Search

Technological advances in the field of histocompatibility have allowed us to define anti-human leukocyte antigen (HLA) antibody specificity at the allelic level. However, how allele-specific antibodies affect organ allocation is poorly studied. We examined allelic specificities of class I HLA antibodies in 6726 consecutive serum samples from 2953 transplant candidates and evaluated their impact on the corresponding crossmatch and organ allocation. Out of 17 class I HLA antigens represented by >1 allele in the LABScreen single antigen bead assay, 12 had potential allele-specific reactivity. Taking advantage of our unbiased cohort of deceased donor-candidate testing (123,135 complement-dependent cytotoxicity crossmatches between 2014 and 2017), we estimated that the presence of allele-specific antibody detected using a single antigen bead assay (median fluorescence intensity, >3000) against only the rare allele was a poor predictor of a positive complement-dependent cytotoxicity crossmatch, with a positive predictive value of 0% to 7%, compared with 52.5% in allele-concordant class I HLA antibodies against A or B locus antigens. Further, we confirmed allele-specific reactivity using flow crossmatch in 3 scenarios: A11:01/A11:02, A68:01/A68:02, and B44:02/B44:03. Our results suggest that allele-specific antibodies may unnecessarily exclude transplant candidates (up to 10%) from organ offers by overcalling unacceptable antigens; incorporation of selective reactivity pattern in allocation may promote precision matching and more equitable allocation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Melissa Yeung reports a relationship with One Lambda Inc that includes: consulting or advisory. Mike Chen reports a relationship with One Lambda Inc that includes: employment. Jar-How Lee reports a relationship with One Lambda Inc that includes: employment., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: People with chronic kidney disease (CKD) experience reduced quality of life (QoL) because of the high symptom and treatment burden. Limited data exist on the factors associated with overall and domain-specific QoL across all CKD stages., Methods: Using data from a prospective, multinational study (Australia, New Zealand, Canada, and Spain) in 1696 participants with CKD, we measured overall and domain-specific QoL (pain, self-care, activity, mobility, anxiety/depression) using the EuroQoL, 5 dimension, 3 level. Multivariable linear regression and logistic modeling were used to determine factors associated with overall and domain-specific QoL., Results: QoL for patients with CKD stages 3 to 5 (n = 787; mean, 0.81; SD, 0.20) was higher than in patients on dialysis (n = 415; mean, 0.76; SD, 0.24) but lower than in kidney transplant recipients (n = 494; mean, 0.84; SD, 0.21). Factors associated with reduced overall QoL (β [95% confidence intervals]) included being on dialysis (compared with CKD stages 3-5: -0.06 [-0.08 to -0.03]), female sex (-0.03 [-0.05 to -0.006]), lower educational attainment (- 0.04 [-0.06 to -0.02), lacking a partner (-0.04 [-0.06 to -0.02]), having diabetes (-0.05 [-0.07 to -0.02]), history of stroke (-0.09 [-0.13 to -0.05]), cardiovascular disease (-0.06 [-0.08 to -0.03]), and cancer (-0.03 [-0.06 to -0.009]). Pain (43%) and anxiety/depression (30%) were the most commonly affected domains, with dialysis patients reporting decrements in all 5 domains. Predictors for domain-specific QoL included being on dialysis, presence of comorbidities, lower education, female sex, and lack of a partner., Conclusions: Being on dialysis, women with CKD, those with multiple comorbidities, lack of a partner, and lower educational attainment were associated with lower QoL across all stages of CKD., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Purpose: Tomosynthesis is proposed to improve breast cancer assessment and staging. We compared tomosynthesis and mammography in estimating the size of newly-diagnosed breast cancers., Methods: All pathologically-confirmed cancers detected in the STORM-2 trial (90 cancers, 85 women) were retrospectively measured on tomosynthesis by two independent readers. One reader also measured cancers on mammography. Relative mean differences (MDs) and 95% limits of agreement (LOA) with pathology were estimated for tomosynthesis and mammography within a single reader (Analysis 1) and between two readers (Analysis 2)., Results: Where cancers were detected and hence measured by both tests, tomosynthesis overestimated pathologic size relative to mammography (Analysis 1: MD 5% versus 1%, Analysis 2: 7% versus 3%; P = 0.10 both analyses). There was similar, large measurement variability for both tests (LOA range: -60% to +166%). Overestimation by tomosynthesis was attributable to the subgroup with dense breasts (MDs = 12-13% versus 4% for mammography). There was low average bias for both tests in the low-density subgroup (MDs = 0-4%). LOA were larger in dense breasts for both tomosynthesis and mammography (P ≤ 0.02 all comparisons). Cancers detected only by tomosynthesis were more frequently in dense breasts (60-68%): for those tumours size was estimated with increased measurement variability (LOA ranging from -75% to +293%)., Conclusions: On average, tomosynthesis overestimates pathologic tumour size in women with dense breasts; that difference is more likely to impact management in women with larger tumours. The main