Interpatient Coefficient Of Variation Research Articles

Fine-tuning the use of a skin prick test device

BackgroundSkin prick tests (SPTs) are the gold standard for the diagnosis of IgE-mediated allergic diseases. Newly introduced devices have different results in performance. This study aimed to provide data for sensitivity, reproducibility, and acceptability of a new SPT device by using different techniques. MethodsThe study was conducted in 4 sections. Different application techniques were evaluated. In the first section, a drop of histamine/saline was put by vial (V). In the second section, it was taken from a well via the test device (W). ALK® Lancet served as a reference in both sections. The techniques were as follows; 1) apply vertical pressure (VP/WP), 2) apply vertical pressure and rotate 90° clockwise (VC/WC), 3) apply vertical pressure and rotate 90° clockwise and then counter-clockwise (VCC/WCC). Pain assessment was performed by using the Wong-Baker FACES Pain Rating Scale. Different histamine concentrations were transferred from the well by the Oryum device and applied as WC in section 3. Lancet and Oryum-WP were compared in terms of time and allergen adequacy in section 4. ResultsIn the first section the sensitivity of all techniques for Oryum and lancet were 100%. The false positivity of Oryum-VP, WP and lancet were found 0%. The Oryum-VP technique was found the best for intrapatient coefficient of variation (CV) (10.72%) (p < 0.001). The interpatient CV was similar in the Oryum-VP, VC, VCC and lancet techniques and was different from the Oryum-WP (p < 0.001). In the second section, all Oryum techniques yielded high sensitivities (100%). False-positive results were obtained more in Oryum-WC and WCC. Oryum-WP technique had the lowest pain score. In the 3rd section, the high positive correlation between histamine concentrations was observed (r = 0.731). In terms of time and allergen adequacy, Oryum-WP was superior to the lancet. ConclusionOryum-VP and WP techniques are reliable, tolerable and comparable with the lancet technique.

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations.

The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (Cmin) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS Cmin for the two formulations and identify determinants of the POS-tab Cmin and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 Cmin) treated with POS-tab (n = 41), POS-susp (n = 29), or both (n = 7) from January 2015 to December 2016 were collected retrospectively. Interpatient and within-subject coefficients of variation (CVs) of the Cmin adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS Cmin was higher for the tablet than for the suspension (median [25th-75th percentile]: 1.8 [1.2-2.4] mg/liter versus 1.2 [0.7-1.6] mg/liter, P < 0.0001). Interpatient CVs for the tablet and suspension were 60.8 versus 63.5% (P = 0.7), whereas within-subject CVs were 39.7 and 44.9%, respectively (P = 0.3). Univariate analysis showed that age and treatment by POS-tab were significantly and positively associated with the POS Cmin, whereas diarrhea was associated with a diminished POS Cmin Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS Cmin, with a trend toward a lower impact of diarrhea during treatment with POS-tab (P = 0.07). Despite increased POS exposure with the tablet formulation, the variability of the POS Cmin was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy.

Effects of polymorphisms in NR1I2, CYP3A4, and ABC transporters on the steady-state plasma trough concentrations of bosutinib in Japanese patient with chronic myeloid leukemia.

We investigated the effects of polymorphisms in NR1I2 (7635A>G, 8055C>T), CYP3A4 (20230G>A), ABCB1 (1199G>A, 1236C>T, 2677G>T/A, 3435C>T), and ABCG2 (421C>A) on the mean plasma trough concentrations (C0) of bosutinib at the steady-state in 30 Japanese patients with chronic myeloid leukemia. Bosutinib C0 values were monitored using high-performance liquid chromatography. The median coefficient of variation (CV) value of the bosutinib C0 for one patient (intrapatient) during bosutinib therapy was 25.9% (range: 7.66-44.24%). During bosutinib therapy, 17 of 30 patients received 300mg/day bosutinib. The interpatient CV value for the bosutinib C0 after administration of 300mg/day was 45.0%. There were no significant differences in the bosutinib C0 between genotypes for ABCB1, ABCG2, and CYP3A4 polymorphisms. However, the bosutinib C0 in patients with the NR1I2 7635G/G or 8055T/T genotype was significantly lower than those in patients with the 7635A allele or 8055C allele, respectively (P = 0.050 and 0.022, respectively). In addition, the bosutinib C0 in patients with both NR1I2 7635G/G and 8055T/T genotypes was significantly lower than those in patients with other genotypes (P = 0.022). Because patients with the NR1I2 7635G/G or 8055T/T genotype may have increased activity of pregnane X receptor-regulated genes and thereafter higher intestinal expression of CYP3A4 and ABC efflux drug transporters, these patients may have a lower bosutinib C0. Therefore, information on the NR1I2 genotype may be useful for achieving optimal systemic exposure of bosutinib.

