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Background: Cardiovascular disease (CVD) prevention guidelines encourage assessment of absolute CVD risk - the probability of a CVD event within a fixed time period, based on the most predictive risk factors. However, few General Practitioners (GPs) use absolute CVD risk consistently, and communication difficulties have been identified as a barrier to changing practice. This study aimed to explore GPs' descriptions of their CVD risk communication strategies, including the role of absolute risk., Methods: Semi-structured interviews were conducted with a purposive sample of 25 GPs in New South Wales, Australia. Transcribed audio-recordings were thematically coded, using the Framework Analysis method to ensure rigour., Results: GPs used absolute CVD risk within three different communication strategies: 'positive', 'scare tactic', and 'indirect'. A 'positive' strategy, which aimed to reassure and motivate, was used for patients with low risk, determination to change lifestyle, and some concern about CVD risk. Absolute risk was used to show how they could reduce risk. A 'scare tactic' strategy was used for patients with high risk, lack of motivation, and a dismissive attitude. Absolute risk was used to 'scare' them into taking action. An 'indirect' strategy, where CVD risk was not the main focus, was used for patients with low risk but some lifestyle risk factors, high anxiety, high resistance to change, or difficulty understanding probabilities. Non-quantitative absolute risk formats were found to be helpful in these situations., Conclusions: This study demonstrated how GPs use three different communication strategies to address the issue of CVD risk, depending on their perception of patient risk, motivation and anxiety. Absolute risk played a different role within each strategy. Providing GPs with alternative ways of explaining absolute risk, in order to achieve different communication aims, may improve their use of absolute CVD risk assessment in practice.

Objective: To understand general practitioners' (GPs) use of individual risk factors (blood pressure and cholesterol levels) versus absolute risk in cardiovascular disease (CVD) risk management decision-making., Design: Randomised experiment. Absolute risk, systolic blood pressure (SBP), cholesterol ratio (total cholesterol/high-density lipoprotein (TC/HDL)) and age were systematically varied in hypothetical cases. High absolute risk was defined as 5-year risk of a cardiovascular event >15%, high blood pressure levels varied between SBP 147 and 179 mm Hg and high cholesterol (TC/HDL ratio) between 6.5 and 7.2 mmol/L., Setting: 4 GP conferences in Australia., Participants: 144 Australian GPs., Outcomes: GPs indicated whether they would prescribe cholesterol and/or blood pressure lowering medication. Analyses involved logistic regression., Results: For patients with high blood pressure: 93% (95% CI 86% to 96%) of high absolute risk patients and 83% (95% CI 76% to 88%) of lower absolute risk patients were prescribed blood pressure medication. Conversely, 30% (95% CI 25% to 36%) of lower blood pressure patients were prescribed blood pressure medication if absolute risk was high and 4% (95% CI 3% to 5%) if lower. 69% of high cholesterol/high absolute risk patients were prescribed cholesterol medication (95% CI 61% to 77%) versus 34% of high cholesterol/lower absolute risk patients (95% CI 28% to 41%). 36% of patients with lower cholesterol (95% CI 30% to 43%) were prescribed cholesterol medication if absolute risk was high versus 10% if lower (95% CI 8% to 13%)., Conclusions: GPs' decision-making was more consistent with the management of individual risk factors than an absolute risk approach, especially when prescribing blood pressure medication. The results suggest medical treatment of lower risk patients (5-year risk of CVD event <15%) with mildly elevated blood pressure or cholesterol levels is likely to occur even when an absolute risk assessment is specifically provided. The results indicate a need for improving uptake of absolute risk guidelines and GP understanding of the rationale for using absolute risk., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Introduction: Women are largely unaware that mammography screening can cause overdetection of inconsequential disease, leading to overdiagnosis and overtreatment of breast cancer. Evidence is lacking about how information on overdetection affects women's breast screening decisions and experiences. This study investigates the consequences of providing information about overdetection of breast cancer to women approaching the age of invitation to mammography screening., Methods and Analysis: This is a randomised controlled trial with an embedded longitudinal qualitative substudy. Participants are a community sample of women aged 48-50 in New South Wales, Australia, recruited in 2014. Women are randomly allocated to either quantitative only follow-up (n=904) or additional qualitative follow-up (n=66). Women in each stream are then randomised to receive either the intervention (evidence-based information booklet including overdetection, breast cancer mortality reduction and false positives) or a control information booklet (including mortality reduction and false positives only). The primary outcome is informed choice about breast screening (adequate knowledge, and consistency between attitudes and intentions) assessed via telephone interview at 2 weeks postintervention. Secondary outcomes measured at this time include decision process (decisional conflict and confidence) and psychosocial outcomes (anticipated regret, anxiety, breast cancer worry and perceived risk). Women are further followed up at 6 months, 1 and 2 years to assess self-reported screening behaviour and long-term psychosocial outcomes (decision regret, quality of life). Participants in the qualitative stream undergo additional in-depth interviews at each time point to explore the views and experiences of women who do and do not choose to have screening., Ethics and Dissemination: The study has ethical approval, and results will be published in peer-reviewed journals. This research will help ensure that information about overdetection may be communicated clearly and effectively, using an evidence-based approach, to women considering breast cancer screening., Trial Registration Number: Australian New Zealand Clinical Trials Registry ACTRN12613001035718., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objectives: To evaluate the optimal lipid to measure in monitoring patients, we assessed three factors that influence the choice of monitoring tests: (1) clinical validity; (2) responsiveness to therapy changes and (3) the size of the long-term 'signal-to-noise' ratio., Design: Longitudinal analyses of repeated lipid measurement over 5 years., Setting: Subsidiary analysis of a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study-a clinical trial in Australia, New Zealand and Finland., Participants: 9014 patients aged 31-75 years with previous acute coronary syndromes., Interventions: Patients were randomly assigned to 40 mg daily pravastatin or placebo., Primary and Secondary Outcome Measures: We used data on serial lipid measurements-at randomisation, 6 months and 12 months, and then annually to 5 years-of total cholesterol; low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and their ratios; triglycerides; and apolipoproteins A and B and their ratio and their ability to predict coronary events., Results: All the lipid measures were statistically significantly associated with future coronary events, but the associations between each of the three ratio measures (total or LDL cholesterol to HDL cholesterol, and apolipoprotein B to apolipoprotein A1) and the time to a coronary event were better than those for any of the single lipid measures. The two cholesterol ratios also ranked highly for the long-term signal-to-noise ratios. However, LDL cholesterol and non-HDL cholesterol showed the most responsiveness to treatment change., Conclusions: Lipid monitoring is increasingly common, but current guidelines vary. No single measure was best on all three criteria. Total cholesterol did not rank highly on any single criterion. However, measurements based on cholesterol subfractions-non-HDL cholesterol (total cholesterol minus HDL cholesterol) and the two ratios-appeared superior to total cholesterol or any of the apolipoprotein options. Guidelines should consider using non-HDL cholesterol or a ratio measure for initial treatment decisions and subsequent monitoring.