advantage of tomosynthesis appears to be detecting mammographically-occult cancers; however tomosynthesis less accurately measured those cancers in dense breasts (large measurement variability)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background & Methods: The prospective 'screening with tomosynthesis or standard mammography' (STORM) trial recruited women participating in biennial breast screening in Italy (2011-2012), and compared sequential screen-readings based on 2D-mammography alone or based on tomosynthesis (integrated 2D/3D-mammography). The STORM trial showed that tomosynthesis screen-reading significantly increased breast cancer detection compared to 2D-mammography alone. The present study completes reporting of the trial by examining interval breast cancers ascertained at two year follow-up., Results: 9 interval breast cancers were identified; the estimated interval cancer rate was 1.23/1000 screens [9/7292] (95%CI 0.56 to 2.34) or 1.24/1000 negative screens [9/7235] (95%CI 0.57 to 2.36). In concurrently screened women who attended the same screening services and received 2D-mammography, interval cancer rate was 1.60/1000 screens [40/25,058] (95% CI 1.14 to 2.17) or 1.61/1000 negative screens [40/24,922] (95% CI 1.15 to 2.18). Estimated screening sensitivity for the STORM trial was 85.5% [59/69] (95%CI 75.0%-92.8%), and that for 2D-mammography screening was 77.3% [136/176] (95%CI 70.4%-83.2%)., Conclusion: Interval breast cancer rate amongst screening participants in the STORM trial was marginally lower (and screening sensitivity higher) than estimates amongst 2D-screened women; these findings should be interpreted with caution given the small number of interval cases and the sample size of the trial. Much larger screening studies, or pooled analyses, are required to examine interval cancer rates arising after breast tomosynthesis screening versus digital mammography screening., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Most population breast cancer (BC) screening programs use double-reading of 2D-mammography. We recently reported the screening with tomosynthesis or standard mammography-2 (STORM-2) trial, showing that double-read tomosynthesis (pseudo-3D-mammography) detected more BC than double-read 2D-mammography. In this study, we compare screen-detection measures for single-reading of 3D-mammography with those for double-reading of 2D-mammography, to inform screening practice., Methods: This is a secondary analysis based on STORM-2 which prospectively compared 3D-mammography and 2D-mammography in sequential screen-readings. Asymptomatic women ≥49 years who attended population-based screening (Trento, 2013-2015) were recruited. Participants recalled at any screen-read from parallel double-reading arms underwent further testing and/or biopsy. Single-reading of 3D-mammography, integrated with acquired or synthetized 2D-mammograms, was compared to double-reading of 2D-mammograhy alone for screen-detection measures: number of detected BCs, cancer detection rate (CDR), number and percentage of false-positive recall (FPR). Paired binary data were compared using McNemar's test., Results: Screening detected 90, including 74 invasive, BCs in 85 of 9672 participants. CDRs for single-reading using integrated 2D/3D-mammography (8.2 per 1000 screens; 95% CI 6.5-10.2) or 2D synthetic/3D-mammography (8.4 per 1000 screens; 95% CI: 6.7-10.4) were significantly higher than CDR for double-reading of 2D-mammography (6.3 per 1000 screens; 95% CI: 4.8-8.1), P<0.001 both comparisons. FPR% for single-read 2D/3D-mammography (2.60%; 95% CI: 2.29-2.94), or single-read 2D synthetic/3D-mammography (2.76%; 95% CI: 2.45-3.11), were significantly lower than FPR% for double-read 2D-mammography (3.42%; 95% CI: 3.07-3.80), P<0.001 and P=0.002 respectively., Conclusions: Single-reading of 3D-mammography (integrated 2D/3D or 2Dsynthetic/3D) detected more BC, and had lower FPR, compared to current practice of double-reading 2D-mammography alone - these findings have implications for population BC screening programs., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) and to propose a novel modification so as to enhance sensitivity based on results of individual patient data (IPD)., Methods: Individual patient data were available from 8 studies comparing the diagnostic accuracy of Awaji and revised El Escorial (rEEC) criteria. The sensitivity of a novel updated Awaji criteria, incorporating a "probable-laboratory supported" category, was also tested., Results: Individual patient data were available from 1086 patients, consisting of 881 ALS and 205 patients with disorders mimicking ALS. Summary sensitivities based on random effects logistic regression modelling disclosed a higher sensitivity of the Awaji criteria (0.70, 95% confidence interval [CI] 0.51-0.83) and updated Awaji criteria (0.73, 95% CI 0.56-0.85) when compared to rEEC (0.58, 95% CI 0.48-0.68). Paired analysis revealed higher sensitivities of Awaji criteria in 4 studies, and of updated Awaji criteria in 7 studies, when compared to rEEC., Conclusion: Individual patient data analysis established a higher sensitivity of Awaji criteria when compared to rEEC. The updated Awaji criteria enhanced the diagnostic sensitivity in limb-onset ALS., Significance: The updated Awaji criteria should be considered in clinical practice and future therapeutic trials., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

