Long-term Coefficient Of Variation Research Articles

Evaluation of a large-scale aptamer proteomics platform among patients with kidney failure on dialysis

Background Patients with kidney failure suffer high mortality, and we currently lack markers for risk stratification for these patients. We carried out a quality control study of a modified aptamer assay (SomaScan v.4.0) that measures ~ 5000 proteins, in preparation for a larger study using this platform in cohorts with kidney failure. Methods Forty participants from the Cardiac, Endothelial Function and Arterial Stiffness in End-Stage Renal Disease (CERES study) were selected to analyze technical and short-term biological variability, orthogonal correlations and differential protein expression in plasma from patients who died during 2.5 year follow-up. Long-term (one year) variability was studied in 421 participants in the Chronic Renal Insufficiency Cohort. We evaluated 4849 aptamers (4607 unique proteins) using data formats including raw data and data formatted using Adaptive Normalization by Maximum Likelihood (ANML), an algorithm developed for SomaScan data in individuals with normal kidney function. Results In ANML format, median[IQR] intra-assay coefficient of variation (CV) was 2.38%[1.76, 3.40] and inter-assay CV was 7.38%[4.61, 13.12]. Short-term within-subject CV was 5.76% [3.35, 9.72]; long-term CV was 8.71%[5.91, 13.37]. Spearman correlations between aptamer and traditional assays for PTH, NT-proBNP, FGF-23 and CRP were all > 0.7. Fold-change (FC) in protein levels among non-survivors, significant after Bonferroni correction, included SVEP1 (FC[95% CI] 2.14 [1.62, 2.82]), keratocan (1.74 [1.40, 2.15]) and LanC-like protein 1 (0.56 [0.45, 0.70]). Compared to raw aptamer data, technical and short-term biological variability in paired samples was lower in ANML-formatted data. ANML formatting had minimal impact on orthogonal correlations with traditional assays or the associations of proteins with the phenotype of mortality. Conclusions SomaScan had excellent technical variability and low within-subject short-term variability. ANML formatting could facilitate comparison of biomarker results with other studies that utilize this format. We expect SomaScan to provide novel and reproducible information in patients with kidney failure on dialysis.

The Value of Long-Term Stream Invertebrate Data Collected by Citizen Scientists.

The purpose of this investigation was to systematically examine the variability associated with temporally-oriented invertebrate data collected by citizen scientists and consider the value of such data for use in stream management. Variability in invertebrate data was estimated for three sources of variation: sampling, within-reach spatial and long-term temporal. Long-term temporal data were also evaluated using ordinations and an Index of Biotic Integrity (IBI). Through two separate investigations over an 11-year study period, participants collected more than 400 within-reach samples during 44 sampling events at three streams in the western United States. Within-reach invertebrate abundance coefficient of variation (CV) ranged from 0.44–0.50 with approximately 62% of the observed variation strictly due to sampling. Long-term temporal CV ranged from 0.31–0.36 with 27–30% of the observed variation in invertebrate abundance related to climate conditions (El Niño strength) and sampling year. Ordinations showed that citizen-generated assemblage data could reliably detect differences between study streams and seasons. IBI scores were significantly different between streams but not seasons. The findings of this study suggest that citizen data would likely detect a change in mean invertebrate density greater than 50% and would also be useful for monitoring changes in assemblage. The information presented here will help stream managers interpret and evaluate changes to the stream invertebrate community detected by citizen-based programs.

Potential diagnostic role of the MRI-derived internal magnetic field gradient in calcaneus cancellous bone for evaluating postmenopausal osteoporosis at 3 T

