The AutoPap system for primary screening in cervical cytology. Comparing the results of a prospective, intended-use study with routine manual practice

OBJECTIVE: To evaluate the effectiveness of the AutoPap System in detecting abnormal and normal cervical smears when used in a primary screening/quality control mode, as compared with currently established laboratory practices. STUDY DESIGN: Slides were obtained prospectively and were initially processed in the routine fashion with cytotechnologist screening followed by 10% random quality control rescreening. Slides were then processed on the AutoPap System and allocated into the following groups: (1) approximately 25% of the lowest-ranking slides were placed in the laboratory's archives as within normal limits; (2) the remaining approximately 75% of slides were subjected to manual screening. Approximately 15% of the highest-ranking slides in this group underwent quality control rescreening. For each slide needing manual screening, the cytotechnologist was supplied with a report giving the ranking score of that slide. All discrepant slides for either adequacy or diagnosis were subjected to a truth-determination process. The results obtained from the two arms of the protocol were then compared. RESULTS: The AutoPap System-assisted arm of the study was superior to the current practice arm for the identification of abnormal slides at the level of atypical squamous cells of undetermined significance and above (ASCUS+), low grade squamous intraepithelial lesion (LSIL) and higher LSIL+. AutoPap System-assisted practice was equivalent to current practice for the identification of unsatisfactory and satisfactory but limited by slides. All results showed statistical significance. In addition, AutoPap System-assisted practice in the study indicated improved specificity of diagnosis. CONCLUSION: AutoPap System-assisted practice shows superior sensitivity and specificity when compared to current practice. Its clinical use as a primary screening device should improve the overall practice of cervical cytology as well as provide potential enhancement in overall laboratory productivity.     

Wasp venom immunotherapy changes IgG antibody specificity

OBJECTIVE: To evaluate the quality of studies seeking to establish measurement properties (reliability and validity) of ultrasonic estimation of urinary bladder volume. DESIGN: Online searching of the MEDLINE database between 1966 and 1995, and scanning of bibliography of known studies on ultrasonic bladder volume estimation. Study selection and study quality assessment were performed independently by two reviewers. Each article was evaluated for suitability of the reference standard, adequacy of reported blinding of the observers and appropriateness of the statistical index of concordance. The last two of these guidelines were applied to reliability studies (evaluating the relation among observed ultrasonic estimations), and all three guidelines were applied to validity studies (evaluating the relation of ultrasonic estimation with a definitive measurement). POPULATION: One hundred and twenty-five participants enrolled in the five reliability studies and 769 participants in the 27 validity studies selected for appraisal of their quality. MAIN OUTCOME MEASURE: Rate of study compliance with preset criteria for high quality. RESULTS: None of the studies complied with all of the criteria for high methodologic quality. In the five reliability studies, investigators did not report adequate blinding of observers in three (60%) and an appropriate index of reliability was not used in any. Among the 27 validity studies, there was a lack of a suitable reference standard in 6 (22%), an inadequate blinding in 25 (93%), and an inappropriate index of validity in all (100%). CONCLUSION: Based on our guidelines for quality assessment, a large proportion of studies on measurement properties was found to have inadequate methods, raising concern about the credibility of the reliability and validity estimates reported. These deficiencies highlight the lack of rigour employed in the design, conduct and analysis of reliability and validity studies, which has the potential for leading to patient mismanagement due to biases in the assessment of measurement variability in clinical investigations.     

Interpretation of simulation studies for efficient estimation of population pharmacokinetic parameters

