower (3.1 ± 0.4 vs. 3.3 ± 0.5 m.s-1, p = 0.040). TT performance was improved (4.6 ± 0.4 vs. 4.3 ± 0.4 m.s-1, p < 0.001) and MRan was higher (31.3 ± 8.0 vs. 27.5 ± 6.5 kJ.min-1, p < 0.01) for NR compared to WR, with no difference in V. O2 max or MRae. For skiing WR, TT performance was correlated to speed@ 4 mmol (r = 0.81, p < 0.001), MRan (r = 0.65, p < 0.01), V. O2 max (r = 0.51, p < 0.05), and relative muscle (r = 0.67, p < 0.01) and fat (r = -0.67, p < 0.01) masses. Speed@ 4 mmol together with MRan explained more than 80% of the variation in TT performance (WR 84%, NR 81%). Despite a higher relative mass of the rifle in females compared with males (5.6 ± 0.4 vs. 5.0 ± 0.4% of body mass, p = 0.012), there were no sex differences associated with rifle carriage measured as absolute or relative differences. Conclusion: Rifle carriage in biathlon skiing led to significantly higher physiological demands during submaximal exercise and reduced performance during maximal treadmill roller-skiing compared to NR for both sexes. The most important variables for performance in biathlon treadmill skiing seem to be speed@ 4 mmol combined with MRan, both of which were lower for WR compared to NR. To improve skiing performance in biathlon, improving speed at 4 mmol.L-1 of blood lactate and anaerobic energy delivery while carrying the rifle are recommended.
Project description:BACKGROUND: Explicit evolutionary models are required in maximum-likelihood and Bayesian inference, the two methods that are overwhelmingly used in phylogenetic studies of DNA sequence data. Appropriate selection of nucleotide substitution models is important because the use of incorrect models can mislead phylogenetic inference. To better understand the performance of different model-selection criteria, we used 33,600 simulated data sets to analyse the accuracy, precision, dissimilarity, and biases of the hierarchical likelihood-ratio test, Akaike information criterion, Bayesian information criterion, and decision theory. RESULTS: We demonstrate that the Bayesian information criterion and decision theory are the most appropriate model-selection criteria because of their high accuracy and precision. Our results also indicate that in some situations different models are selected by different criteria for the same dataset. Such dissimilarity was the highest between the hierarchical likelihood-ratio test and Akaike information criterion, and lowest between the Bayesian information criterion and decision theory. The hierarchical likelihood-ratio test performed poorly when the true model included a proportion of invariable sites, while the Bayesian information criterion and decision theory generally exhibited similar performance to each other. CONCLUSIONS: Our results indicate that the Bayesian information criterion and decision theory should be preferred for model selection. Together with model-adequacy tests, accurate model selection will serve to improve the reliability of phylogenetic inference and related analyses.
Project description:Cardiopulmonary exercise testing (CPET) may predict which patients are at risk for adverse outcomes after major abdominal surgery. The primary aim of this study was to determine whether CPET variables are predicative of morbidity.High-risk patients undergoing elective, one-stage, open hepatic resection were preoperatively assessed using CPET. Morbidity, as defined by the Postoperative Morbidity Survey (POMS), was assessed on postoperative day 3.A total of 104 patients underwent preoperative CPET and were included in the analysis. Of these, 73 patients (70.2%) experienced postoperative morbidity. Oxygen consumption at anaerobic threshold (V?O2 at AT, ml/kg/min) was the only CPET predictor of postoperative morbidity on multivariable analysis, with an area under the curve (AUC) of 0.66 [95% confidence interval (CI) 0.55-0.76]. In patients requiring a major hepatic resection (three or more segments), a V?O2 at AT of <10.2 ml/kg/min gave an AUC of 0.79 (95% CI 0.68-0.86) with 83.9% sensitivity and 52.0% specificity, 80.6% positive predictive value and 62.5% negative predictive value.The application of a cut-off value for V?O2 at AT of <10.2 ml/kg/min in patients undergoing major hepatic resection may be useful for predicting which patients will experience morbidity.
Project description:Purpose:Healthy patients with unilateral diaphragm paralysis (UDP) are often asymptomatic; those with UDP and comorbidities that increase work of breathing are often dyspneic. We report the effect of obesity on exercise capacity in UDP patients. Methods:All obese and nonobese patients with UDP undergoing cardiopulmonary exercise testing (CPET) during a 32-month period in the exercise laboratory of an academic hospital were compared to a retrospectively identified cohort of obese and nonobese controls without UDP, matched for key features. CPET used a modified Bruce treadmill protocol with breath-to-breath expired gas analysis. O2 uptake, minute ventilation, exercise time, and work rate were recorded at peak exercise. Static pulmonary functions were measured. Kruskal-Wallis, Wilcoxon rank sum, and Fisher's exact tests were used to compare continuous and categorical variables, respectively. Stratified linear regression was used to quantify the effect of UDP and obesity on CPET variables. Results:Twenty-two UDP patients and 46 controls were studied. The BMI of obese and nonobese patients was 33.0±4.2 and 25.8±2.4?kg/m2, respectively. UDP subjects with obesity, compared to controls with neither condition, showed significantly reduced peak O2 uptake normalized to actual body weight (1.57±0.64 versus 2.01±0.88?L/min), shorter exercise time (5.7±2.0 versus 8.5±2.9 minutes), and lower peak ventilation. This was not observed in UDP alone or obesity alone. Peak work rate trended lower in the combined UDP-obesity group. Conclusion:Neither UDP nor obesity alone significantly reduced exercise capacity. Superimposed UDP and obesity interact to create a ventilatory limitation to exercise, with reduced peak-VO2, exercise time, and work rate.