Objectives: To describe how evidence from trials and cohort studies may be used to guide choice of test for monitoring patients with chronic disease., Study Design and Setting: Exploration of potential criteria for choosing the best monitoring test. Criteria are defined and options for assessment measures for test performance on each criterion discussed., Results: Monitoring in clinical practice occurs in three main phases: before treatment, response to treatment, and long-term monitoring. Four important criteria may be used to choose the best test for monitoring a patient in each of these phases. Clinical validity describes the ability of the test to predict the clinically relevant outcome that we are trying to control or prevent. Responsiveness describes how much the test changes in response to an intervention relative to background random variation. Detectability of long-term change describes the size of changes in the test over the long term relative to background random variation. Practicality describes the ease of use, invasiveness, and cost of the test. Test performance generally requires longitudinal data from trial and/or cohort studies using statistical methods such as those discussed., Conclusion: Four specific criteria can help clinicians inform evidence-based decisions on which monitoring test to use., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To review the evidence on diagnostic accuracy of red flag signs and symptoms to screen for fracture or malignancy in patients presenting with low back pain to primary, secondary, or tertiary care., Design: Systematic review., Data Sources: Medline, OldMedline, Embase, and CINAHL from earliest available up to 1 October 2013., Inclusion Criteria: Primary diagnostic studies comparing red flags for fracture or malignancy to an acceptable reference standard, published in any language., Review Methods: Assessment of study quality and extraction of data was conducted by three independent assessors. Diagnostic accuracy statistics and post-test probabilities were generated for each red flag., Results: We included 14 studies (eight from primary care, two from secondary care, four from tertiary care) evaluating 53 red flags; only five studies evaluated combinations of red flags. Pooling of data was not possible because of index test heterogeneity. Many red flags in current guidelines provide virtually no change in probability of fracture or malignancy or have untested diagnostic accuracy. The red flags with the highest post-test probability for detection of fracture were older age (9%, 95% confidence interval 3% to 25%), prolonged use of corticosteroid drugs (33%, 10% to 67%), severe trauma (11%, 8% to 16%), and presence of a contusion or abrasion (62%, 49% to 74%). Probability of spinal fracture was higher when multiple red flags were present (90%, 34% to 99%). The red flag with the highest post-test probability for detection of spinal malignancy was history of malignancy (33%, 22% to 46%)., Conclusions: While several red flags are endorsed in guidelines to screen for fracture or malignancy, only a small subset of these have evidence that they are indeed informative. These findings suggest a need for revision of many current guidelines.