OBJECTIVE: To develop new approaches for evaluating results obtained from simulation studies used to determine sampling strategies for efficient estimation of population pharmacokinetic parameters. METHODS: One-compartment kinetics with intravenous bolus injection was assumed and the simulated data (one observation made on each experimental unit [human subject or animal]), were analyzed using NONMEM. Several approaches were used to judge the efficiency of parameter estimation. These included: (1) individual and joint confidence intervals (CIs) coverage for parameter estimates that were computed in a manner that would reveal the influence of bias and standard error (SE) on interval estimates; (2) percent prediction error (%PE) approach; (3) the incidence of high pair-wise correlations; and (4) a design number approach. The design number (phi) is a new statistic that provides a composite measure of accuracy and precision (using SE). RESULTS: The %PE approach is useful only in examining the efficiency of estimation of a parameter considered independently. The joint CI coverage approach permitted assessment of the accuracy and reliability of all model parameter estimates. The phi approach is an efficient method of achieving an accurate estimate of parameter(s) with good precision. Both the phi for individual parameter estimation and the overall phi for the estimation of model parameters led to optimal experimental design. CONCLUSIONS: Application of these approaches to the analyses of the results of the study was found useful in determining the best sampling design (from a series of two sampling times designs within a study) for efficient estimation of population pharmacokinetic parameters.     

Interaction of spontaneous and organised screening for cervical cancer in Turin, Italy

In a screening programme for cervical cancer, coverage of the target population is a major determinant of effectiveness and cost-effectiveness and is one of the parameters for programme monitoring recommended by the "European Guidelines for Quality Assurance". An organised screening programme was started in Turin, Italy, in 1992. Spontaneous screening was already largely present, but coverage (proportion of women who had at least a test within 3 years) was low (< 50%) and distribution of smears uneven. No comprehensive registration of spontaneous smears was available. All women were invited for the first round, independently of their previous test history. Coverage was estimated by integrating routine data from the organised programme with data on spontaneous screening obtained by interviews of a random sample of 268 non-compliers to invitation and 167 compliers. Overall (spontaneous + organised) coverage was estimated to be 74% (95% CI, 71-78%). The proportion of the target population covered as an effect of invitation was estimated to be 17% (95% CI, 15-20%). Invitations were successful in increasing coverage in previously poorly screened groups. Although 20-25% of compliers was estimated to have had further tests before the end of the round, we estimated that switching to a 3-year interval saved approximately 0.26 tests per complier. This suggests that invitations to an organised programme even to previously covered women, can be a cost-effective policy. Our method of estimating overall coverage can be useful in many other European areas where a comprehensive registration of smears is not available.     

Are endoscopic measurements of colonic polyps reliable?

Many clinical studies of colorectal adenomatous polyps rely on endoscopic estimation of polyp size. To examine the reliability of such measurements, we conducted a study using artificial polyps in an endoscopy teaching model. Eight experienced endoscopists estimated the size of 13 polyps in two separate sessions 2 wk apart. Endoscopic estimates of polyp size tended to be significantly lower than the true polyp size for all polyps and all endoscopists at both sessions. We also found a statistically significant difference in the magnitude of the underestimation between the first and second session (p < 0.0001). At the first session, polyps tended to be estimated at 64% of their true size, and at the second session, the estimates tended to be at 77% of the actual polyp size. We estimate the magnitude of the variation in polyp measurements due to individual polyps, endoscopist, and examination session, and discuss the impact these sources of variation have in planning of clinical trials.     

Complex renal lithiasis: conservative surgery

Interpretation of the available studies for the purpose of predicting the recommended Ca and P needs of LBW infants is difficult because of the number of confounding variables that can affect Ca and P metabolism. Clinically, the most important measure of Ca/P "adequacy" must also be determined. Clearly, the predicted recommended intakes for dietary Ca and P would be different if normalization of serum and urine Ca and P levels is chosen rather than achievement of intrauterine retention of mineral or bone mineral content as the index of adequacy of mineral intake. The factorial approach to the estimation of Ca/P requirements was previously proposed by Ziegler et al. A reevaluation of their estimation is warranted in the light of recent data on estimates of fetal accretion of minerals in the third trimester (2.9 used by Zeigler et al.) vs. 3.7 estimated by Widdowson et al. and reported efficiencies of absorption of various sources of Ca and P in feedings for LBW infants. Based on the observed differences in bioavailability of Ca and P from different salts and combined with various milks, it may be appropriate to recommend intakes of Ca and possibly P that are specific for premature formulas separate from that recommended for supplements to preterm mother's milk.     