Intra-tumor heterogeneity of microRNA-92a, microRNA-375 and microRNA-424 in colorectal cancer

Various microRNAs (miRNAs) have been investigated in order to improve diagnostics and risk assessment in colorectal cancer (CRC). To clarify the potential of miRNA profiling in CRC, knowledge of intra-tumor heterogeneity in expression levels is crucial.The study aim was to estimate the intra-tumor variance of three selected miRNAs: miR-92a, miR-375 and miR-424 in CRC tissue. Material and methodsA retrospective study on archived formalin-fixed paraffin embedded tissue from 9 patients with CRC. miRNA tissue expression levels were analyzed by qRT-PCR on tissue representing luminal, central and invasive border zones. Variance components were estimated based on ∆∆Cp values using mixed modeling and presented as coefficients of variation (CV). ResultsIntra-tumor variance was approximately half of the variance observed between patients with a mean intra-tumor CV of 56.4% (range 33.1–77.1%) and a mean inter-patient CV of 101.7% (range 48.8–152.7%). Furthermore we found a significant systematic difference in expression levels between tumor zones for miR-92a and miR-375 with a luminal-invasive difference equal to 0.60 Cp (95% CI: 0.30–0.89, p=0.0003) for miR-92a and a luminal-invasive difference equal to 0.78 Cp (95% CI: 0.10–1.46, p=0.027) for miR-375. ConclusionWhile the intra-tumor variance of miR-92a, miR-375 and miR-424 is substantial, it only constitutes approximately 30% of the total variation. Functional deregulation between tumor zones might contribute to variations in measured expression levels, and thus knowledge of specific intra-tumor expression patterns is crucial in tissue sampling for research as well as in future diagnostics.

Abstract W P158: Permeability as a Biomarker of Cavernous Malformations

Introduction: Vascular hyperpermeability in lesions and nonlesional brain is a cardinal feature of cerebral cavernous malformation (CCM) pathogenesis. Thus we implemented a novel magnetic resonance imaging (MRI) technique in order to quantitate vascular permeability in CCMs and non-CCM brain tissue in humans. We hypothesize that permeability of lesions and background brain will differ between familial and sporadic patients and measurements will be consistent between observers and over time. Method: We used a T 1 -weighted dynamic contrast-enhanced quantitative perfusion (DCEQP) protocol in 30 patients (13 sporadic, 12 familial, and 5 non-CCM cases) in conjunction with routine MRI scans. Regions of interest (ROIs) for permeability measurement included the entire lesion and areas of 12.9 mm 2 (16 pixels) of grey and white matter near and far from the lesion. Measurements were repeated by two observers and at two time points on a subset of patients. Results: For each ROI category except white matter near lesions, the mean permeability was higher in the familial than in the sporadic patients with p-values of 0.04, 0.005, 0.05, and 0.007 for CCM lesions, grey matter near, grey matter far (GMF), and white matter far (WMF) from lesions respectively. No difference was seen between sporadic and non-CCM cases, however familial WMF had higher permeability than both those groups (p0.05) except GMF with p=0.04. The intrapatient coefficients of variation between measurements were 0.74 and 0.63 and interpatient coefficients of variation were 1.36 and 1.56 for sporadic and familial cases respectively. Lastly, it was found that 3 of 4 patients with two scans had stable background (WMF) brain permeability over time. Conclusion: Results show the higher lesional and background brain permeability of familial cases, corroborating previous findings in mice. We also demonstrate the feasibility of DCEQP in CCM disease and the potential of permeability as a biomarker of disease activity or response to treatment. It also highlights the need for further investigation into clinical factors that may impact disease activity and permeability measures.