We examined interpretive efficiency and variability in true- and false-positive detection (TP, FP) for radiologists screen-reading with digital breast tomosynthesis as adjunct to full-field digital mammography (2D/3D) relative to 2D alone in population-based screening studies. A systematic literature search was performed to identify screening studies that provided radiologist-specific data for TP and FP detection. Radiologist interpretive efficiency (trade-off between TPs and FPs) was calculated using the FP:TP ratio which expresses the number of FP recalls for each screen-detected breast cancer. We modeled a pooled FP:TP ratio to assess variability in radiologists' interpretive efficiency at study-level using random effects logistic regression. FP:TP ratio improved (ratio decreased) for 2D/3D screen-reading (relative to 2D) for a majority of radiologists (18 of 22) across all studies. Variability in radiologists' FP:TP ratio was consistently lower in all studies for 2D/3D screen-reading, as suggested by lower variance in ratios. Study-level pooled FP:TP ratio for 2D- and 2D/3D-mammography respectively, were 5.96 (95%CI: 4.08 to 8.72) and 3.17 (95%CI: 2.25 to 4.47) for the STORM trial; 10.25 (95%CI: 6.42 to 16.35) and 7.07 (95%CI: 4.99 to 10.02) for the Oslo trial; and 20.84 (95%CI: 13.95 to 31.12) and 8.37 (95%CI: 5.87 to 11.93) for the Houston study. This transfers into study-level improved interpretative efficiencies of 48%, 30% and 55%, respectively, for 2D/3D screen-reading (relative to 2D). In summary, study-level FP:TP trade-off improved using 2D/3D-mammography for all studies, which was also seen for most individual radiologists. There was variability in the FP:TP trade-off between readers and studies for 2D-as well as for 2D/3D-interpretations but variability in radiologists' interpretive efficiency was relatively lower using 2D/3D-mammography., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background & Objectives: Three-dimensional (3D)-mammography (tomosynthesis) may improve breast cancer detection. We examined centre-specific effect of integrated 2D/3D mammography based on the STORM (screening with tomosynthesis or standard mammography) trial., Methods: Asymptomatic women who attended population-based screening through Trento and Verona screening centres were recruited into STORM, a prospective comparison of screen-reading in two sequential phases: 2D-mammography only and integrated 2D/3D mammography. Outcomes were the number and rates of detected cancers and of false positive recalls (FPR), and incremental cancer detection rate (CDR). Paired binary data were compared using Mc Nemar's test., Results: Of 33 cancers detected in Trento, 21 were detected at both 2D and 2D/3D screening, 12 cancers were detected only with integrated 2D/3D screening compared with none detected at 2D-only screening (P < 0.001). Of the 26 cancers detected in Verona, 18 were detected at both 2D and 2D/3D screening, 8 cancers were detected only with integrated 2D/3D screening compared with none detected at 2D-only screening (P = 0.008). There were no differences between centres in baseline CDR, and incremental CDR attributable to 3D-mammography was similar for Trento (2.8/1000 screens) and for Verona (2.6/1000 screens). Trento had 239 FPR (5.7% of screens): 103 FPR at both screen-readings, 93 FPR only at 2D-mammography compared with 43 FPR only at 2D/3D-mammography (p < 0.001). Verona had 156 FPR (5.2% of screens): 78 FPR at both screen-readings, 48 FPR only at 2D-mammography compared with 30 FPR only at 2D/3D-mammography (p = 0.054). Estimated reduction in FPR proportion had recall been conditional to 2D/3D-mammography-positivity differed between centres (21.0% versus 11.5%; P = 0.02)., Conclusion: Integrated 2D/3D-mammography significantly increased cancer detection for both screening services; potential reduction in FPR is likely to differ between centres with those experiencing relatively higher FPR most likely to benefit from 2D/3D-mammography screening., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Magnetic resonance imaging (MRI) has been proposed to have a role in predicting final pathologic response when undertaken early during neoadjuvant chemotherapy (NAC) in breast cancer. This paper examines the evidence for MRI's accuracy in early response prediction. A systematic literature search (to February 2011) was performed to identify studies reporting the accuracy of MRI during NAC in predicting pathologic response, including searches of MEDLINE, PREMEDLINE, EMBASE, and Cochrane databases. 13 studies were eligible (total 605 subjects, range 16-188). Dynamic contrast-enhanced (DCE) MRI was typically performed after 1-2 cycles of anthracycline-based or anthracycline/taxane-based NAC, and compared to a pre-NAC baseline scan. MRI parameters measured included changes in uni- or bidimensional tumour size, three-dimensional volume, quantitative dynamic contrast measurements (volume transfer constant [Ktrans], exchange rate constant [k(ep)], early contrast uptake [ECU]), and descriptive patterns of tumour reduction. Thresholds for identifying response varied across studies. Definitions of response included pathologic complete response (pCR), near-pCR, and residual tumour with evidence of NAC effect (range of response 0-58%). Heterogeneity across MRI parameters and the outcome definition precluded statistical meta-analysis. Based on descriptive presentation of the data, sensitivity/specificity pairs for prediction of pathologic response were highest in studies measuring reductions in Ktrans (near-pCR), ECU (pCR, but not near-pCR) and tumour volume (pCR or near-pCR), at high thresholds (typically >50%); lower sensitivity/specificity pairs were evident in studies measuring reductions in uni- or bidimensional