Perioperative management for patients with chronic liver injury and the strategy for preventing postoperative liver failure

OBJECTIVE: To quantify the interobserver variability in the sonographic estimation of renal volume in children. MATERIALS AND METHODS: Three observer pairs measured the lengths and diameters of 176 kidneys in 90 children. Renal volumes were estimated from the formula for a prolate ellipsoid. The mean and standard deviation of the absolute and percentage differences between observers were calculated. The 95 % limits of agreement for each pair of observers were derived. Log-transformed data were used to derive overall limits of agreement. RESULTS: Absolute interobserver variation increased with renal volume. Percentage variation was independent of renal size. There is a 95 % probability that a measurement of renal volume by one observer will be between 0.69 and 1.44 times a measurement made by a different observer. CONCLUSION: The interobserver variation in the sonographic estimation of renal volume represents approximately 2-3 years' normal growth in children aged over 2 years.     

Upper bound risk estimates for mixtures of carcinogens

The excess cancer risk that might result from exposure to a mixture of chemical carcinogens usually is estimated with data from experiments conducted on individual chemicals. An upper bound on the total excess risk is estimated commonly by summing individual upper bound risk estimates. The degree to which this approach might overstate the true risk associated with the mixture has not been evaluated previously. This paper reports the results of a Monte Carlo simulation study on the degree of reduction in conservation that might be achieved using alternative methods for calculating mixture upper bounds. An unexpected finding is that for chemicals that exhibit strongly linear dose-response relationships, the summing of multistage-model-based upper bounds on excess risk can be anti-conservative, that is, it can provide less than the nominal 100(1-alpha)% coverage.     

In vitro evaluation of three-dimensional ultrasonography based on magnetic scanhead tracking

The objective of this study was to evaluate the accuracy and precision of a magnetic position sensor system for acquisition of three-dimensional (3D) ultrasound images in volume estimation of phantoms in vitro. Installation of either 0.9% solution of saline at 37 degrees C or distilled water at 20 degrees C to a condom was performed. Scanning was performed either by a continuous or stepwise acquisition. This 3D ultrasound system demonstrated good correlation (r = 0.99-1.0, n = 8) between estimated (EV) and true volumes (TV). The errors were in the range 1.3%+/-0.3% (SEM) to 1.9%+/-0.6%, independent of sound velocity. Scanning through a porcine abdominal wall positioned at the fluid surface yielded a systematic underestimation of the volume: mean (EV - TV) = -7.2+/-0.8 ml. Eight repeated scans of the same volume yielded a coefficient of variation of 1.1%. Interobserver error of the tracing procedure was 2.6%+/-0.9%. This 3D ultrasound system gave high accuracy and precision in volume estimation in vitro, and yielded low interobserver error. A change in ultrasound velocity of approximately 60 m/s did not influence the accuracy significantly. Scanning through an abdominal wall underestimated volumes slightly.     

Reliable disparity estimation through selective integration

A network model of disparity estimation was developed based on disparity-selective neurons, such as those found in the early stages of processing in the visual cortex. The model accurately estimated multiple disparities in regions, which may be caused by transparency or occlusion. The selective integration of reliable local estimates enabled the network to generate accurate disparity estimates on normal and transparent random-dot stereograms. The model was consistent with human psychophysical results on the effects of spatial-frequency filtering on disparity sensitivity. The responses of neurons in macaque area V2 to random-dot stereograms are consistent with the prediction of the model that a subset of neurons responsible for disparity selection should be sensitive to disparity gradients.     