IntroductionBone mineral density (BMD) result has a low predictive value on patients' risk for future fractures. Thus, new approaches for examining patients at risk for developing osteoporosis would be desirable. Magnetic resonance (MR) investigations in cancellous bone have been shown to yield useful quantitative information on both trabecular-bone microstructure and bone marrow composition.This work was undertaken to address the hypothesis that the effective internal magnetic field gradient (IMFG), a new MR parameter, discriminates between healthy, osteopenic and osteoporotic postmenopausal women, classified on the basis of bone mineral density (BMD) criteria. The work builds on preliminary results indicating that IMFG, measured in trabecular-bone pores and quantified by spin-echo decay and water diffusion MR near the bone–bone marrow interface depends on both the bone marrow water rate of diffusion and the magnetic susceptibility difference (ΔX) between water and bone. Materials and methodsMR relaxometry, MR spectroscopy and diffusion-weighted MR imaging of the heel was performed in fifty-five women (mean age, 62.9±6.6years) at 3T. Moreover, in order to study the reproducibility of IMFG measurement, five young women (mean age 31.0±3.2years; age range, 28–36years) were scanned and rescanned. The study protocol was approved by the local Ethics Committee. Quantitative Computer Tomography (QCT) of the L1–L3 vertebral segments was performed to classify the postmenopausal women into three groups according to QCT BMD: healthy (n=8); osteopenic (n=25); and osteoporotic (n=22). In all subjects, BMD T-scores, marrow fat content (Mfc), T2*, apparent diffusion coefficient (ADC) and IMFG (estimated from the additional spin-echo decay due to diffusion of water in local magnetic field gradients), were assessed in the whole calcaneus as well as in three calcaneal subregions: subtalar, tuber calcaneus, and cavum calcaneus. Between-group comparisons to assess group differences and Pearson correlation analysis were performed. Short and long-term coefficients of variation (CVS and CVL, respectively) were evaluated in young subjects. ResultsReproducibility of the IMFG measurement was satisfactory. No significant difference was found in the IMFG measurement performed in both calcaneus and subtalar calcaneal region between the two separate sessions comprised of five young women. Mfc did not significantly differ between groups. The IMFG in the subtalar region was significantly different between all three groups (P<0.01), being greatest in healthy women, intermediate in those with osteopenia, and lowest in osteoporotic subjects. Conversely neither T2* nor ADC is able to discriminate healthy subjects from those with osteopenia and osteoporosis. Increased inter-trabecular space, as it typically occurs in patients with osteoporosis, modifies water diffusion, conferring higher ADC values, thereby lowering the IMFG. ConclusionThe IMFG measured in the calcaneal subtalar region shows a high ability in identifying healthy subjects. The new quantitative MR method based on measurement of the IMFG may provide a new means for assessing patients with osteoporosis.

Within-Subject Variation in Hemoglobin Mass in Elite Athletes

Illicit autologous blood transfusion to improve performance in elite sport is currently undetectable, but the stability of longitudinal profiles of an athlete's hemoglobin mass (Hbmass) might be used to detect such practices. Our aim was to quantify within-subject variation of Hbmass in elite athletes, and the effects of potentially confounding factors such as reduced training or altitude exposure. A total of 130 athletes (43 females and 87 males) were measured for Hbmass an average of six times during a period of approximately 1 yr using carbon monoxide rebreathing. Linear mixed models were used to quantify within-subject variation of Hbmass and its associated analytical and biological components for males and females, as well as the effects of reduced training and moderate altitude exposure in certain athletes. The maximum within-subject coefficient of variation (CV) for Hbmass was 3.4% for males and 4.0% for females. The analytical CV was ~2.0% for both males and females, and the long-term biological CV, after allowing for analytical variation, was 2.8% for males and 3.5% for females. On average, self-reported reduced training resulted in a 2.8% decrease in Hbmass and altitude exposure increased Hbmass by 1.5% to 2.9%, depending on the duration and type of exposure. The within-subject CV for Hbmass of ~4% indicates that athletes may experience changes up to ~20% with a 1-in-1000 probability. Changes of this magnitude for measures taken a few months apart suggest that Hbmass has a limited capacity to detect autologous blood doping. However, changes in Hbmass may be a useful indicator when combined with other measures of blood manipulation.

Relationships between fault geometry, slip rate variability and earthquake recurrence in extensional settings

Field observations and modelling indicate that elastic interaction between active faults can lead to variations in earthquake recurrence intervals measured on timescales of 102-104 yr. Fault geometry strongly influences the nature of the interaction between adjacent structures as it controls the spatial redistribution of stress when rupture occurs. In this paper, we use a previously published numerical model for elastic interaction between spontaneously growing faults to investigate the relationships between fault geometry, fault slip rate variations and the statistics of earthquake recurrence. These relationships develop and become systematic as a long-term consequence of stress redistribution in individual rupture events even though on short timescales earthquake activity appears to be stochastic. We characterize fault behaviour using the coefficient of variation (CV) of earthquake recurrence intervals and introduce a new measure, slip-rate variability (SRV) that takes into account the size and time ordering of slip events. CV generally increases when the strain is partitioned on more than one fault but the relationship between long-term fault slip rate (SRmean) and CV is poorly defined. In contrast, SRV increases systematically where faulting is more distributed and SRmean is lower. To first order, SRV is inversely proportional to SRmean. We also extract earthquake recurrence statistics and compare these to previously published probability density functions used in earthquake forecasting. The histograms of earthquake recurrence vary systematically as a function of fault geometry and are best characterized by a Weibull distribution with fitting parameters that vary from site to site along the fault array. We explain these phenomena in terms of a time-varying, geometrical control on stress loading of individual faults arising from the history of elastic interactions and compare our results with published data on SRV and earthquake recurrence along normal faults in New Zealand and in the Italian Apennines. Our results suggest that palaeoseismic data should be collected and analysed with structural geometry in mind and that information on SRV, CV and SRmean should be integrated with data from earthquake catalogues when evaluating seismic hazard.