Objectives: To identify factors that influence the extent to which general practitioners use absolute risk (AR) assessment in cardiovascular disease (CVD) risk assessment., Design, Setting and Participants: Semi-structured interviews with 25 currently practising GPs from eight Divisions of General Practice in New South Wales, Australia, between October 2011 and May 2012. Data were analysed using framework analysis., Results: The study identified five strategies that GPs use with patients in different situations, defined in terms of the extent to which AR was used and the reasons given for this: the AR-focused strategy, used when AR assessment was considered useful for the patient; the AR-adjusted strategy, used to account for additional risk factors such as family history; the clinical judgement strategy, used when GPs considered that their judgement took multiple risk factors into account as effectively as AR; the passive disregard strategy, used when GPs lacked sufficient time, access or experience to use AR; and the active disregard strategy, used when AR was considered to be inappropriate for the patient. The strategies were linked with different opportunity, capability and motivation barriers to the use of AR., Conclusions: This study provides an in-depth insight into the factors that influence GPs' use of AR in CVD risk assessment. The results suggest that GPs use a range of strategies in different situations, so different approaches may be required to improve the use of AR guidelines in practice.

Background: Magnetic resonance imaging (MRI) has been proposed to guide breast cancer surgery by measuring residual tumour after neoadjuvant chemotherapy. This study-level meta-analysis examines MRI's agreement with pathology, compares MRI with alternative tests and investigates consistency between different measures of agreement., Methods: A systematic literature search was undertaken. Mean differences (MDs) in tumour size between MRI or comparator tests and pathology were pooled by assuming a fixed effect. Limits of agreement (LOA) were estimated from a pooled variance by assuming equal variance of the differences across studies., Results: Data were extracted from 19 studies (958 patients). The pooled MD between MRI and pathology from six studies was 0.1 cm (95% LOA: -4.2 to 4.4 cm). Similar overestimation for MRI (MD: 0.1 cm) and ultrasound (US) (MD: 0.1 cm) was observed, with comparable LOA (two studies). Overestimation was lower for MRI (MD: 0.1 cm) than mammography (MD: 0.4 cm; two studies). Overestimation by MRI (MD: 0.1 cm) was smaller than underestimation by clinical examination (MD: -0.3 cm). The LOA for mammography and clinical examination were wider than that for MRI. Percentage agreement between MRI and pathology was greater than that of comparator tests (six studies). The range of Pearson's/Spearman's correlations was wide (0.21-0.92; 16 studies). Inconsistencies between MDs, percentage agreement and correlations were common., Conclusion: Magnetic resonance imaging appears to slightly overestimate pathologic size, but measurement errors may be large enough to be clinically significant. Comparable performance by US was observed, but agreement with pathology was poorer for mammography and clinical examination. Percentage agreement can provide supplementary information to MDs and LOA, but Pearson's/Spearman's correlation does not provide evidence of agreement and should be avoided. Further comparisons of MRI and other tests using the recommended methods are warranted.

Background: The aim of this project was to investigate the reliability of a new 11-item quality appraisal tool for studies of diagnostic reliability (QAREL). The tool was tested on studies reporting the reliability of any physical examination procedure. The reliability of physical examination is a challenging area to study given the complex testing procedures, the range of tests, and lack of procedural standardisation., Methods: Three reviewers used QAREL to independently rate 29 articles, comprising 30 studies, published during 2007. The articles were identified from a search of relevant databases using the following string: "Reproducibility of results (MeSH) OR reliability (t.w.) AND Physical examination (MeSH) OR physical examination (t.w.)." A total of 415 articles were retrieved and screened for inclusion. The reviewers undertook an independent trial assessment prior to data collection, followed by a general discussion about how to score each item. At no time did the reviewers discuss individual papers. Reliability was assessed for each item using multi-rater kappa (κ)., Results: Multi-rater reliability estimates ranged from κ = 0.27 to 0.92 across all items. Six items were recorded with good reliability (κ > 0.60), three with moderate reliability (κ = 0.41 - 0.60), and two with fair reliability (κ = 0.21 - 0.40). Raters found it difficult to agree about the spectrum of patients included in a study (Item 1) and the correct application and interpretation of the test (Item 10)., Conclusions: In this study, we found that QAREL was a reliable assessment tool for studies of diagnostic reliability when raters agreed upon criteria for the interpretation of each item. Nine out of 11 items had good or moderate reliability, and two items achieved fair reliability. The heterogeneity in the tests included in this study may have resulted in an underestimation of the reliability of these two items. We discuss these and other factors that could affect our results and make recommendations for the use of QAREL.

We propose an expanded approach to evidence for cancer screening policy and practice. First, we need to better understand why and how screening happens the way it does, sometimes at odds with evidence of benefits and harms. Second, we need to systematically investigate the ethics of cancer screening to illuminate moral concerns and expand the scope of screening research to address ethical dilemmas. An expanded approach will offer essential information to better support well reasoned judgements, and develop more accountable and less contested cancer screening policies.