Optimizing the Use of a Skin Prick Test Device on Children

Background: Studies comparing skin prick test (SPT) devices have revealed varying results in performance and there is little known about their use on children. Methods: We performed 2 complementary studies to test the sensitivity, reproducibility and acceptability of commercially available SPT devices (Stallerpoint, Antony, France) using different application techniques. In the first part, histamine/saline was put on as a drop by use of a vial (V), and in the second part it was transferred from a well with the aid of the test device (W). The techniques were as follows: apply vertical pressure (Stallerpoint-VP or Stallerpoint-WP), apply vertical pressure with 90° clockwise rotation (Stallerpoint-VC or Stallerpoint-WC) and apply vertical pressure with 90° clockwise and counter-clockwise rotations (Stallerpoint-VCC or Stallerpoint-WCC). For comparison, ALK Lancet was used with a technique of ‘drop and apply vertical pressure'. Results: In the first part, sensitivities of the Stallerpoint-VC (96.6%), Stallerpoint-VCC (95.5%) and ALK Lancet (93.2%) techniques were superior (p < 0.001) to the other Stallerpoint-VP and Stallerpoint-WP techniques (76.1 and 46.6%). Intrapatient coefficient of variation (CV) values were 15.0, 18.9, 15.4, 22.4 and 48.5%, respectively. Interpatient CV ranged between 22.8 and 55.1%. In the second part, the Stallerpoint-WC (98.8%), WCC (97.5%) and ALK Lancet (98.8%) techniques yielded high sensitivities, whereas the sensitivity of Stallerpoint-WP (28.7%) was very low. There were false-positive reactions in the Stallerpoint-VCC and WCC techniques. Conclusion: In children, the SPT technique was found to be as important as the testing device. Stallerpoint-VC and WC techniques are reliable, tolerable and comparable with the ALK Lancet technique.

Observational Study of Humidified High-Flow Nasal Cannula Compared with Nasal Continuous Positive Airway Pressure

To conduct an in vitro evaluation of a humidified high-flow nasal cannula (HFNC) system at different flows, cannula sizes, and air leaks and also an in vivo analysis of mean end-expiratory esophageal pressure (EEEP) from nasal continuous positive airway pressure at 6 cm H(2)O (NCPAP+6) versus HFNC. In the in vitro study, we measured HFNC system pressure and flow, with varying degrees of leak and with and without the use of a pressure-limiting valve. In the in vivo study, we measured EEEP in 15 newborns on NCPAP+6 and then on HFNC at 6 L/minute, with flow decreased by 1 L/minute every 30 minutes. Heart rate, respiratory rate, fraction of inspired oxygen, arterial oxygen saturation, respiratory distress syndrome score, and EEEP were recorded for each intervention. Data analysis was done using repeated-measures analysis of variance and linear regression. In the in vitro study, in the absence of leaks, the pressures were limited by the pressure-limiting valve only at flows > or = 2 L/minute. With leaks of 30% and 50%, delivered pressures were always < 3 cm H(2)O. In the in vivo study, respiratory rate increased from baseline (NCPAP+6) as flow decreased (P < .02). Intrapatient and interpatient coefficients of variation were always high. A pressure-limiting valve is necessary in a HFNC system. Although mean EEEP levels were similar in NCPAP+6 and HFNC, tachypnea developed as flow diminished. This system apparently cannot predict EEEP, because of interpatient and intrapatient variation.

Inter-relationships between inflammatory markers in patients with stable COPD with bronchitis: intra-patient and inter-patient variability

Background:Measurements of pulmonary biomarkers can be used to monitor airway inflammation in chronic obstructive pulmonary disease (COPD), but the variability of sampled biomarkers and their inter-relationships are poorly understood. A...

Pergolide

The primary objective of this study was to describe the pharmacokinetics of oral pergolide in patients with mild to moderate Parkinson disease using a new high-performance liquid chromatography-tandem mass spectrometry assay. A secondary objective was to investigate the relationship between plasma concentrations and efficacy. Fourteen patients with a diagnosis of Parkinson disease completed this multicenter, open-label, dose-escalating study. Pergolide was administered for 58 days, using increasing daily doses from 0.05 mg daily up to 1 mg three times daily and then tapering the dose. The steady-state pharmacokinetic profile and motor score were determined at dose levels of 0.25, 0.5, and 1 mg three times a day and during elimination after the last dose. Pergolide was absorbed with a median time to maximum concentration of 2 to 3 hours across the dose range. Systemic exposure appeared to increase proportionally with dose over the range of 0.25 to 1 mg three times daily within a patient, but there was a large variability in exposures between patients (interpatient coefficients of variation were 56.4% for the area under the curve). Pergolide was widely distributed (volume of distribution, approximately 14,000 L) and was eliminated with a mean half-life of 21 hours. Motor scores improved as both peak plasma pergolide concentrations and exposure increased. No unexpected safety concerns were identified. Pergolide is absorbed relatively quickly into the systemic circulation, has a large apparent volume of distribution, and has a relatively long half-life (mean, 21 hours). This prolonged half-life is of particular interest, given the current hypothesis that more continuous dopaminergic receptor stimulation may reduce motor complications in patients with Parkinson disease.