tumour size. However, limitations in study methodology and data reporting preclude definitive conclusions. Methods proposed to address these limitations include: statistical comparison between MRI parameters, and MRI vs other tests (particularly ultrasound and clinical examination); standardising MRI thresholds and pCR definitions; and reporting changes in NAC based on test results. Further studies adopting these methods are warranted., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Statistical process control charts have been advocated for use in monitoring of lung function in asthma. We aimed to evaluate their application in asthma using existing data from a randomized trial., Study Design and Setting: Patients on optimal inhaled corticosteroid/bronchodilator therapy (n=81) were randomized to continue the same or change to corticosteroid alone. Baseline statistical control was assessed from 20 days of electronically recorded lung function (peak expiratory flow [PEF], forced expiratory volume in one second [FEV(1)]). The ability to detect lung function changes was assessed during 10 days after randomization., Results: PEF measurements were in statistical control during baseline for only 59-79% of patients for different combinations of five control chart rules (e.g., Rule 1: >3 standard deviations outside mean and 95% expected to be in control), with similar proportions for FEV(1). After randomization, among those previously in statistical control, Rule 1 signaled lower FEV(1) for 35% of patients randomized to treatment change compared with 6% continuing baseline treatment (P=0.004). Control charts performed poorly for PEF, signaling a decrease for 8% of patients randomized to treatment change compared with 11% continuing treatment (P=0.7). A paradoxical increase was signaled for many patients continuing treatment., Conclusion: Control charts may not be suitable for use in many patients with asthma., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objective: In systematic reviews of the reliability of diagnostic tests, no quality assessment tool has been used consistently. The aim of this study was to develop a specific quality appraisal tool for studies of diagnostic reliability., Methods: Key principles for the quality of studies of diagnostic reliability were identified with reference to epidemiologic principles, existing quality appraisal checklists, and the Standards for Reporting of Diagnostic Accuracy (STARD) and Quality Assessment of Diagnostic Accuracy Studies (QUADAS) resources. Specific items that encompassed each of the principles were developed. Experts in diagnostic research provided feedback on the items that were to form the appraisal tool. This process was iterative and continued until consensus among experts was reached., Results: The Quality Appraisal of Reliability Studies (QAREL) checklist includes 11 items that explore seven principles. Items cover the spectrum of subjects, spectrum of examiners, examiner blinding, order effects of examination, suitability of the time interval among repeated measurements, appropriate test application and interpretation, and appropriate statistical analysis., Conclusions: QAREL has been developed as a specific quality appraisal tool for studies of diagnostic reliability. The reliability of this tool in different contexts needs to be evaluated., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective: To explain which measures of accuracy and which statistical methods should be used in studies to assess the value of a new binary test as a replacement test, an add-on test, or a triage test., Study Design and Setting: Selection and explanation of statistical methods, illustrated with examples., Results: Statistical methods for comparative diagnostic accuracy studies are described that take into account the purpose of the new diagnostic test. Methods are described within a framework that defines the major purpose of test comparison: assessing the value of a new test as a replacement test, an add-on test, or a triage test. Methods appropriate for both unpaired and paired study designs for binary test data are given, including regression modeling of diagnostic test accuracy. Implications for efficient study designs are also discussed., Conclusions: Appropriate selection of existing statistical methods is necessary to address research questions about the comparative accuracy of new tests., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective: To demonstrate how mixed models may be used to estimate treatment effects, and inform decisions on the need for monitoring initial response., Study Design and Setting: Mixed models were used to analyze data from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), which examined the effects of perindopril and indapamide in 6,105 patients at high risk of a cerebrovascular event., Results: The mean effect of perindopril was to lower blood pressure (BP) (systolic/diastolic) by 6/3 mmHg. The mean effects of perindopril/indapamide varied according to baseline BP, and lowering of BP ranged from 9/5 to 14/5 mmHg (for individuals with a baseline systolic BP <140 and >150 mmHg, respectively). We found no variation in the effects of treatment on BP for either perindopril alone or in combination with indapamide. The effects of treatment on the individual can be predicted from the mean effect of treatment for the group (perindopril) or baseline systolic BP subgroup (perindopril/indapamide)., Conclusion: Monitoring initial treatment response is unnecessary for antihypertensives similar to those examined in this study. To address this issue for other therapies, we suggest that trials should report estimates of treatment effects from mixed models, and the CONSORT statement should be expanded to include this item.

