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PubMed1997

Diagnostic imaging of acute pulmonary embolism.

The common strategy of combining clinical information, lung scintigraphy and pulmonary angiography in the diagnosis of acute pulmonary embolism (PE), has many limitations in clinical use. The major causes are that pulmonary angiography and lung scintigraphy are not universally available, and that pulmonary angiography is very expensive. The purpose of this thesis was to analyse different aspects of validity in regard to lung scintigraphy, pulmonary angiography, spiral CT, and ultrasound of the legs, with the subsequent intention of discussing new diagnostic strategies. Observer variations in lung scintigraphy interpretation when applying the PIOPED criteria were tested in 2 studies with 2 and 3 observers respectively and expressed as kappa values. The ability to improve agreement in lung scintigraphy interpretation was tested by training 2 observers from different hospitals. The impact of 3 observers' variations in lung scintigraphy interpretation when compared to pulmonary angiography, was tested by comparing the ROC areas of the observers. The value of combining subjectively derived numerical probabilities and the PIOPED categorical probabilities in lung scintigraphy reporting was compared to using the PIOPED categorization only, and this was tested by comparing ROC areas. The sensitivity and specificity of detecting an embolic source in the deep veins of the legs by ultrasound as a sign of PE when lung scintigraphy is inconclusive, was tested by comparison with pulmonary angiography. The sensitivity and specificity of spiral CT, compared to pulmonary angiography, was tested by comparison to pulmonary angiography. The inter- and intra-observer kappa values were in the range of moderate and fair. It was not possible to achieve better kappa values after training. Although observer variations were substantial, the accuracy did not differ significantly between the 3 observers. Incoorporating subjectively derived probabilities into lung scan reporting could not reduce the number of inconclusive investigations. Sensitivity and specificity of ultrasound in detecting PE was 0.70 and 0.97, respectively. However, 2 patients (of 9) had deep venous thrombosis and no pulmonary emboli at angiography. The sensitivity and specificity of spiral CT was 0.90 and 0.96, respectively. The observer variations at lung scintigraphy are substantial and may be difficult to improve between hospitals, even though the accuracy of observers in general is good. Although subjectively derived interpretation criteria did not show to be useful when added to categorical interpretation criteria, they may be useful when substituting established criteria. Despite recent progress in refining interpretation criteria, a substantial fraction of the patients still need pulmonary angiography to be performed. However, in many patients pulmonary angiography is not performed as prescribed. Spiral CT and ultrasound of the legs is a new favourable diagnostic strategy with a high validity in detecting venous thromboembolic disease, and a good availability and cost-effectiveness.

Acute Disease↗

PubMed2002

Definition of gross tumor volume in lung cancer: inter-observer variability.

BACKGROUND AND PURPOSE: To determine the inter-observer variation in gross tumor volume (GTV) definition in lung cancer, and its clinical relevance. MATERIALS AND METHODS: Five clinicians involved in lung cancer were asked to define GTV on the planning CT scan of eight patients. Resulting GTVs were compared on the base of geometric volume, dimensions and extensions. Judgement of invasion of lymph node (LN) regions was evaluated using the ATS/LCSG classification of LN. Clinical relevance of the variation was studied through 3D-dosimetry of standard conformal plans: volume of critical organs (heart, lungs, esophagus, spinal cord) irradiated at toxic doses, 95% isodose volumes of GTVs, normal tissue complication probabilities (NTCP) and tumor control probabilities (TCP) were compared for evaluation of observer variability. RESULTS: Before evaluation of observer variability, critical review of planning CT scan led to up- (two cases) and downstaging (one case) of patients as compared to the respective diagnostic scans. The defined GTVs showed an inter-observer variation with a ratio up to more than 7 between maximum and minimum geometric content. The dimensions of the primary tumor had inter-observer ranges of 4.2 (transversal), 7.9 (cranio-caudal) and 5.4 (antero-posterior) cm. Extreme extensions of the GTVs (left, right, cranial, caudal, anterior and posterior) varied with ranges of 2.8-7.3 cm due to inter-observer variation. After common review, only 63% of involved lymph node regions were delineated by the clinicians (i.e. 37% are false negative). Twenty-two percent of drawn in lymph node regions were accepted to be false positive after review. In the conformal plans, inter-observer ranges of irradiated normal tissue volume were on average 12%, with a maximum of 66%. The probability (in the population of all conformal plans) of irradiating at least 95% of the GTV with at least 95% of the nominal treatment dose decreased from 96 to 88% when swapping the matched GTV with an unmatched one. The average (over all patients) inter-observer range in NTCP varied from 5% (spinal cord) to 20% (ipsilateral lung), whereas the maximal ranges amounted 16% (spinal cord) to 45% (heart). The average TCP amounted 51% with an average range of 2% (maximally 5%) in case of matched GTVs. These values shifted to 42% (average TCP) with an average range of 14% (maximally 31%) when defining unmatched GTVs. Four groups of causes are suggested for the large inter-observer variation: (1) problems of methodology; (2) impossible differentiation between pathologic structures and tumor; or (3) between normal structures and tumor, and (4); lack of knowledge. Only the minority of these can be resolved objectively. For most of the causal factors agreements have to be made between clinicians, intra- and inter-departmentally. Some of the factors will never be unequivocally solved. CONCLUSIONS: GTV definition in lung cancer is one of the cornerstones in quality assurance of radiotherapy. The large inter-observer variation in GTV definition jeopardizes comparison between clinicians, institutes and treatments.

