Biological quality control for cardiopulmonary exercise testing in multicenter clinical trials.

BackgroundPrecision 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.MethodsBioQC 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 [V̇O2], carbon dioxide output [V̇CO2], and minute ventilation [V̇E] within ±10%); and 2) a criterion that V̇O2 at 20 W and 70 W, and ∆V̇O2/∆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 V̇O2 at 70 W and ∆V̇O2/∆WR, was compared with the other methods.ResultsOf 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 V̇O2 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.ConclusionsStudy-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.Trial registrationClinicalTrials.gov identifier: NCT01072396; February 19, 2010

The Continuum of Physiological Impairment during Treadmill Walking in Patients with Mild-to-Moderate COPD: Patient Characterization Phase of a Randomized Clinical Trial

<div><p>Background</p><p>To have a better understanding of the mechanisms of exercise limitation in mild-to-moderate chronic obstructive pulmonary disease (COPD), we compared detailed respiratory physiology in patients with COPD and healthy age- and sex-matched controls.</p><p>Methods</p><p>Data were collected during the pre-treatment, patient characterization phase of a multicenter, randomized, double-blind, crossover study. Patients with COPD met Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1 or 2 spirometric criteria, were symptomatic, and had evidence of gas trapping during exercise. All participants completed pulmonary function and symptom-limited incremental treadmill exercise tests.</p><p>Results</p><p>Chronic activity-related dyspnea measured by Baseline Dyspnea Index was similarly increased in patients with GOLD 1 (n = 41) and 2 (n = 63) COPD compared with controls (n = 104). Plethysmographic lung volumes were increased and lung diffusing capacity was decreased in both GOLD groups. Peak oxygen uptake and work rate were reduced in both GOLD groups compared with controls (p<0.001). Submaximal ventilation, dyspnea, and leg discomfort ratings were higher for a given work rate in both GOLD groups compared with controls. Resting inspiratory capacity, peak ventilation, and tidal volume were reduced in patients with GOLD 2 COPD compared with patients with GOLD 1 COPD and controls (p<0.001).</p><p>Conclusions</p><p>Lower exercise tolerance in patients with GOLD 1 and 2 COPD compared with controls was explained by greater mechanical abnormalities, greater ventilatory requirements, and increased subjective discomfort. Lower resting inspiratory capacity in patients with GOLD 2 COPD was associated with greater mechanical constraints and lower peak ventilation compared with patients with GOLD 1 COPD and controls.</p><p>Trial Registration</p><p>ClinicalTrials.gov: <b> </b><a href="http://clinicaltrials.gov/ct2/results?term=NCT01072396" target="_blank">NCT01072396</a></p></div

Pulmonary function.

<p>Data are presented as mean ± standard deviation.</p><p>GOLD, Global Initiative for Chronic Obstructive Lung Disease; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; SVC, slow vital capacity; IC, inspiratory capacity; FRC, functional residual capacity; RV, residual volume; TLC, total lung capacity; sR_aw, specific airway resistance; DL_CO, diffusing capacity of the lung for carbon monoxide.</p><p>P-values are from a linear regression model, adjusted for age, sex, alcohol status, employment status, and body mass index.</p><p>**p<0.01 versus control;</p><p>***p<0.001 versus control.</p>#<p>p<0.05 GOLD 1 versus GOLD 2;</p>###<p>p<0.001 GOLD 1 versus GOLD 2.</p>†<p>GOLD 1, n = 40; GOLD 2, n = 62.</p>‡<p>GOLD 2, n = 61.</p

Breathing pattern and operating lung volume measurements versus work rate during incremental treadmill exercise.

<p>(A) Breathing frequency (<i>F</i>b), (B) tidal volume, (C) inspiratory capacity (IC), and (D) inspiratory reserve volume (IRV) showing that all three groups reach a similar minimal value at end-exercise (shaded area). Data are shown as mean ± standard error. TLC, total lung capacity. *p<0.05 GOLD 1 and 2 versus controls at a standardized work rate; ^#p<0.05 GOLD 1 versus controls; ^†p<0.05 GOLD 2 versus GOLD 1 and controls (confidence intervals do not overlap indicating p<0.05).</p

Intensity ratings of (A) dyspnea and (B) leg discomfort versus work rate during incremental treadmill exercise.