Objective: To examine women's informed preference for the management of a mildly abnormal Pap smear and the impact of a decision aid., Methods: Women (n=106) were given a choice of management supported by a decision aid and surveyed before, and after decision making to evaluate predictors of choice and decision aid impact., Results: HPV triage was preferred by most women (65%) although a substantial minority selected repeat Pap testing (35%). Women who chose HPV triage were more likely to have had children, have had a previous abnormal Pap smear and were more distressed than women who chose a repeat Pap test. In total, 68% of women made an informed choice. Rapid timing of follow-up was important for women choosing HPV testing. The lower chance of colposcopy and greater opportunity for regression, were rated as important by women choosing Pap testing. Decisional conflict was lower among women who chose HPV triage. No other differences in short-term psychological outcomes were found., Conclusion: The decision aid supported informed choice among the majority of women. Women tailored their choice to their practical, health and psychological needs., Practice Implications: Offering women an informed choice for a mildly abnormal Pap smear may enable women to select the management that best suits their circumstances.

Objective: To compare three predictive models based on logistic regression to estimate adjusted likelihood ratios allowing for interdependency between diagnostic variables (tests)., Study Design and Setting: This study was a review of the theoretical basis, assumptions, and limitations of published models; and a statistical extension of methods and application to a case study of the diagnosis of obstructive airways disease based on history and clinical examination., Results: Albert's method includes an offset term to estimate an adjusted likelihood ratio for combinations of tests. Spiegelhalter and Knill-Jones method uses the unadjusted likelihood ratio for each test as a predictor and computes shrinkage factors to allow for interdependence. Knottnerus' method differs from the other methods because it requires sequencing of tests, which limits its application to situations where there are few tests and substantial data. Although parameter estimates differed between the models, predicted "posttest" probabilities were generally similar., Conclusion: Construction of predictive models using logistic regression is preferred to the independence Bayes' approach when it is important to adjust for dependency of tests errors. Methods to estimate adjusted likelihood ratios from predictive models should be considered in preference to a standard logistic regression model to facilitate ease of interpretation and application. Albert's method provides the most straightforward approach.

Long-term survival and progression of disability in multiple sclerosis have not been studied previously in Australia. We report the findings in a cohort of 159 patients from Newcastle. Median survival time from onset of symptoms to death was 42 years. When expected survival rates are compared with those of the Australian population, there is approximately a 10% reduction in survival time in multiple sclerosis patients, after 20 years or more from disease onset. The expected time to reach DSS 3 and DSS 6 was 7 years and 27 years respectively. Survival time of multiple sclerosis patients and rate of progression of the disease are similar in the Northern and Southern Hemispheres.

Objective: Whether tests such as imaging should be read with or without access to prior clinical information is controversial. Naïve comparisons may suggest that the provision of prior information improves test accuracy, whereas in fact the opposite may be true. This is because provision of clinical background may actually bias test readers to over- or underinterpret relevant test findings, and they may suboptimally integrate the previous and current evidence. We propose comparing the combined accuracy of prior information and a test read (i) with or (ii) without knowledge of prior information. Analysis methods include simple decision rules and logistic regression., Study Design and Setting: A study of cancer detection in women presenting with breast symptoms, in whom ultrasound could be read with or without reviewing prior mammography., Results: Naïve analysis gave an area under the receiver operating characteristics curve (AUC) for ultrasound read with mammography on view that was 4.6% higher (P < .01) than without mammography on view. Our approach, comparing the combined accuracy of mammography and ultrasound read i) with and ii) without knowledge of mammographic findings, showed much smaller differences., Conclusion: Our approach is more appropriate than naïve analyses. The particular choice of analytic method depends on the study size and the diagnostic accuracy of combinations of the prior information and the test reading.