Carcinoma, Non-Small-Cell Lung↗

PubMed1985

Stress, catecholamines, and sleep.

Difficulties in defining stress stem from its subjective nature. Measurements of stress based on its effects on physical and mental morbidity tend to be speculative because of the multifactorial causation of stress-related diseases, and the characteristically long time-lag between stress states and morbidity. In this study catecholamine output was measured in a group of adults Oxfordshire villagers and the observed variations were related to their lifestyles and health perceptions. A marked circadian variation was observed with adrenaline showing the most marked associations with lifestyle. In men it was possible to account for a relatively high proportion of the variation in adrenaline excretion by relating values to certain factors associated with stress. In women there appears to be a similar association between adrenaline output and the social class of the husband. Data were also obtained on sleep characteristics, which were assessed with regard to lifestyle. Very broadly, sleep duration is related to the level of waking activity, while sleep latency and quality are correlated with people's self-perception of health.

Adolescent↗

PubMed2005

Mutation of DNA polymerase beta in esophageal carcinoma of different regions.

AIM: To observe the variation of DNA polymerase beta (polbeta) in esophageal carcinoma. METHODS: Thirty specimens containing adjacent normal epithelial tissues were collected from patients in Linzhou region (a high risk area for esophageal squamous carcinoma) and 25 specimens were from a non-high risk area. Total RNA was extracted from the samples and reverse transcription polymerase chain reaction (RT-PCR) was performed. PCR products were cloned and sequenced to investigate the polbeta gene with DNASIS and OMIGA. Statistical significance was evaluated using the chi(2) test. RESULTS: High-incidence area group: polbeta gene variation was detected in 13 of 30 esophageal carcinoma tissue specimens, and only one variation was found in 30 corresponding adjacent normal tissue specimens. Non high-incidence area group: polbeta gene variation was detected in 5 of 25 esophageal carcinoma tissue specimens, and no variation was found in 25 corresponding adjacent normal tissue specimens. The incidence of polbeta gene variation observed in the high-incidence area group was significantly higher than in the non-high incidence area group. Two mutation hot spots (454-466 and 648-670 nt) and a 58 bp deletion (177-234 nt) were found. CONCLUSION: Variations of polbeta perform different functions between the high-incidence areas and the other areas, and may play a more important role in the high-incidence areas.

Base Sequence↗

PubMed1996

[Diagnostic accuracy of 201T1 SPECT.MRI in brain diseases and inter-reader variance of diagnostic performance].