Scan optimization of gadolinium contrast-enhanced three-dimensional MRA of peripheral arteries with multiple bolus injections and in vitro validation of stenosis quantification

OBJECTIVE: Development of a method for semiautomated preparation of purified, representative and conventionally stained monolayer smears from bronchial secretions suitable for subjective and/or automated cytodiagnosis. STUDY DESIGN: Bronchial secretions from 50 patients with and 48 without carcinoma cells of different types were collected in Saccomanno's fixative. After routine pick-and-smear processing, residual material was subjected to a mucolytic agent (ammonium thioglycolate). Separation of cells was performed by differential centrifugation through aqueous sucrose. The pellet was automatically processed by the AutoCyte PREP system. RESULTS: Slides revealed well-preserved, slightly shrunken, homogeneously distributed cells devoid of mucus, cellular debris and bacteria in monolayer arrangement nearly without overlap. Granulocytes were eliminated to a large extent. Comparison with pick-and-smear specimens showed more tumor cells per square centimeter of slide surface in 100% of AutoCyte PREP slides. The number of tumor cells per AutoCyte PREP slide was higher in 46% and lower in 54%. Selecting slides at random and requiring at least 10 abnormal cells to establish a tumor diagnosis were achieved in 82.7% if only one, in 88.0% if two and 94.0% if seven or eight AutoCyte PREP slides were investigated. CONCLUSION: The semiautomated method yielded conventionally stained, purified monolayer smears from bronchial secretions with cellular morphology suitable for evaluation by cytologists and screening machines. Representativity of AutoCyte PREP monolayers was superior to that of pick-and-smear slides.     

Ictal cognitive assessment of partial seizures and pseudoseizures

BACKGROUND: Previous studies suggest that responsiveness is impaired during complex partial seizures (CPS) and pseudoseizures (PS); however, to our knowledge, there has been no systematic comparison using both response and memory testing. OBJECTIVE: To compare CPS with PS using ictal cognitive assessment (ICA) of responsiveness and memory. PATIENTS AND METHODS: We used a nonautomated method of ICA by bedside observers, consisting of family members and staff, during video electroencephalographic monitoring to test responsiveness and memory during the ictal phase in 245 events. We assessed the adequacy of testing and compared the testing results in 31 patients during CPS and 13 patients during PS. RESULTS: The ictal presentation of a command was successful in 58% of the events. The ictal presentation of at least 2 memory items with testing for recall after orientation was adequate in 57% of events. Impaired responsiveness was shown during both CPS and PS. However, some response was detected during 48% of PS compared with 18% of CPS (P<.01). Memory items were recalled during 63% of PS but during only 4% of CPS (P<.001). The International Classification of Epileptic Seizures remained useful, but in 11 events (8%), distinguishing complex from simple partial seizures was difficult. Recall of various types of stimuli (aural-verbal vs visual-pictorial) during ICA did not correlate with the side or location of the seizure focus, but this may have been confounded by the rarity of any memory recall during CPS. CONCLUSIONS: Ictal cognitive assessment by bedside observers is practical and provides the interaction necessary for properly classifying seizures; ICA, especially memory, may help to distinguish CPS from PS.     

Characterization of a novel gene disrupted by a balanced chromosomal translocation t(2;19)(q11.2;q13.3) in a family with cleft lip and palate

Paleodemographers must work to understand how representative any archaeologically recovered skeletal series is and the potential effects of series bias on their demographic reconstructions. We examine two forms of bias: 1) infant underenumeration caused by differential preservation or incomplete archaeological recovery and 2) the underenumeration of individuals over age 45 related to methodological bias. We generated 60 simulated skeletal series of 250 individuals each based on the Brass ([1971] Biological Aspects of Demography (London: Taylor and Francis), pp. 69-110) logit models. In the first test, age bias was introduced deterministically for all individuals with age at death over 40 years using the Lovejoy et al. ([1985] Am. J. Phys. Anthropol. 68:1-14) bias estimates. In the second test, 50% of all individuals under 5 years old were removed from each simulated distribution. The simulated series were analyzed using the model life table fitting procedure developed by the authors (Milner et al. [1989] Am. J. Phys. Anthropol. 80:49-58; Paine [1989] Am. J. Phys. Anthropol. 79:51-62). Forms of adult age estimation bias described by Lovejoy and coworkers inflate estimates by 10-20% of the true crude birth rate (CBR) (the number of births per year per 1,000 population). Overestimation of fertility and birth rates increases both absolutely and as a percentage of the true rate as population growth increases. This bias is very consistent. Because Lovejoy and colleagues have estimated the methodological bias itself, its effects can be estimated. Infant underenumeration is a more serious obstacle. It is not presently possible to estimate infant underenumeration reliably without prior knowledge of fertility rates. This reduces fertility reconstructions based on infant-biased samples to minimum fertility estimates.     