Background: Women with a personal history of breast cancer (PHBC) have increased risk of an interval cancer. We aimed to identify risk factors for second (ipsilateral or contralateral) screen-detected or interval breast cancer within 1 year of screening in PHBC women., Methods: Screening mammograms from women with history of early-stage breast cancer at Breast Cancer Surveillance Consortium-affiliated facilities (1996-2008) were examined. Associations between woman-level, screen-level, and first cancer variables and the probability of a second breast cancer were modeled using multinomial logistic regression for three outcomes [screen-detected invasive breast cancer, interval invasive breast cancer, or ductal carcinoma in situ (DCIS)] relative to no second breast cancer., Results: There were 697 second breast cancers, of these 240 were interval cancers, among 67,819 screens in 20,941 women. In separate models for women with DCIS or invasive first cancer, first breast cancer surgery predicted all three second breast cancer outcomes (P < 0.001), and high ORs for second breast cancers (between 1.95 and 4.82) were estimated for breast conservation without radiation (relative to mastectomy). In women with invasive first breast cancer, additional variables predicted risk (P < 0.05) for at least one of the three outcomes: first-degree family history, dense breasts, longer time between mammograms, young age at first breast cancer, first breast cancer stage, and adjuvant systemic therapy for first breast cancer; and risk of interval invasive breast cancer was highest in women <40 years at first breast cancer (OR, 3.41; 1.34-8.70), those with extremely dense breasts (OR, 2.55; 1.4-4.67), and those treated with breast conservation without radiation (OR, 2.67; 1.53-4.65)., Conclusion: Although the risk of a second breast cancer is modest, our models identify risk factors for interval second breast cancer in PHBC women., Impact: Our findings may guide discussion and evaluations of tailored breast screening in PHBC women, and incorporating this information into clinical decision-making warrants further research.

Objective: To estimate the probability of becoming high risk for cardiovascular disease among people at low and intermediate risk and not being treated for high blood pressure or lipid levels., Design: Observational study., Setting: General communities in Japan and the United States., Participants: 13,757 participants of the Tokyo health check-up study and 3855 of the Framingham studies aged 30-74 years with complete data on risk equation covariates, not receiving blood pressure or cholesterol lowering treatment, and with an estimated risk of cardiovascular disease <20% within 10 years. We stratified participants on the basis of baseline risk: <5%, 5-<10%, 10-<15%, and 15-<20%.We used follow-up measurements from the Tokyo study done annually over three years (2006-10) and follow-up visits in the Framingham study done between eight (1968-75) and 19 years (1990-1995) after baseline., Main Outcome Measure: Estimated 10 year risk of a cardiovascular event >20% using the Framingham equation., Results: At baseline most participants had <5% risk (60.6% of Tokyo cohort and 45.7% of Framingham cohort) or 5-<10% risk (24.0% and 28.0%, respectively) of a cardiovascular event within 10 years. There was <10% probability of crossing the treatment threshold at 19, 8, and 3 years for baseline risk groups <5%, 5-<10%, and 10-<15%, respectively, and >10% probability of crossing the treatment threshold at one year for the 15-<20% baseline risk group., Conclusions: Decisions on the frequency of remeasuring for cardiovascular risk should be made on the basis of baseline risk. Repeat risk estimation before 8-10 years is not warranted for most people initially not requiring treatment. However, remeasurement within a year seems warranted in those with an initial 15-<20% risk.