Fifteen-four studies of 201T1 brain tumor SPECT were independently interpreted by 9 nuclear medicine physicians with and without reference magnetic resonance images in 2 separate sessions to define an effect of referring images, and inter-observer variations. The physicians were requested to detect foci of abnormal deposits, and to discriminate whether they were malignant or not according to 5-grade scaling of subjective diagnostic confidence. Receiver-operating characteristics (ROC) analysis was performed. Mean sensitivity for presence of lesions (SEP), and sensitivity and specificity for malignancy of 201T1 SPECT were 84, and 53 and 55%, which were changed to 94, and 74 and 55% after referring to the MR images. The SFP was significantly improved (p < 0.05), but sensitivity and specificity for malignancy, assessed by areas under the ROC curves, were not significantly improved. Inter-observer variation of the SFP was significantly reduced with addition of the referring MR images. Cerebral lobar localization of lesions by SPECT showed great inter-observer variations (true localization ranged from 30 to 68.4%). It is concluded that 201T1 brain tumor SPECT has moderate sensitivity and specificity for malignancy, which is not improved by addition of anatomical reference images, that additional MR images reduce inter-observer variation of confidence on lesion presence, and that SPECT localization of lesions has great inter-observer variations.

Adolescent↗

PubMed2006

Predicting leaf-level fluxes of O3 and NO2: the relative roles of diffusion and biochemical processes.

Pollutants like O(3) and NO(2) enter leaves through the stomata and cause damage during reactions with components of biological cell membranes. The steady-state flux rates of these gases into the leaf are determined by a series of physical and biochemical resistances including stomatal aperture, reactions occurring within the cell wall and the ability of the leaf to remove the products of apoplastic reactions. In the present study, multiple regression models incorporating stomatal conductance, apoplastic and symplastic ascorbate concentrations, and nitrate reductase (NR) activities were generated to explain the observed variations in leaf-level flux rates of O(3) and NO(2). These measurements were made on the plant Catharanthus roseus (Madagascar periwinkle). The best-fit model explaining NO(2) flux included stomatal conductance, apoplastic ascorbate and NR activity. This model explained 89% of the variation in observed leaf fluxes and suggested physical resistances, reaction between NO(2) and apoplastic ascorbate, and the removal rate of nitrate (generated by reactions of NO(2) and water) from the apoplast all play controlling roles in NO(2) flux to leaves. O(3) flux was best explained by stomatal conductance and symplastic ascorbate explaining 66% of the total variation in leaf flux. Both models demonstrate the importance of measuring processes other than stomatal conductance to explain steady-state leaf-level fluxes of pollutant gases.

Biological Transport↗

PubMed1993

An algorithm for automatic analysis of portal images: clinical evaluation for prostate treatments.

The aim of this study is to assess the clinical value of an algorithm for automatic analysis of portal images by measuring the method's performance in a clinical study of treatment of prostate cancer. The algorithm is based on chamfer matching and measures displacements of patients relative to prescribed radiation beam positions. In this paper we propose a method to quantify the mean standard deviation (MSD) of the performance of automatic analysis relative to the MSD of the performance of trained radiographers using the clinical data set only, i.e. without using additional phantoms or simulations. The clinical data set in this study consists of 99 regional AP prostate images of 15 different patients. To assess the performance the automatic analysis in relation to that of the human observers, we studied the results of the unsupervised automatic analysis, as well as the results of a less-trained human observer and a well-trained human observer assisted by the automatic analysis (in this combination, automatic analysis is done first and the result is modified by the well-trained observer if the observer does not agree). First, the intra-observer variations of the well-trained observer are measured by repetitive analysis of a small subset of the clinical data. The distribution of differences in analysis between two arbitrary observers is described by the chi 2 distribution, and is tabulated in literature. We define the agreement histogram of an observer O as an estimator for the chi 2 distribution between O and the well-trained human observer, parameterized by the ratio of the intra-observer variations of O and the well-trained observer.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗

PubMed1977

Variation between observers in the estimation of airway resistance and thoracic gas volume.

Variations in the estimation of airway resistance (Raw) and thoracic gas volume (Vtg) made by different observers using body plethysmography have been investigated. Five observers determined Raw and Vtg in normal subjects using prerecorded signals so that intrasubject variations were eliminated. The slopes of the oscillography tracings required to make the determinations were assessed using a cursor and a scale fitted to the oscilloscope. Significant and consistent differences in Raw determined by different observers were found,with a mean range of 37%. Great care should therefore be taken when comparing results obtained by different observers. The variation between observers measuring Vtg was significant and consistent but of much smaller magnitude than was the case for Raw, having a mean range of 12%.