Background: Liquid-based cytology is reported to increase the sensitivity of cervical cytology and the proportion of slides that are satisfactory for assessment, in comparison with conventional cytology. Although some countries have changed to liquid-based cytology for cervical screening, controversy remains. We reviewed the published work to assess the performance of liquid-based cytology relative to conventional cytology in primary studies assessed to be of low, medium, or high methodological quality., Methods: 56 primary studies were reviewed and assessed with strict methodological criteria. Liquid-based cytology and conventional cytology were compared in terms of the percentage of slides classified as unsatisfactory, the percentage of slides classified in each cytology category, and the accuracy of detection of high-grade disease. Data were examined for studies overall and in strata to examine the effect of study quality on results., Findings: The median difference in the percentage of unsatisfactory slides between liquid-based cytology and conventional cytology was 0.17%. Only one small study was a randomised controlled trial. The classification of high-grade squamous epithelial lesion varied according to study quality (p=0.04), with conventional cytology classifying more slides in this category than did liquid-based cytology in high-quality studies (n=3) only. In medium-quality (n=30) and high-quality studies, liquid-based cytology classified more slides as atypical squamous cells of unknown significance than did conventional cytology when compared with low-quality studies (n=17; p=0.05). Only four studies provided sufficient verified data to allow estimation of sensitivity and specificity and comparison of test accuracy., Interpretation: We saw no evidence that liquid-based cytology reduced the proportion of unsatisfactory slides, or detected more high-grade lesions in high-quality studies, than conventional cytology. This review does not lend support to claims of better performance by liquid-based cytology. Large randomised controlled trials are needed.

Background and Objective: Publication bias and other sample size effects are issues for meta-analyses of test accuracy, as for randomized trials. We investigate limitations of standard funnel plots and tests when applied to meta-analyses of test accuracy and look for improved methods., Methods: Type I and type II error rates for existing and alternative tests of sample size effects were estimated and compared in simulated meta-analyses of test accuracy., Results: Type I error rates for the Begg, Egger, and Macaskill tests are inflated for typical diagnostic odds ratios (DOR), when disease prevalence differs from 50% and when thresholds favor sensitivity over specificity or vice versa. Regression and correlation tests based on functions of effective sample size are valid, if occasionally conservative, tests for sample size effects. Empirical evidence suggests that they have adequate power to be useful tests. When DORs are heterogeneous, however, all tests of funnel plot asymmetry have low power., Conclusion: Existing tests that use standard errors of odds ratios are likely to be seriously misleading if applied to meta-analyses of test accuracy. The effective sample size funnel plot and associated regression test of asymmetry should be used to detect publication bias and other sample size related effects.

Background and Objective: A range of fixed-effect and random-effects meta-analytic methods are available to obtain summary estimates of measures of diagnostic test accuracy. The hierarchical summary receiver operating characteristic (HSROC) model proposed by Rutter and Gatsonis in 2001 represents a general framework for the meta-analysis of diagnostic test studies that allows different parameters to be defined as a fixed effect or random effects within the same model. The Bayesian method used for fitting the model is complex, however, and the model is not widely used. The objective of this report is to show how the model may be fitted using the SAS procedure NLMIXED and to compare the results to the fully Bayesian analysis using an example., Methods: The HSROC model, its assumptions, and its interpretation are described. The advantages of this model over the usual summary ROC (SROC) regression model are outlined. A complex example is used to compare the estimated SROC curves, expected operating points, and confidence intervals using the alternative approaches to fitting the model., Results: The empirical Bayes estimates obtained using NLMIXED agree closely with those obtained using the fully Bayesian analysis., Conclusion: This alternative and more straightforward method for fitting the HSROC model makes the model more accessible to meta-analysts.

When estimating the treatment effect in a randomized controlled trial, it is common to have a continuous outcome which is also observed at baseline. These observations are often prone to measurement error, for example due to within-patient variability. Controversy exists in the literature about whether baseline measurement error should be adjusted for in this context. Computer simulations were used to compare the biases in the estimated treatment effect, with and without adjusting for measurement error, and for different levels of observed baseline imbalance. The impacts of sample size (30 per group and 300 per group) and reliability coefficient (0.6, 0.8 and 1) were also assessed. The results show that in randomized controlled trials, the ordinary least squares (OLS) estimator without adjusting for measurement error is unbiased. On the contrary, adjusting for measurement error leads to bias, especially when sample sizes are small and/or measurement error is large. The treatment effect adjusting for measurement error is on average overestimated when the baseline mean of the control group is larger than that of the treated group. It is underestimated when the control group has a smaller baseline mean.