<p>Data are shown as mean ± standard error. *p<0.05 GOLD 1 and GOLD 2 versus controls at a standardized work rate; ^#p<0.05 GOLD 1 versus controls (confidence intervals do not overlap indicating p<0.05).</p

Operating lung volumes versus work rate during incremental treadmill exercise.

<p>End-expiratory lung volume (EELV) and end-inspiratory lung volume (EILV) measurements were significantly greater (p<0.05) throughout exercise in GOLD 1 and 2 compared with controls (p-values based on two-sample t-test with unequal variance). Data are shown as means. TLC, total lung capacity; IRV, inspiratory reserve volume; VT, tidal volume.</p

Subject disposition during the characterization phase of the study.

<p>IET, incremental exercise testing. *Since 104 control subjects had full characterization data available, only the first 104 patients with COPD, who were eligible for randomization, were age- and sex-matched with the controls for characterization data analysis.</p

Subject characteristics.

<p>Data are presented as mean ± standard deviation for continuous variables and number of patients (%) for categorical variables.</p><p>GOLD, Global Initiative for Chronic Obstructive Lung Disease; N/A, not applicable.</p><p>***p<0.001 versus control, using a two-sample <i>t</i>-test with unequal variance.</p>†<p>Drinks alcohol, but to an extent that would not interfere with participation in the trial.</p>‡<p>1 pack-year represents 20 cigarettes per day for 1 year.</p

Peak symptom-limited incremental treadmill exercise.

<p>Data are presented as mean ± standard deviation.</p><p>GOLD, Global Initiative for Chronic Obstructive Lung Disease; , oxygen uptake; , carbon dioxide production; , minute ventilation; MBC, maximum breathing capacity; Vt, tidal volume; <i>F</i>b, breathing frequency; Ti, inspiratory time; Ttot, total respiratory time; Ti_/Ttot, inspiratory duty cycle; IC, inspiratory capacity; Δ, change; IRV, inspiratory reserve volume; EELV, end-expiratory lung volumes; SpO₂, arterial oxygen saturation measured by pulse oximetry.</p><p>P-values are from a linear regression model, adjusted for age, sex, alcohol status, employment status, and body mass index.</p><p>*p<0.05 versus control;</p><p>**p<0.01 versus control;</p><p>***p<0.001 versus control</p>#<p>p<0.05 GOLD 1 versus GOLD 2;</p>##<p>p<0.01 GOLD 1 versus GOLD 2;</p>###<p>p<0.001 GOLD 1 versus GOLD 2.</p>†<p>GOLD 2, n = 62.</p

Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States.

Data on the detailed clinical progression of COVID-19 in conjunction with epidemiological and virological characteristics are limited. In this case series, we describe the first 12 US patients confirmed to have COVID-19 from 20 January to 5 February 2020, including 4 patients described previously1,2,3. Respiratory, stool, serum and urine specimens were submitted for SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing, viral culture and whole genome sequencing. Median age was 53 years (range: 21–68); 8 patients were male. Common symptoms at illness onset were cough (n = 8) and fever (n = 7). Patients had mild to moderately severe illness; seven were hospitalized and demonstrated clinical or laboratory signs of worsening during the second week of illness. No patients required mechanical ventilation and all recovered. All had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2–3 weeks after illness onset. Lowest real-time PCR with reverse transcription cycle threshold values in the upper respiratory tract were often detected in the first week and SARS-CoV-2 was cultured from early respiratory specimens. These data provide insight into the natural history of SARS-CoV-2. Although infectiousness is unclear, highest viral RNA levels were identified in the first week of illness. Clinicians should anticipate that some patients may worsen in the second week of illness