Background: Patients treated for melanoma are advised to have lifelong full body skin examinations. Extended intervals between examinations have been proposed, but although this may be clinically effective, psychosocial aspects of follow-up are not well understood. This systematic review summarised patient and clinician preferences, experiences and adherence with recommended follow-up of stage I/II melanoma., Methods: Medline, PsycINFO, CINAHL, Embase, Cochrane Library, ACP Journal Club and NHS Economic Evaluation Database were searched from database inception to week 3 April 2010, to identify original studies of psychosocial outcomes of follow-up after treatment of stage I/II primary cutaneous melanoma, as reported by patients or clinicians. The results were synthesised, and characteristics likely to maximise patients' well-being and adherence to follow-up schedules were proposed., Results: We found 15 studies that met the inclusion criteria. Anxiety with melanoma follow-up was common; patients valued reassurance, information and psychosocial support, but long-term adherence to schedules was variable. Some wanted more emotional support from their clinician than was provided. Clinicians sometimes ordered additional blood and imaging tests to reassure patients. GPs were hesitant to conduct melanoma follow-up, but a trial providing technical training and protocols reported positive outcomes. Both patients and GPs wanted prompt access to melanoma specialists when suspicious lesions were found., Conclusion: Psychosocial aspects of follow-up impact on patient well-being and potential adherence to schedules, and may influence clinician practice. If follow-up schedules or personnel are to be revised, psychosocial impacts on patients must be explicitly addressed, as well as guidance and specialist support for clinicians., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: There is limited evidence on the relative effectiveness of different follow-up schedules for patients with AJCC stage I or II melanoma, but less frequent follow-up than is currently recommended has been proposed., Objectives: To describe melanoma clinicians' perspectives on the functions of follow-up, factors that influence follow-up intervals, and important considerations for extending intervals., Methods: Qualitative interviews with 16 clinicians (surgical oncologists, dermatologists, melanoma unit physicians) who conduct follow-up at two of Australia's largest specialist centers., Results: Follow-up is conducted for early detection of recurrences or new primary melanomas, to manage patient anxiety, support patient self-care, and as part of shared care. Recommended intervals are based on guidelines but account for each patient's clinical risk profile, level of anxiety, patient education requirements, capacity to engage in skin self-examination, and how the clinician prefers to manage any suspicious lesions., Conclusions: To revise guidelines and implement change it is important to understand the rationale underpinning existing practice. Extended follow-up intervals for early stage melanoma are more likely to be adopted after the first year when patients are less anxious and sufficiently prepared to conduct self-examination. Clinicians may retain existing schedules for highly anxious patients or those unable to examine themselves., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: It has been proposed that magnetic resonance imaging (MRI) be used to guide breast cancer surgery by differentiating residual tumor from pathologic complete response (pCR) after neoadjuvant chemotherapy. This meta-analysis examines MRI accuracy in detecting residual tumor, investigates variables potentially affecting MRI performance, and compares MRI with other tests., Methods: A systematic literature search was undertaken. Hierarchical summary receiver operating characteristic (HSROC) models were used to estimate (relative) diagnostic odds ratios ([R]DORs). Summary sensitivity (correct identification of residual tumor), specificity (correct identification of pCR), and areas under the SROC curves (AUCs) were derived. All statistical tests were two-sided., Results: Forty-four studies (2050 patients) were included. The overall AUC of MRI was 0.88. Accuracy was lower for "standard" pCR definitions (referent category) than "less clearly described" (RDOR = 2.41, 95% confidence interval [CI] = 1.11 to 5.23) or "near-pCR" definitions (RDOR = 2.60, 95% CI = 0.73 to 9.24; P = .03.) Corresponding AUCs were 0.83, 0.90, and 0.91. Specificity was higher when negative MRI was defined as contrast enhancement less than or equal to normal tissue (0.83, 95% CI = 0.64 to 0.93) vs no enhancement (0.54, 95% CI = 0.39 to 0.69; P = .02), with comparable sensitivity (0.83, 95% CI = 0.69 to 0.91; vs 0.87, 95% CI = 0.80 to 0.92; P = .45). MRI had higher accuracy than mammography (P = .02); there was only weak evidence that MRI had higher accuracy than clinical examination (P = .10). No difference in MRI and ultrasound accuracy was found (P = .15)., Conclusions: MRI accurately detects residual tumor after neoadjuvant chemotherapy. Accuracy was lower when pCR was more rigorously defined, and specificity was lower when test negativity thresholds were more stringent; these definitions require standardization. MRI is more accurate than mammography; however, studies comparing MRI and ultrasound are required.

Background: Little is known about the value of long-term follow-up for localised cutaneous melanoma from the patients' perspective. This study aimed to explore the benefits and potential downsides of follow-up; feelings about changes to frequency of follow-up, and patient-centred recommendations for improving follow-up care., Methods: Qualitative analysis of 29 in-depth interviews conducted with Australian patients undergoing long-term follow-up after surgical treatment of stage I/II melanoma., Results: Patient-perceived benefits of follow-up included reassurance, early detection of new melanomas and non-melanoma skin cancers, education about skin self-examination, the opportunity to ask questions, and reinforcement of 'sunsafe' behaviours. Downsides included anxiety leading up to and during follow-up visits; inconvenience of travel to attend visits; and lost work time. Patients varied in their engagement with skin self-examination, and their views on multiple skin excisions, but highly valued access to specialists for unscheduled visits. Most patients felt their follow-up intervals could be extended to 12 months if recommended by their clinician., Conclusion: The benefits and potential downsides of follow-up should be discussed with patients when deciding on a melanoma follow-up plan to achieve a balance between inducing additional patient anxiety and providing reassurance. Follow-up intervals of 12 months appear to be acceptable to patients., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The identification of serious pathologies, such as spinal malignancy, is one of the primary purposes of the clinical assessment of patients with low-back pain (LBP). Clinical guidelines recommend awareness of "red flag" features from the patient's clinical history and physical examination to achieve this. However, there are limited empirical data on the diagnostic accuracy of these features and there remains very little information on how best to use them in clinical practice., Objectives: To assess the diagnostic performance of clinical characteristics identified by taking a clinical history and conducting a physical examination ("red flags") to screen for spinal malignancy in patients presenting with LBP., Search Methods: We searched electronic databases for primary studies (MEDLINE, EMBASE, and CINAHL) and systematic reviews (PubMed and Medion) from the earliest date until 1 April 2012. Forward and backward citation searching of eligible articles was also performed., Selection Criteria: We considered studies if they compared the results of history taking and physical examination on patients with LBP with those of diagnostic imaging (magnetic resonance imaging, computed tomography, myelography)., Data Collection and Analysis: Two review authors independently assessed the quality of each included study with the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) tool and extracted details on patient characteristics, study design, index tests, and reference standard. Diagnostic accuracy data were presented as sensitivities and specificities with 95% confidence intervals for all index tests., Main Results: We included eight cohort studies of which six were performed in primary care (total number of patients; n = 6622), one study was from an accident and emergency setting (n = 482), and one study was from a secondary care setting (n = 257). In the six primary care studies, the prevalence of spinal malignancy ranged from 0% to 0.66%. Overall, data from 20 index tests were extracted and presented, however only seven of these were evaluated by more than one study. Because of the limited number of studies and clinical heterogeneity, statistical pooling of diagnostic accuracy data was not performed.There was some evidence from individual studies that having a previous history of cancer meaningfully increases the probability of malignancy. Most "red flags" such as insidious onset, age > 50, and failure to improve after one month have high false positive rates.All of the tests were evaluated in isolation and no study presented data on a combination of positive tests to identify spinal malignancy., Authors' Conclusions: For most "red flags," there is insufficient evidence to provide recommendations regarding their diagnostic accuracy or usefulness for detecting spinal malignancy. The available evidence indicates that in patients with LBP, an indication of spinal malignancy should not be based on the results of one single "red flag" question. Further research to evaluate the performance of different combinations of tests is recommended.