COMPARISON OF FOVEAL THICKNESS MEASURED WITH THE RETINAL THICKNESS ANALYZER AND OPTICAL COHERENCE TOMOGRAPHY

To assess and compare the reliability and reproducibility of retinal thickness measurements for the retinal thickness analyzer (RTA) and optical coherence tomography (OCT) in normal and edematous retina. The authors measured the foveal thickness of 21 normal eyes and 9 eyes with macular edema with both methods in random order. With the RTA, the fovea was measured 10 times; with the OCT, six scans (one horizontal and five vertical cross-sections) of the fovea were obtained. Mean foveal thickness of normal eyes measured 153 microm with OCT and 181 microm with RTA (median for both methods 150 microm). Coefficients of variation (CV) within the same subjects were 10% (OCT) and 9% (RTA) reducing to 9% (OCT) and 7% (RTA) when scans were repeated only five times for both methods. The RTA, however, yielded an interpatient CV of 33% (OCT 17%), which was caused by several falsely high readings in normal individuals. In eyes with retinal thickening the OCT measured a mean of 324 microm with 15% intra- and 58% interpatient CV. The RTA yielded a mean of 403 microm with CV of 18% and 73%, respectively. Both methods yield reproducible measurements of foveal thickness in normal individuals and individuals with macular edema. However, falsely high measurements may occur with the RTA, reducing its reliability as compared to the OCT.

Pharmacokinetics and dose requirements of vancomycin in neonates

AIMSTo design and evaluate dosing guidelines for vancomycin based on data collected during routine use of the drug.METHODSFollowing the observation that 66% of neonatal vancomycin trough concentrations were outside the...

Ticarcillin-clavulanic acid pharmacokinetics in preterm neonates with presumed sepsis

The objective of the reported study was to characterize the pharmacokinetics of ticarcillin and clavulanic acid in premature low-birth-weight (less than 2,200 g) neonates with presumed sepsis. Eleven infants received 12 courses of ticarcillin-clavulanic acid at 75 mg/kg of body weight intravenously every 12 h. Blood samples were collected at 0.5, 1.5, 4, and 8 h following the infusion of the initial dose. The concentrations of ticarcillin and clavulanic acid were determined by a microbiologic assay. Median (interpatient coefficients of variation) values for the volume of the central compartment, total steady-state volume, distributional clearance, total clearance, and terminal elimination half-life for ticarcillin were 0.030 liter/kg (21%), 0.26 liter/kg (48%), 0.41 liter/h/kg (47%), 0.047 liter/h/kg (47%), and 4.2 h (45%), respectively. For clavulanic acid the parameters were 0.28 liter/kg (32%), 0.36 liter/kg (34%), 11 liters/h/kg (36%), 0.12 liters/h/kg (72%), and 1.95 h (40%), respectively. Our results suggest that the current dosing recommendations of 75 mg/kg every 12 h risk subtherapeutic clavulanic acid concentrations and that 50 mg/kg every 6 h is a more rational dosing strategy.

Leucotomy

<h3>Background:</h3> Measurements of pulmonary biomarkers can be used to monitor airway inflammation in chronic obstructive pulmonary disease (COPD), but the variability of sampled biomarkers and their inter-relationships are poorly understood. A study was undertaken to examine the intra- and inter-patient variability in spontaneous sputum samples from patients in the stable state and to describe the relationship between biomarkers, cell counts and markers of disease. <h3>Methods:</h3> Sputum interleukin-1β, tumour necrosis factor α, interleukin 8, myeloperoxidase, leucotriene B4, growth-related oncogene α and differential cell counts were measured in patients with moderate to severe stable COPD (n = 14) on 11 occasions over a 1-month period. <h3>Results:</h3> There was significant variability in all inflammatory indices (median intra-patient coefficient of variation (CV) 35% (IQR 22–69), median inter-patient CV 102% (IQR 61–145)). Variability could be reduced by using a rolling mean of individual patient data points. Sample size calculations were undertaken to determine the number of patients required to detect a 50% reduction in neutrophil count. Using a crossover design of a putative effective treatment, the number needed using one data point per patient was 72, reducing to 23 when a mean of three data points was used. Significant correlations were demonstrated both between the inflammatory biomarkers themselves and between inflammatory biomarkers and markers of disease. Some relationships were not apparent when results from a single sample were used. The reliability of inter-relationships improved as more data points were used for each patient. <h3>Conclusions:</h3> Clear relationships exist between inflammatory biomarkers in patients with stable COPD. Sequential sampling reduced the variability of individual mediators and the potential number of patients needed to power proof of concept interventional studies.