Effect of burn injury on glucose turnover in guinea pigs

The Reflomat System for rapid estimation of plasma or blood glucose concentration has been evaluated. The System gave a linear response throughout its analytical range and the recovery of glucose added to glucose-free plasma was 97-105%. Addition of sodium fluoride to plasma produced a 7-15% reduction in the estimated glucose concentration. Plasma glucose concentration estimated with the Reflomat agreed closely with results of a glucose oxidase and a hexokinase based method, and blood glucose concentration measured with the Reflomat agreed well with results of a glucose oxidase method.     

Confidence intervals for the receiver operating characteristic area in studies with small samples

RATIONALE AND OBJECTIVES: The authors performed this study to address two practical questions. First, how large does the sample size need to be for confidence intervals (CIs) based on the usual asymptotic methods to be appropriate? Second, when the sample size is smaller than this threshold, what alternative method of CI construction should be used? MATERIALS AND METHODS: The authors performed a Monte Carlo simulation study where 95% CIs were constructed for the receiver operating characteristic (ROC) area and for the difference between two ROC areas for rating and continuous test results--for ROC areas of moderate and high accuracy--by using both parametric and nonparametric estimation methods. Alternative methods evaluated included several bootstrap CIs and CIs with the Student t distribution. RESULTS: For the difference between two ROC areas, CIs based on the asymptotic theory provided adequate coverage even when the sample size was very small (20 patients). In contrast, for a single ROC area, the asymptotic methods do not provide adequate CI coverage for small samples; for ROC areas of high accuracy, the sample size must be large (more than 200 patients) for the asymptotic methods to be applicable. The recommended alternative (bootstrap percentile, bootstrap t, or bootstrap bias-corrected accelerated method) depends on the estimation approach, format of the test results, and ROC area. CONCLUSION: Currently, there is not a single best alternative for constructing CIs for a single ROC area for small samples.     

Accuracy of helical CT for acute pulmonary embolism: ROC analysis of observer performance related to clinical experience

The aim of this study was to test the influence of observer experience on the accuracy for interpreting helical CT for acute pulmonary embolism (PE) and to identify sources of observer errors. Three observers of different expertise blindly assessed 147 helical CT scans for suspected PE (true status regarding absence or presence of PE known from independent reference studies). These observers were (a) an experienced CT radiologist, (b) a fellow in CT, and (c) a second-year resident without any formal training in CT. None of them had prior experience with CT for PE. Firstly, 70 CT scans were scored without revealing true PE status. Afterwards, feedback was provided and another 77 CT scans were evaluated. The CT scans were scored on a 5-point confidence scale and receiver-operator-characteristic analysis was performed. Different sources of interpretation errors were analyzed. The two observers with CT experience were significantly more accurate than the unexperienced observer. Their performance was not influenced by feedback training. Certain observer errors were identified, but there was no clear difference among the three observers considering the type of errors. There is significant influence of observer experience on accuracy of reading helical CT for PE: A basic working experience with whole-body CT seems to be a prerequisite. These results suggest that with this experience any radiologist should be able to achieve good accuracy; helical CT thus might become a suitable technique for acute PE in routine clinical practice.     