Airway Resistance↗

PubMed1995

Reproducibility of the Glaucoma-scope in cadaver eyes.

We evaluated the intra- and inter-observer variability of depth measurements of the optic disc in cadaver eyes using the Glaucoma-scope. Intra-observer variation of 10 separately captured images became significantly greater with increasing depth of the optic cup (p < 0.001). The standard deviation of depth measurements were 9.06 mu over the neural rim, 25.00 mu along the cup wall, and 40.94 mu at the bottom of the optic cup. However, intra-observer variation of a single captured image did not increase with greater optic cup depth. Intra-observer variation, but not inter-observer variation, generally was greater when measuring the superior than inferior optic disc (p < 0.05). This study suggests that when capturing separate optic disc images with the Glaucoma-scope, increased variation in depth measurements can be expected with greater optic cup depth and in the superior portion of the optic disc.

Cadaver↗

PubMed1996

The development and validation of a measure of parent-reported child health and morbidity: the Warwick Child Health and Morbidity Profile.

OBJECTIVE: to validate a simple instrument for the measurement of parent-reported health and morbidity in infancy and childhood suitable for research and service planning purposes and capable of measuring both cross-sectional and longitudinal health and morbidity experience in a child population. SETTING: child health clinic (CHC), child development unit (CDU) and paediatric outpatient department (OPD) in Coventry. DESIGN: 3-phase field testing to establish test-retest reliability, validity and inter-observer variation of the instrument. Field testing samples: phases 1 and 2; 188 parents of pre-school children attending one of the three health service settings-CHC, CDU or paediatric OPD; phase 3; 40 parents of pre-school children attending CHCs. METHODS: test-retest reliability of each domain of the WCHMP was estimated using weighted Kappa; criterion validity was estimated for selected domains against health records; construct validity against medically plausible constructs was tested by comparing responses between domains; Inter-observer variation was estimated using weighted Kappa. RESULTS: the test-retest reliability of the WCHMP varied from 'moderate' for behaviour, functional health and life quality status to 'very good' for acute significant illness and hospital admission status; criterion and construct validity were high; weighted Kappas for all domains for inter-observer variation between the researcher and family health visitor were in the 'good' to 'very good' range and inter-observer variation remained unaffected by change in the order of administration of the WCHMP. CONCLUSIONS: the WCHMP is a simple measure of parent-reported health and illness which, on field-testing, has been shown to be reliable and valid with low inter-observer variation. After further development and validation including incorporation into the parent-held record, it should be suitable for use in infancy and early childhood to collect cross-sectional and longitudinal health and morbidity data for research and service planning purposes.

Chi-Square Distribution↗

PubMed2004

A likelihood-based method for testing for nonstochastic variation of diversification rates in phylogenies.

Observed variations in rates of taxonomic diversification have been attributed to a range of factors including biological innovations, ecosystem restructuring, and environmental changes. Before inferring causality of any particular factor, however, it is critical to demonstrate that the observed variation in diversity is significantly greater than that expected from natural stochastic processes. Relative tests that assess whether observed asymmetry in species richness between sister taxa in monophyletic pairs is greater than would be expected under a symmetric model have been used widely in studies of rate heterogeneity and are particularly useful for groups in which paleontological data are problematic. Although one such test introduced by Slowinski and Guyer a decade ago has been applied to a wide range of clades and evolutionary questions, the statistical behavior of the test has not been examined extensively, particularly when used with Fisher's procedure for combining probabilities to analyze data from multiple independent taxon pairs. Here, certain pragmatic difficulties with the Slowinski-Guyer test are described, further details of the development of a recently introduced likelihood-based relative rates test are presented, and standard simulation procedures are used to assess the behavior of the two tests in a range of situations to determine: (1) the accuracy of the tests' nominal Type I error rate; (2) the statistical power of the tests; (3) the sensitivity of the tests to inclusion of taxon pairs with few species; (4) the behavior of the tests with datasets comprised of few taxon pairs; and (5) the sensitivity of the tests to certain violations of the null model assumptions. Our results indicate that in most biologically plausible scenarios, the likelihood-based test has superior statistical properties in terms of both Type I error rate and power, and we found no scenario in which the Slowinski-Guyer test was distinctly superior, although the degree of the discrepancy varies among the different scenarios. The Slowinski-Guyer test tends to be much more conservative (i.e., very disinclined to reject the null hypothesis) in datasets with many small pairs. In most situations, the performance of both the likelihood-based test and particularly the Slowinski-Guyer test improve when pairs with few species are excluded from the computation, although this is balanced against a decline in the tests' power and accuracy as fewer pairs are included in the dataset. The performance of both tests is quite poor when they are applied to datasets in which the taxon sizes do not conform to the distribution implied by the usual null model. Thus, results of analyses of taxonomic rate heterogeneity using the Slowinski-Guyer test can be misleading because the test's ability to reject the null hypothesis (equal rates) when true is often inaccurate and its ability to reject the null hypothesis when the alternative (unequal rates) is true is poor, particularly when small taxon pairs are included. Although not always perfect, the likelihood-based test provides a more accurate and powerful alternative as a relative rates test.