An acid hydrolysis method for quantification of plasma free and total carnitine by flow injection tandem mass spectrometry

Objectives To develop a tandem mass spectrometry (MS/MS) method for plasma free and total carnitine, incorporating acid hydrolysis for total carnitine measurement, for improved accuracy and sample throughput. Design and methods Limit of detection (LOD), limit of quantitation (LOQ), linearity, accuracy, precision coefficient of variation (CV), method comparison with a radioenzymatic assay (REA) and liquid chromatography tandem mass spectrometry assay (LC-MS/MS) were performed. The method was tested for interferences and for long-term performance. Results The method LOD and LOQ were 0.87 and 1.36 μmol/L for free carnitine and 1.79 and 2.54 μmol/L for total carnitine, respectively. No interferences were detected. Long-term measurement CVs for both free and total carnitine were < 4%. Conclusions The method shows acceptable performance characteristics with improved speed and low level accuracy compared to existing REA and MS/MS methods.

Precision and accuracy of measuring changes in bone mineral density by dual-energy X-ray absorptiometry

Long-term precision of two Hologic DXA scanners was derived from repeated clinical measurements. With typical subjects, the long-term coefficients of variation were about twice the short-term. The accuracy of the measurement of changes was compromised by anomalies, but this did not seriously affect clinical conclusions. Long-term precision and accuracy of BMD measurements need review. Long-term precision was examined by selecting, from Hologic databases, subjects who had had four scans over a period of 2 to 5 years and was calculated from the SEE of a regression of BMD against time. Accuracy was assessed from relationships between changes (delta) in BA, BMD and BMC. For one group of subjects, the long-term precision was 2.4% for lumbar spine, 2.3% for total hip and 2.7% for femoral neck when expressed as CVs. These values were nearly twice the short-term CVs of 1.3% for spine, 1.2% for total hip and 1.4% for femoral neck. For another group, a negative exponential regression gave a better fit, leading to CVs of 1.3% for the spine, 1.4% for total hip and 2.1% for femoral neck. Significant correlations between deltaBA and deltaBMC were found. These led to an underestimate of deltaBMD in spine and hip by 25%. The poorer long-term precision for typical patients should be borne in mind in monitoring progress. The underestimate of changes could account for only a part of the underestimation by BMD measurements of the anti-fracture effects of anti-resorptive drugs.

Reproducibility of skin microcirculatory measurements in humans, with special emphasis on capillaroscopy.

The reproducibility of capillaroscopic measurements of capillary blood cell velocity (CBV) in human nailfolds was investigated by use of the computerized system CapiFlow. Therefore, CBV measurements of two capillaries of each of three fingers together with laser Doppler fluxmetry (LDF) and skin temperature measurements were performed three times in five healthy volunteers. Short-term (1.5 h) intra-individual coefficient of variation (CV) of CBV was 18.4%. Long-term (7 days) CV amounted to 55.8%. Inter-individual CV was 55.9%. Short- and long-term intra-individual CVs of LDF were 25.4% and 37.3%. Inter-individual variation was 36.0%. Skin temperature showed short- and long-term CVs of 3.7% and 5.5% and inter-individual CV of 5.8%. In conclusion, measurement of CBV using CapiFlow is a suitable method to assess acute effects, but has limited value in investigating long-term effects. Because of the wide interindividual variability in both CBV and LDF, power calculations will reveal large numbers to investigate. Skin temperature has a relatively small intra- and inter-individual variation and is more suitable for long-term studies.