Objective: To develop and demonstrate efficient methods to estimate the relative true positive and false positive rates of two cervical screening tests (conventional cytology and PAPNET)., Methods: We designed the study to meet stringent methodologic criteria for comparison of two tests while simultaneously minimizing the numbers requiring reference standard verification. We used a cytology reference standard and also assessed histology when available. For the primary analysis, slides with discordant results around the test threshold (CIN 1) were reviewed by a panel of two cytopathologists, blind to previous results, to establish the reference standard result (reference standard threshold for abnormality CIN2). Where histology was available, a secondary analysis was conducted with the reference standard based on the highest grade lesion (either cytology or histology)., Results: Among 21,747 Pap smears, 372 were discordant around the test threshold, requiring verification. In the primary analysis PAPNET detected four more true positives than conventional reading; difference in sensitivity 1.29% (95%CI -5.79 to 8.36%, P=.40). There were two extra false positives using PAPNET; difference in the false positive rate 0.0097% (95%CI -0.122 to 0.142%, P=.47). The results of the combined cytology and histology analysis were similar; difference in true positive rate 0.29% (95%CI -6.76 to 7.34%, P=.50) and difference in false positive rate 0.024% (95%CI -0.098 to 0.15%, P=.39)., Conclusion: This is an efficient and valid study design where the objective is to examine the comparative accuracy of two tests. The design provides an efficient means of estimating the difference between true positive and false positive detection by the two tests, which often is sufficient information for policy decisions.

The prevalence of multiple sclerosis (MS) in Newcastle, Australia increased significantly between 1961 and 1981 and the incidence of the disease also increased between the decades 1950-1959 and 1971-1981. The present study sought to determine whether there has been a further increase in the frequency of MS in the subsequent 15 years, and to examine the potential factors underlying this change. The incidence, prevalence and clinical profile of multiple sclerosis were therefore re-examined in Newcastle, Australia in 1996 using comparable diagnostic criteria and methods to those employed in studies in the same region in 1961 and 1981. There has been a significant progressive increase in prevalence from 19.6 to 59.1 per 100,000 population and a significant increase in incidence from 1.2 to 2.4 per 100,000 population from 1961 to 1996. The most pronounced increase in prevalence was in females and in the age-group over 60 years, and there was also an increased incidence in females aged 20-29 years. There was little change in the age of disease onset, but duration of disease in females had increased substantially. The significant increase in prevalence is attributed to increased incidence, particularly in females; and to increased survival. Although such trends in prevalence have been observed in the Northern Hemisphere, this is the first such study in the Southern Hemisphere to show a longitudinal increase in prevalence and incidence over a period of this duration.

Objective: To examine the prevalence and socio-demographic distribution of physical activity among New South Wales school students in Years 8 and 10., Methods: Cross-sectional survey of 2,026 randomly selected NSW high school students in 1997. The survey participants self-reported their physical activity participation during a normal week in summer and winter school terms., Results: During summer school terms, 80.9% and 85.9% of Year 8 and Year 10 boys, respectively, and 80.8% and 77.7% of Year 8 and Year 10 girls, respectively, were adequately active. During winter school terms, 75.6% and 84.0% of Year 8 and Year 10 boys, respectively, and 69.4% and 66.0% of Year 8 and Year 10 girls, respectively, were adequately active. The associations between socio-economic status, urban/rural place of residence and physical activity participation were neither strong nor consistent. There were complex relationships between physical activity participation and cultural background among boys, and large differences between different cultural groups of girls and large declines in participation from Year 8 to Year 10 among girls., Conclusions: Although the majority of boys and girls are adequately active, it is clear that a smaller proportion of girls than boys are vigorously active, particularly during winter. There were no clear differences across tertiles of SES or place of residence, but there were significant differences between girls from different cultural backgrounds., Implications: Efforts to increase the proportion of young people who are vigorously active should emphasise the needs and interests of girls, particularly those from Middle-Eastem and Asian cultural backgrounds.

This paper reviews and summarises evidence on the investigation of breast symptoms based on triple testing. The triple test (where any component is positive) has a sensitivity of 99.6%, a specificity of 62%, a likelihood ratio of 2.62 for a positive result, and a likelihood ratio of 0.006 for a negative result. We present measures of test accuracy for the components of the triple test that allow easy estimation of the probability of breast cancer in symptomatic women, given any possible combination of results.