Background: Low-back pain (LBP) is a common condition seen in primary care. A principal aim during a clinical examination is to identify patients with a higher likelihood of underlying serious pathology, such as vertebral fracture, who may require additional investigation and specific treatment. All 'evidence-based' clinical practice guidelines recommend the use of red flags to screen for serious causes of back pain. However, it remains unclear if the diagnostic accuracy of red flags is sufficient to support this recommendation., Objectives: To assess the diagnostic accuracy of red flags obtained in a clinical history or physical examination to screen for vertebral fracture in patients presenting with LBP., Search Methods: Electronic databases were searched for primary studies between the earliest date and 7 March 2012. Forward and backward citation searching of eligible studies was also conducted., Selection Criteria: Studies were considered if they compared the results of any aspect of the history or test conducted in the physical examination of patients presenting for LBP or examination of the lumbar spine, with a reference standard (diagnostic imaging). The selection criteria were independently applied by two review authors., Data Collection and Analysis: Three review authors independently conducted 'Risk of bias' assessment and data extraction. Risk of bias was assessed using the 11-item QUADAS tool. Characteristics of studies, patients, index tests and reference standards were extracted. Where available, raw data were used to calculate sensitivity and specificity with 95% confidence intervals (CI). Due to the heterogeneity of studies and tests, statistical pooling was not appropriate and the analysis for the review was descriptive only. Likelihood ratios for each test were calculated and used as an indication of clinical usefulness., Main Results: Eight studies set in primary (four), secondary (one) and tertiary care (accident and emergency = three) were included in the review. Overall, the risk of bias of studies was moderate with high risk of selection and verification bias the predominant flaws. Reporting of index and reference tests was poor. The prevalence of vertebral fracture in accident and emergency settings ranged from 6.5% to 11% and in primary care from 0.7% to 4.5%. There were 29 groups of index tests investigated however, only two featured in more than two studies. Descriptive analyses revealed that three red flags in primary care were potentially useful with meaningful positive likelihood ratios (LR+) but mostly imprecise estimates (significant trauma, older age, corticosteroid use; LR+ point estimate ranging 3.42 to 12.85, 3.69 to 9.39, 3.97 to 48.50 respectively). One red flag in tertiary care appeared informative (contusion/abrasion; LR+ 31.09, 95% CI 18.25 to 52.96). The results of combined tests appeared more informative than individual red flags with LR+ estimates generally greater in magnitude and precision., Authors' Conclusions: The available evidence does not support the use of many red flags to specifically screen for vertebral fracture in patients presenting for LBP. Based on evidence from single studies, few individual red flags appear informative as most have poor diagnostic accuracy as indicated by imprecise estimates of likelihood ratios. When combinations of red flags were used the performance appeared to improve. From the limited evidence, the findings give rise to a weak recommendation that a combination of a small subset of red flags may be useful to screen for vertebral fracture. It should also be noted that many red flags have high false positive rates; and if acted upon uncritically there would be consequences for the cost of management and outcomes of patients with LBP. Further research should focus on appropriate sets of red flags and adequate reporting of both index and reference tests.