Biodiversity↗

PubMed1989

A simplified working formulation of non-Hodgkin's lymphomas based on quantifiable histologic criteria.

Quantifiable criteria for a Simplified Working Formulation of non-Hodgkin's lymphomas are proposed. Biopsy specimens from 582 patients followed from 8.5 to 18.0 years were classified according to the Working Formulation. In addition, on hematoxylin and eosin-stained histologic sections, differential counts among six lymphoma cell types were performed. In each lymphoma 100 cells were counted from representative areas. The intralymphoma variation observed by this method was insignificant for the reproducibility of classification. Five histologic types were defined: (1) follicular small cell (less than or equal to 25% large cells), (2) follicular large cell (greater than 25% large cells), (3) diffuse small (less than or equal to 10% large cells), (4) diffuse large cell (greater than 10% large cells), and (5) lymphoblastic (greater than 20% lymphoblasts). These criteria had clinical significance with regard to prognosis, leukemic conversion, and meningeal involvement. The intraobserver and interobserver reproducibility of the Simplified Working Formulation was, respectively, 91% and 88%.

Cell Count↗

PubMed2004

GM haplotype diversity of 82 populations over the world suggests a centrifugal model of human migrations.

This study investigates the GM genetic relationships of 82 human populations, among which 10 represent original data, within and among the main broad geographic areas of the world. Different approaches are used: multidimensional scaling analysis and test for isolation by distance, to assess the correlation between genetic variation and spatial distributions; analysis of variance, to investigate the genetic structure at different hierarchical levels of population subdivision; genetic similarity map (geographic map distorted by available genetic information), to identify regions of high and low genetic variation; and minimal spanning network, to point out possible migration routes across continental areas. The results show that the GM polymorphism is characterized by one of the highest amounts of genetic variation observed so far among populations of different continents (Fct=0.3915, P < 0.0001). GM diversity can be explained by a model of isolation by distance (IBD) at most continental levels, with a particularly significant fit to IBD for the Middle East and Europe. Five peripheral regions of the world (Europe, west and south sub-Saharan Africa, Southeast Asia, and America) exhibit a low level of genetic diversity both within and among populations. By contrast, East and North African, Southwest Asian, and Northeast Asian populations are highly diverse and interconnected genetically by large genetic distances. Therefore, the observed GM variation can be explained by a "centrifugal model" of modern humans peopling history, involving ancient dispersals across a large intercontinental area spanning from East Africa to Northeast Asia, followed by recent migrations in peripheral geographic regions.

Demography↗

PubMed1977

Pyruvate carboxylase and phosphoenopyruvate carboxykinase in cultured human fibroblasts.

The activities of pyruvate carboxylase and phosphoenolpyruvate carboxykinase were measured in cultural human fibroblasts. Considerable variation was observed in strains derived from different individuals. The activities of both enzymes throughout the culture cycle were measured in two strains. In these strains the specific activities of the enzymes increased during log phase and remained constant during the stationary phase. However, one cell strain exhibited a high activity of pyruvate carboxylase which remained unchanged throughout the culture cycle, suggesting that this enzyme may be regulated differently in different strains of cultured human cells. Familial studies suggest that the observed variations in pyruvate carboxylase activity may be due to a genetic polymorphism.