Bone metabolic changes in antarctic wintering team members

Bone mass, bone metabolic markers, and calcium regulation hormones were measured in members of an Antarctic wintering team who stayed at the Japanese Antarctic station, Syowa (latitude: south 69°00′, longitude: east 39°35′) for 1 year. Subjects included 31 healthy Japanese males, aged 24–51 years (mean age 34.5 years) at the beginning of this study, ingesting 488 IU/day of vitamin D and 550.9 mg/day of calcium per person. The long-term coefficient of variation (CV) of the equipment used in the assessments of bone mass was 0.67% in single X-ray absorptiometry (SXA), 0.17% in the speed of sound (SOS) by quantitative ultrasound method (QUS), and 0.63% in broadband ultrasound attenuation (BUA) by QUS. The seasonal changes in the calcaneal bone mineral density (BMD) by SXA were not significant, whereas the SOS measured by QUS decreased during the measurement period (0.55%, p < 0.001), and BUA increased (1.9%, p < 0.01). Bone-specific alkaline phosphatase and osteocalcin levels increased significantly during summer ( p < 0.001) and urinary calcium level decreased significantly during winter ( p < 0.05). Urinary pyridinoline and deoxypyridinoline levels decreased significantly at the end of winter ( p < 0.001). Serum 1,25(OH) 2D 3 level did not change significantly, whereas serum 25(OH)D 3 level decreased significantly during winter ( p < 0.001). Serum parathyroid hormone (PTH) level significantly increased at the end of winter ( p < 0.01), although both PTH level and 25(OH)D 3 level remained within the normal range. We concluded that the 25(OH)D 3 level in subjects who stayed in Antarctica for 1 year decreased significantly with the reduction in duration of sunshine, but there were no clear changes in bone mass.

Standardization of HPLC measurements of pyridinium crosslinks

Measurement of the total amount of the two crosslinks, pyridinoline and deoxypyridinoline, can be made simultaneously by high pressure liquid chromatography preceded by an acidic hydrolysis of the sample and an extraction on cellulose columns. To compensate for the losses and variation in the extraction procedure and increase precision and accuracy a suitable internal standard should be used. A simple procedure to isolate a compound to be used as an internal standard is discussed. With this compound a total, long term coefficient of variation of 7% and 5% for the two crosslinks is achieved.The present inter-laboratory variation reflected by the big differences in reference intervals is probably due to the presence of several different ways to purify and quantify crosslinks to be used as calibrators. Recently the molar absorptivity for both pyridinoline and deoxypyridinoline in the ultra violet range has been defined. This may be the first step towards the creation of a primary international reference material.

Accuracy, precision, and utility of spine and whole-skeleton mineral measurements by DXA in rats.

We evaluated the precision and accuracy of dual-energy x-ray bone densitometry (DXA) in 38 male and female rats aged 1-10 months. The coefficients of variation (CV) estimated from same-day paired measurements of bone mineral content (BMC) were 1.26% at the lumbar spine and 0.69% at the whole skeleton, and the corresponding CV for BMC corrected for projected bone area (i.e., bone mineral density, BMD) were 0.57 and 0.66%. BMC, measured in vivo, correlated closely with the subsequently determined ash weights (spine r2 = 0.94, whole-skeleton r2 = 0.97). The long-term CV for BMC measurements, assessed by measuring a frozen animal daily for 4 weeks, were 1.28% for the spine and 1.03% for the whole skeleton; for BMD the corresponding CV were 0.88 and 1.15%. To examine the utility of serial DXA measurements we followed female rats subjected to ovariectomy (OVX) or sham operation at 10 months of age and male rats given daily subcutaneous injections of hPTH-(1-34) or vehicle starting at 10 months of age every 3 weeks for 15 weeks. In the OVX rats a progressive decrease in spine BMC was observed that was most rapid during the first 6 weeks. By 15 weeks the mean spine BMC decreased by 17% in the OVX rats (p < 0.007 versus sham operation). OVX did not affect the accuracy of DXA measurements as assessed by comparison with the ash weight at the end of the 15 week study. PTH treatment increased spine BMC by a mean of 32% and increased whole-skeleton BMC by a mean of 19% within 15 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Validation and Use of Ontario's Trophic Status Model for Establishing Lake Development Guidelines

ABSTRACT The Trophic Status Model of Ontario's Lakeshore Capacity Study is a refinement of the Dillon-Rigler (1975) model for predicting total phosphorus concentration and several trophic status indicators in lakes. A recent version of this model allows the modeling of watersheds, extending 3 lakes upstream for up to 15 catchments of a study lake. This feature enables lake managers to predict the effect of lakeshore development throughout an entire watershed, including downstream lakes. Differences between modeled and measured concentrations of total phosphorus for the ice-free period were less than 20% in 11 of a set of 15 lakes in a south-central Ontario watershed. Annual, seasonal and long-term coefficients of variation for measured phosphorus concentrations were 19–22% over a 9-year period in an intensively studied lake. Assumptions and sources of error in modeled and measured phosphorus concentrations are discussed. The ability of the Trophic Status Model to predict phosphorus concentrations in the a...