Despite its importance for clinical policy, there is little research on the age at which ultrasound or mammography is the preferred initial diagnostic test in women with breast symptoms. We analysed data from a series of 3799 consecutively presenting cancers. The overall sensitivity was 77.6% for mammography and 80.5% for ultrasound. Sensitivity increased with age in both mammography and ultrasound, though more steeply for mammography. In the 975 women who had both tests, ultrasound had a higher sensitivity than mammography in women younger than 62 years of age, whereas mammography had a higher sensitivity than ultrasound in women older than 62 years. However, if the test results of the 2393 women who had mammography only are compared with the ultrasound results of the 975 women who had both tests, the 'cross-over' age at which the sensitivity of the two tests is equal occurs at the earlier age of 48 years. The presence of a palpable finding increases the sensitivity of ultrasound but does not influence the sensitivity of mammography.

Objective: To compare the ability of tests of visual function to detect the presence of eye disease., Design: Cross-sectional study., Participants: Three thousand six hundred fifty-four of 4433 (82.4%) eligible residents of an area near Sydney aged 49 years and older had a detailed eye examination, including retinal and lens photography and subsequent grading of eye disease, tests of presenting and corrected visual acuity, contrast sensitivity, screening visual field and intraocular pressure., Main Outcome Measures: Receiver operator characteristic (ROC) curves were created and area under the curve compared for each vision test. Sensitivity and specificity were calculated for each test., Results: No single vision test predicted the presence of eye disease with any consistency. Best-corrected visual acuity or contrast sensitivity had the highest area under the ROC curve for most eye diseases examined but had poor sensitivity and specificity. For glaucoma and diabetic retinopathy there was no difference in area under the curve for any of the tests examined, and no test had a good balance of sensitivity and specificity. Screening tests (performed with presenting correction) did not perform as well as nonscreening tests (those carried out after refraction with best correction)., Conclusions: Current vision tests are not particularly good at detecting eye disease compared with the "gold standard" of a full eye examination performed by an ophthalmologist. Further work in this area should be carried out before vision screening programs can be recommended for implementation among older people.

This study describes the health risks and health behaviour of a sample of 283 out-of-school 16-year-olds in New South Wales. We sampled study participants through the Commonwealth Employment Service offices in 1994 using a multistage sampling procedure. Of those surveyed, 129 responded to a letter inviting them to participate and 154 were recruited opportunistically. This paper describes the study methods and results for self-reported binge drinking, weekly use of tobacco and marijuana, sexual abuse, physical abuse, drink-driving, violence, and use of health services, by sex and method of recruitment. High rates of substance use were observed. Reported substance use in the out-of-school group was consistently higher than for 16-year-olds in school, except for binge drinking for girls recruited by letter. Of the out-of-school group, 34 per cent reported weekly use of tobacco, marijuana and also binge drinking. Boys were more likely to report drink-driving than girls (28 per cent and 13 per cent respectively). Having been in trouble with police ranged from 32 per cent for girls recruited by letter to 75 per cent for boys recruited opportunistically. A high proportion of girls reported sexual abuse (34 per cent of the 'letter' group and 41 per cent of the 'opportunistic' group). Overall, 87 per cent of respondents had used health services in the previous year. The results indicate that this is a disadvantaged group of young people who are an important target for health service provision and interventions.

Meta-analyses of diagnostic test accuracy are uncommon and often based on separate pooling of sensitivity and specificity, which can lead to biased estimates. Recently, several appropriate methods have been developed for meta-analysing diagnostic test data from primary studies. Primary studies usually only provide binary test data, for which Moses et al. have developed a method to estimate Summary Receiver Operating Characteristic Curves, thereby taking account of possible test threshold differences between studies. Several methods are also available for analysing multicategory and continuous test data. The usefulness of applying these methods is constrained by publication bias and the generally poor quality of primary studies of diagnostic test accuracy. Meta-analysts need to highlight important defects in quality and how they affect summary estimates to ensure that better primary studies are available for meta-analysis in the future.

Previous reports have established that several variables are of prognostic importance in rectal cancer. The information from a Medical Research Council trial in seventeen centres in the United Kingdom was used to assess the simultaneous contribution of several of these factors in a multivariate analysis. In the preoperative assessment mobility of the tumour and the number of quadrants involved were predictive of the likelihood of a curative resection being possible. Among patients who had curative resections, prognosis was influenced by Dukes' classification, height of tumour, histological grade, and venous invasion. A scoring system based on these criteria was constructed and applied to this group of patients. It successfully defined five prognostic groups with 5-year survival rates ranging from 80% to 19%.