Estimating heading during real and simulated eye movements

The ability to judge heading during tracking eye movements has recently been examined by several investigators. To assess the use of retinal-image and extra-retinal information in this task, the previous work has compared heading judgments with executed as opposed to simulated eye movements. For eye movement velocities greater than 1 deg/sec, observers seem to require the eye-velocity information provided by extra-retinal signals that accompany tracking eye movements. When those signals are not provided, such as with simulated eye movements, observers perceive their self-motion as curvilinear translation rather than the linear translation plus eye rotation being presented. The interpretation of the previous results is complicated, however, by the fact that the simulated eye movement condition may have created a conflict between two possible estimates of the heading: one based on extra-retinal solutions and the other based on retina-image solutions. In four experiments, we minimized this potential conflict by having observers judge heading in the presence of rotations consisting of mixtures of executed and simulated eye movements. The results showed that the heading is estimated more accurately when rotational flow is created by executed eye movements alone. In addition, the magnitude of errors in heading estimates is essentially proportional to the amount of rotational flow created by a simulated eye rotation (independent of the total magnitude of the rotational flow). The fact that error magnitude is proportional to the amount of simulated rotation suggests that the visual system attributes rotational flow unaccompanied by an eye movement to a displacement of the direction of translation in the direction of the simulated eye rotation.     

Effects of information on the reinforcing, subjective, and psychomotor effects of nitrous oxide in healthy volunteers

One method of quality control which has recently been recommended by professional bodies in the UK is the 'rapid review' method. This involves the microscopic 30 s review of all negative cervical smears with the intention of flagging potential missed abnormalities. Although it has been suggested that rapid review is better than 10% random rescreening of negative smears, the efficiency and efficacy of this method of quality control have not been thoroughly evaluated. We have used the AxioHOME system, which can record the area of a slide covered and the screening time, to investigate slide coverage during rapid review quality control, as performed by 15 cytoscreeners and MLSOs reviewing a test set of 22 slides each. The test set comprised 18 negative slides, three positive slides, and one unsatisfactory slide. We have recorded two distinct methods of rapid review in use amongst cytotechnologists, the step method and the whole slide method. The data show that rapid review takes longer on average than the recommended 30 s, the mean screening times being 76 s and 82 s for the step and whole slide methods, respectively. Abnormal smears were missed on three of 15 occasions by the step method (sensitivity 80%, positive predictive value 85%), and on seven of 30 occasions by the whole slide method (sensitivity 76.6%, positive predictive value 45%). However, the 95% confidence intervals were wide (57.7-90.7% for the step method, and 51.9-95.7% for the whole slide method). Analysis of scanning tracks and screening rates shows significant flaws in the methodology of rapid review. Abnormal cells were not identified, although dyskaryotic cells were included in the scanning track on nine occasions, seven using the whole slide method and two using the step method. On one occasion (using the step method) abnormal cells were not identified because they were not included in the scanning track. Further research is in progress to determine optimal methods of rapid review, and whether the rapid review technique is as effective as automated screening systems for quality assurance in cytology.     

The effect of pictorial illusion on prehension and perception

The present study examined the effect of a size-contrast illusion (Ebbinghaus or Titchener Circles Illusion) on visual perception and the visual control of grasping movements. Seventeen right-handed participants picked up and, on other trials, estimated the size of "poker-chip" disks, which functioned as the target circles in a three-dimensional version of the illusion. In the estimation condition, subjects indicated how big they thought the target was by separating their thumb and forefinger to match the target's size. After initial viewing, no visual feedback from the hand or the target was available. Scaling of grip aperture was found to be strongly correlated with the physical size of the disks, while manual estimations of disk size were biased in the direction of the illusion. Evidently, grip aperture is calibrated to the true size of an object, even when perception of object size is distorted by a pictorial illusion, a result that is consistent with recent suggestions that visually guided prehension and visual perception are mediated by separate visual pathways.     

Task frequency rating accuracy: The effect of task engagement and experience.

In this study, researchers examined the effect of task engagement and experience on frequency rating accuracy with an objective measure of task frequency. By contrasting findings from the memory literature on frequency estimation with current task analysis practices, these investigators proposed that task performers and respondents with low levels of experience would generate more accurate frequency estimates compared with task observers and respondents with high levels of experience. Participants were randomly assigned to a task engagement condition (performer vs. observer) as well as to an experience condition (low vs. high). In support of the hypotheses, participants in the performer and low-experience conditions demonstrated greater accuracy in their frequency ratings. These findings were illustrated with several different measures of accuracy. Implications for task analysis research and practices are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)