Avidin↗

PubMed1992

Transcriptional patterns of growth factors and proto-oncogenes in human glioblastomas and normal glial cells.

To document over-expression of proto-oncogenes in tumors, it is necessary to determine the level of expression in the progenitor normal tissue. These studies compare the levels of nuclear transcription of a series of growth-factor related genes and proto-oncogenes in human glioblastoma cell lines with those in three normal glial cell populations. The unusual finding was that levels in the three normal glial cell populations varied considerably for several genes and thus overexpression of a specific gene in a tumor cell when compared to just one normal glial cell population would not necessarily represent overexpression. In this study, we compared the level of 17 genes in 7 tumors to the highest level of each gene found in any of three normal glial cell populations. Over-expression of PDGF-B in 4/7 glioblastoma cell lines, EGFR in 1/7, neu in 1/7 IGF-2 in 1/7 and ros in 2/7 was observed. The variation observed in the normal glial cell populations emphasizes the possibility that the normal glial cell populations represent different glial cell lineages and/or stages of differentiation and that the tumors could have arisen from different normal glial cells. Matching lineages of normal and tumor cells, probably by monoclonal antibody reactions, may be required to accurately define over-expression.

ErbB Receptors↗

PubMed2005

Clinical experience did not reduce the variance in physicians' estimates of pretest probability in a cross-sectional survey.

BACKGROUND AND OBJECTIVES: In light of the increasing popularity of the threshold approach in clinical decision-making, this study assesses the role of expertise in physicians' agreement in estimating the probability of disease in patients. METHODS: A cross-sectional survey of physicians of different specialties, attending weekly staff meetings in four teaching hospitals in Jerusalem, Israel. An anonymous questionnaire describing three case scenarios of patients with chest pain was administered and participants were asked to estimate pretest probabilities of disease. RESULTS: Eighty-six physicians (practicing cardiology, internal medicine, and family medicine, as well as general practitioners and internists) out of 125 approached (response rate 69%). The mean estimated probabilities were very similar for residents and specialists; however, the standard deviation was higher for specialists in all three cases: 20.7, 21.0, and 19.1 among specialists and 16.4, 20.5, and 14.9 among residents, respectively. CONCLUSION: This study, based on case scenarios, did not find that medical expertise improved agreement among doctors when estimating the probability of disease in patients-despite the common belief that senior physicians should have smaller interobserver differences in probability estimates. The wide variation observed calls into question the applicability of the threshold approach.

Cardiology↗

PubMed2000

Leg length measurement: a new method to assure the correct leg length in total hip arthroplasty.

The precise measurement of leg length plays an important role in total hip arthroplasty. Leg length inequality occurs frequently after total hip arthroplasty and may cause patient discomfort. Current clinical methods used for measuring leg length are not accurate enough to meet the demands of precision required for hip replacement. The aim of this study was to examine the validity of determining leg length differences using an ultrasound system. The proposed system measures the distance between three points, in millimetres, so that the difference between preoperative and postoperative measurements gives an indication about the leg length. The mean ultrasound variation observed in in vitro measurements showed a relative error of 1.7% (range: 52-133 mm) that means a leg length inequality of about 0.4 mm (range: 52-133 mm). The method is non-invasive (ultrasound is not limited by radiation hazards), easy, quick to use, and can be used for standard clinical screening.

Anthropometry↗

PubMed1981

Duplication/deletion polymorphism 5' - to the human beta globin gene.

DNA sequence analysis of the human beta globin locus has identified an array of simple tandem repeated sequences upstream from the beta globin structural gene. Comparison of several cloned human beta globin alleles demonstrated a high frequency of sequence heteromorphism at this site apparently due to duplication or deletion of single units of the repeat array. At least two such duplication/deletion events are necessary to account for the observed variation. No other sequence variation was observed, suggesting that duplication/deletion events within the tandem repeat array may be at least 13 to 14 times more frequent than nucleotide substitutions in the surrounding DNA.

Base Sequence↗