Objective: To elicit women's responses to information about the nature and extent of overdiagnosis in mammography screening (detecting disease that would not present clinically during the woman's lifetime) and explore how awareness of overdiagnosis might influence attitudes and intentions about screening., Design: Qualitative study using focus groups that included a presentation explaining overdiagnosis, incorporating different published estimates of its rate (1-10%, 30%, 50%) and information on the mortality benefit of screening, with guided group discussions, Setting: Sydney, Australia, Participants: Fifty women aged 40-79 years with no personal history of breast cancer and with varying levels of education and participation in screening., Results: Prior awareness of breast cancer overdiagnosis was minimal. Women generally reacted with surprise, but most came to understand the issue. Responses to overdiagnosis and the different estimates of its magnitude were diverse. The highest estimate (50%) made some women perceive a need for more careful personal decision making about screening. In contrast, the lower and intermediate estimates (1-10% and 30%) had limited impact on attitudes and intentions, with many women remaining committed to screening. For some women, the information raised concerns, not about whether to screen but whether to treat a screen detected cancer or consider alternative approaches (such as watchful waiting). Information preferences varied: many women considered it important to take overdiagnosis into account and make informed choices about whether to have screening, but many wanted to be encouraged to be screened., Conclusions: Women from a range of socioeconomic backgrounds could comprehend the issue of overdiagnosis in mammography screening, and they generally valued information about it. Effects on screening intentions may depend heavily on the rate of overdiagnosis. Overdiagnosis will be new and counterintuitive for many people and may influence screening and treatment decisions in unintended ways, underscoring the need for careful communication.

Background: Patients with early stage melanoma have high survival rates but require long-term follow-up to detect recurrences and/or new primary tumours. Shared care between melanoma specialists and general practitioners is an increasingly important approach to meeting the needs of a growing population of melanoma survivors., Methods: In-depth qualitative study based on semi-structured interviews with 16 clinicians (surgical oncologists, dermatologists and melanoma unit GPs) who conduct post-treatment follow-up at two of Australia's largest specialist referral melanoma treatment and diagnosis units. Interviews were recorded, transcribed and analysed to identify approaches to shared care in follow-up, variations in practice, and explanations of these., Results: Melanoma unit clinicians utilised shared care in the follow-up of patients with early stage melanoma. Schedules were determined by patients' clinical risk profiles. Final arrangements for delivery of those schedules (by whom and where) were influenced by additional psychosocial, professional and organizational considerations. Four models of shared care were described: (a) surgical oncologist alternating with dermatologist (in-house or local to patient); (b) melanoma unit dermatologist and other local doctor (e.g. family physician); (c) surgical oncologist and local doctor; or (d) melanoma physician and local doctor., Conclusions: These models of shared care offer alternative solutions to managing the requirements for long-term follow-up of a growing number of patients with stage I/II melanoma, and warrant further comparative evaluation of outcomes in clinical trials, with detailed cost/benefit analyses.

Background: Current guidelines recommend that decisions to start preventative therapy for cardiovascular disease (CVD) should be based on absolute risk; however, current risk equations are based on single measurements of risk factors. We aimed to assess whether two measurements of blood pressure and lipids improves the prediction of cardiovascular risk compared to one measurement., Methods and Results: We used sex-specific Cox proportional hazards models to evaluate the risk of first CVD event in 2385 participants of the Framingham Offspring Study attending both the second and third visits. We estimated the effects on risk prediction of using the average of two measurements of blood pressure, total cholesterol, and HDL cholesterol compared to using one measurement of the risk factors. We found that these risk factors were each markedly more predictive of CVD when the average of two measurements was used rather than one measurement and age was less predictive of CVD. There were small improvements in the overall model fit, discrimination, and calibration. Reclassification also showed small improvements across the risk spectrum (net reclassification information, NRI, for women 3.0%, 95% CI -0.9 to 24.8%; NRI for men 4.0%, 95% CI -2.2 to 14.1%) and possibly greater improvements for intermediate-risk individuals (NRI for women 32.3%, 95% CI -21.9 to 46.8%; NRI for men 16.0%, 95% CI -3.3 to 43%)., Conclusions: Averaging two measurements of blood pressure and lipids results in marked increases in the predictiveness of these risk factors and smaller improvements in the overall prediction of cardiovascular risk including reclassification.

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.)

Background: People vary in how they respond to symptoms. The purpose of this study was to assess whether serious disease is more likely to be present in patients who report that they take any symptoms less seriously than other people do, and to assess the reliability of a question which can be used to identify the extent to which patients take any symptom seriously. To do this we assessed whether the likelihood of detecting colorectal cancer is higher in patients who report that they take symptoms less seriously than other people do., Methods: Cross sectional study of 7736 patients who had colonoscopy to find colorectal cancer. Before colonoscopy, patients completed a questionnaire on bowel symptoms and were also asked: "Compared to other people of your age and sex, how seriously do you think you take any symptoms?" Likelihood of detecting colorectal cancer according to responses to this question was assessed by logistic regression models, unadjusted and adjusted for symptoms and other known predictors of colorectal cancer.Question reliability was assessed in a different sample using percentage agreement and the kappa statistic for the answers given by each patient on two occasions. Agreement between patient and doctor responses was also assessed (n = 108)., Results: Patients who reported they took symptoms less seriously were 3.28 (95%CI: 2.02, 5.33) times more likely to have colorectal cancer than patients who took symptoms more seriously than others. The effect was smaller (1.85 (95%CI: 1.11, 3.09)), but remained statistically significant in models including symptoms and other predictors of colorectal cancer. The question was reliable: on repeat questioning, 70% of responses were in absolute agreement and 92% were within 1 category, kappa 57%. Patient-doctor agreement was 66%, within 1 category 92%, kappa 48%., Conclusion: Patients who take their symptoms less seriously have a considerably higher likelihood of colorectal cancer than those who identify themselves as taking any symptoms more seriously than other people. The question is easy to ask and has good reliability. Doctors also reliably identify how patients assess themselves. Assessment of how seriously patients take any symptoms can contribute to the clinical assessment of a patient.