Acute Adrenocorticotropin-(1–24) (ACTH) Adrenal Stimulation in Eumenorrheic Women: Reproducibility and Effect of ACTH Dose, Subject Weight, and Sampling Time*

Assessment of adrenal reserve and the diagnosis of adrenal insufficiency by acute adrenocortical stimulation with ACTH-(1-24) has been well established. Alternatively, estimation of adrenocortical enzymatic activities by this method for the detection of inherited or acquired biosynthetic abnormalities has been less well characterized. Some of the discrepancies between studies estimating adrenocortical enzymatic activities in different pathological conditions (e.g. hyperandrogenism) may result from the different stimulation protocols used. The objective of this prospective study was to establish the inherent variability of the adrenal response to acute ACTH-(1-24) stimulation and to determine the effect of sampling time, stimulation dose, and subject weight on the same. Forty-one normal female volunteers were recruited (mean age, 29.1 yr), 30 within 90-110% ideal body weight and 11 weighing more than 120% ideal body weight. Three protocols were designed to study 1) the effects of sampling time, ACTH-(1-24) dose, and subject weight on adrenal response; 2) the effect of time of the day on the variability of basal steroid levels and the adrenal response to stimulation; and 3) the long term reproducibility of the adrenal response to ACTH-(1-24). Androstenedione, 17-hydroxyprogesterone, 11-deoxycortisol, dehydroepiandrosterone, and cortisol were measured in serum under basal and stimulated conditions. All subjects had normal basal levels of testosterone, androstenedione, dehydroepiandrosterone sulfate, and PRL. The acute iv administration of 0.10, 0.25, and 1.0 mg ACTH-(1-24) elicited similar and maximal steroid responses, with all steroid levels reaching a plateau 60-90 min poststimulation regardless of subject weight. Sampling of basal steroid levels every 5 min in the morning (AM; beginning 0700-0900 h) or evening (PM; 1500-1700 h) did not reveal any difference in steroid variability. Only the mean basal cortisol level was higher in AM than PM testing (P less than 0.03). Although the mean levels of dehydroepiandrosterone and 17-hydroxyprogesterone 60 min after stimulation were significantly higher in AM than PM studies, these differences were minimal. Ten volunteers underwent an average of four (range, 2-6) adrenal stimulation studies using 1.0 mg ACTH-(1-24) over a 1-yr period. The long term coefficient of variation (CV) for basal steroid levels ranged from 15-28%. Calculations of net adrenal response (delta steroid O-T and area delta steroid O-T) were less reproducible (CV, 0-82%) than measures of absolute response (steroid T, area steroid T, and %steroid T; CV, 7-32%). This difference in CV between the measures of net and absolute adrenal responses was significant for all steroids except androstenedione.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparative study of the performances of X-ray and gadolinium 153 bone densitometers at the level of the spine, femoral neck and femoral shaft

We investigated the precision of gadolinium 153 dual photon absorptiometry (DPA) and quantitative digital radiography (QDR) bone densitometers by determining in vitro and in vivo coefficients of variation (CV) of bone mineral density (BMD). In vitro, the long-term CV of spine phantom BMD measured weekly for 40 weeks was 1.2% and 0.7% for DPA and QDR, respectively. Stimulating soft-tissue thickness with water, the CV of 6 repeat measurements of spine phantom at depths from 0 to 27 cm in 1 cm steps (a total of 168 measurements) increased from 0.1% at 0 cm of water to 2.5% at 27 cm for DPA, and from 0.2% at 0 cm to 1.4% at 27 cm for QDR; mean CV of the 28 series (0-27 cm) was higher for DPA (1.2% +/- 0.8%, mean +/- SD) than for QDR (0.7% +/- 0.6%; P less than 0.001). With the hip phantom, femoral neck BMD was determined, and the CV was also dependent on water thickness; mean CV of the 20 series (0-10 cm) was 2.1% +/- 1.2% for DPA and 1.3% +/- 0.9% for QDR (not significant). In vivo, at the spine level, with DPA, mean CV of BMD measured 6 times after repositioning in 6 healthy volunteers was 3.8% +/- 1.9% and 2.1% +/- 0.7% with 153 Gd activity of 0.46 Ci and 1 Ci, respectively (BMD range: 0.796-1.247 g/cm2, no significant difference between the two groups).(ABSTRACT TRUNCATED AT 250 WORDS)