Project description:The precision and accuracy of a quantitative magnetic resonance (EchoMRI Infants) system in newborns were determined.Canola oil and drinking water phantoms (increments of 10 g to 1.9 kg) were scanned four times. Instrument reproducibility was assessed from three scans (within 10 minutes) in 42 healthy term newborns (12-70 hours post birth). Instrument precision was determined from the coefficient of variation (CV) of repeated scans for total water, lean mass, and fat measures for newborns and the mean difference between weight and measurement for phantoms. In newborns, the system accuracy for total body water (TBW) was tested against deuterium dilution (D2 O).In phantoms, the repeatability and accuracy of fat and water measurements increased as the weight of oil and water increased. TBW was overestimated in amounts?>200?g. In newborns weighing 3.14?kg, fat, lean mass, and TBW were 0.52?kg (16.48%), 2.28?kg, and 2.40?kg, respectively. EchoMRI's reproducibility (CV) was 3.27%, 1.83%, and 1.34% for total body fat, lean mass, and TBW, respectively. EchoMRI-TBW values did not differ from D2 O; mean difference, -1.95?±?6.76%, P?=?0.387; mean bias (limits of agreement), 0.046?kg (-0.30 to 0.39?kg).The EchoMRI Infants system's precision and accuracy for total body fat and lean mass are better than established techniques and equivalent to D2 O for TBW in phantoms and newborns.
Project description:BACKGROUND:Aerobic exercise training is associated with beneficial ventricular remodeling and an improvement in cardiac biomarkers in chronic stable heart failure. High-intensity interval training (HIIT) is a time-efficient method to improve V?O2peak in stable coronary heart disease patients. This pilot study aimed to compare the effect of HIIT on ventricular remodeling in patients with a recent acute myocardial infarction (AMI). METHODS:Nineteen post-AMI patients were randomized to either HIIT (n = 9) or usual care (n = 10). A cardiopulmonary exercise test (CPET), transthoracic echocardiography, and cardiac biomarker assessment (ie, N-terminal pro B-type natriuretic peptide levels and G protein-coupled receptor kinase 2 expression) were performed before and after a 12-week training intervention. CPET parameters including oxygen uptake efficiency slope (OUES) and V?O2 at the first ventilatory threshold ( V?O2 VT1) were calculated. left ventricular (LV) structural and functional echocardiographic parameters including myocardial strain imaging were assessed. RESULTS:V?O2peak and OUES improved solely in the HIIT group (P?<?.05 for group/time, respectively). There was a significant training effect for the improvement of peak work load in both groups (P?<?.05). O2 pulse and V?O2 at VT1 both improved only in the HIIT group (P?<?.05 for time, no interaction). HIIT improved radial strain and pulsed-wave tissue Doppler imaging derived e' (P?<?.05 for time, no interaction). Cardiac biomarkers did not change in either group. CONCLUSIONS:In post-AMI patients, HIIT lead to significant improvements in prognostic CPET parameters compared to usual care. HIIT was associated with favorable ventricular remodeling regarding certain echocardiographic parameters of LV function.
Project description:PURPOSE:Statistical equivalence testing is more appropriate than conventional tests of difference to assess the validity of physical activity (PA) measures. This article presents the underlying principles of equivalence testing and gives three examples from PA and fitness assessment research. METHODS:The three examples illustrate different uses of equivalence tests. Example 1 uses PA data to evaluate an activity monitor's equivalence to a known criterion. Example 2 illustrates the equivalence of two field-based measures of physical fitness with no known reference method. Example 3 uses regression to evaluate an activity monitor's equivalence across a suite of 23 activities. RESULTS:The examples illustrate the appropriate reporting and interpretation of results from equivalence tests. In the first example, the mean criterion measure is significantly within ±15% of the mean PA monitor. The mean difference is 0.18 METs and the 90% confidence interval of -0.15 to 0.52 is inside the equivalence region of -0.65 to 0.65. In the second example, we chose to define equivalence for these two measures as a ratio of mean values between 0.98 and 1.02. The estimated ratio of mean V?O2 values is 0.99, which is significantly (P = 0.007) inside the equivalence region. In the third example, the PA monitor is not equivalent to the criterion across the suite of activities. The estimated regression intercept and slope are -1.23 and 1.06. Neither confidence interval is within the suggested regression equivalence regions. CONCLUSIONS:When the study goal is to show similarity between methods, equivalence testing is more appropriate than traditional statistical tests of differences (e.g., ANOVA and t-tests).
Project description:Molecular diagnostics in cancer pharmacogenomics is indispensable for making targeted therapy decisions especially in lung cancer. For routine clinical practice, the flexible testing platform and implemented quality system are important for failure rate and turnaround time (TAT) reduction. We established and validated the multiplex EGFR testing by MALDI-TOF MS according to ISO15189 regulation and CLIA recommendation in Taiwan. Totally 8,147 cases from Aug-2011 to Jul-2015 were assayed and statistical characteristics were reported. The intra-run precision of EGFR mutation frequency was CV 2.15% (L858R) and 2.77% (T790M); the inter-run precision was CV 3.50% (L858R) and 2.84% (T790M). Accuracy tests by consensus reference biomaterials showed 100% consistence with datasheet (public database). Both analytical sensitivity and specificity were 100% while taking Sanger sequencing as the gold-standard method for comparison. EGFR mutation frequency of peripheral blood mononuclear cell for reference range determination was 0.002?±?0.016% (95% CI: 0.000-0.036) (L858R) and 0.292?±?0.289% (95% CI: 0.000-0.871) (T790M). The average TAT was 4.5 working days and the failure rate was less than 0.1%. In conclusion, this study provides a comprehensive report of lung cancer EGFR mutation detection from platform establishment, method validation to clinical routine practice. It may be a reference model for molecular diagnostics in cancer pharmacogenomics.