Outcomes in clinical trials may be affected by the choice of treatment that participants might make, if they were indeed allowed to choose (a so-called selection effect), and by whether they actually receive their preferred treatment (a preference effect). Selection and preference effects can be important, but they cannot be estimated in the conventional trial design. An alternative approach is the two-stage randomised trial, in which participants are first randomly divided into two subgroups. In one subgroup, participants are randomly assigned to treatments, while in the other, participants are allowed to choose their own treatment. This approach yields estimates of the direct treatment effect, and of the preference and selection effects. The latter two provide insight that goes considerably beyond what is possible in the standard randomised trial. In this paper, we determine the optimal proportion of participants who should be allocated to the choice subgroup. The precision of the estimated selection, preference and treatment effects are functions of: the total sample size; the proportion of participants allocated to choose their treatment; the variances of the outcome; the proportions of participants who select each treatment in the choice group; and the selection, preference and treatment effects themselves. We develop general expressions for the optimum proportion of participants in the choice group, depending on which effects are of primary interest. We illustrate the results with trial data comparing alternative clinical management strategies for women with abnormal results on cervical screening., (Copyright © 2012 John Wiley & Sons, Ltd.)

When no gold standard is available to evaluate a diagnostic or screening test, as is often the case, an imperfect reference standard test must be used instead. Furthermore, the errors of the test and its reference standard may not be independent. Some authors have opined that positively dependent errors will lead to overestimation of test performance. Although positive dependence does increase agreement between the test and the reference standard, it is not clear if test accuracy will necessarily be overestimated in this situation, and the case of negatively associated test errors is even less clear. To examine this issue in more detail, we derive the apparent sensitivity, specificity, and overall accuracy of a test relative to an imperfect reference standard and the bias in these parameters. We demonstrate that either positive or negative bias can occur if the reference standard is imperfect. The type and magnitude of bias depend on several components: the disease prevalence, the true test sensitivity and specificity, the covariance between the false-negative test errors among the true disease cases, and the covariance between the false-positive test errors among the true noncases. If, for example, sensitivity and specificity are 0.8 for both the test and reference standard and the errors have a moderate positive dependence, test sensitivity is then underestimated at low prevalence but overestimated at high prevalence, while the opposite occurs for specificity. We illustrate these ideas through general numerical calculations and an empirical example of screening for breast cancer with magnetic resonance imaging and mammography., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Before a new test is introduced in clinical practice, evidence is needed to demonstrate that its use will lead to improvements in patient health outcomes. Studies reporting test accuracy may not be sufficient, and clinical trials of tests that measure patient health outcomes are rarely feasible. Therefore, the consequences of testing on patient management are often investigated as an intermediate step in the pathway. There is a lack of guidance on the interpretation of this evidence, and patient management studies often neglect a discussion of the limitations of measuring patient management as a surrogate for health outcomes., Methods: We discuss the rationale for measuring patient management, describe the common study designs and provide guidance about how this evidence should be reported., Results: Interpretation of patient management studies relies on the condition that patient management is a valid surrogate for downstream patient benefits. This condition presupposes two critical assumptions: the test improves diagnostic accuracy; and the measured changes in patient management improve patient health outcomes. The validity of this evidence depends on the certainty around these critical assumptions and the ability of the study design to minimise bias. Three common designs are test RCTs that measure patient management as a primary endpoint, diagnostic before-after studies that compare planned patient management before and after testing, and accuracy studies that are extended to report on the actual treatment or further tests received following a positive and negative test result., Conclusions: Patient management can be measured as a surrogate outcome for test evaluation if its limitations are recognised. The potential consequences of a positive and negative test result on patient management should be pre-specified and the potential patient benefits of these management changes clearly stated. Randomised comparisons will provide higher quality evidence about differences in patient management using the new test than observational studies. Regardless of the study design used, the critical assumption that patient management is a valid surrogate for downstream patient benefits or harms must be discussed in these studies.

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.)

Biochemical markers of bone turnover have been proposed to monitor the response to bisphosphonate therapy for osteoporosis, but this requires true between-person differences in the response to therapy. Using mixed models we analyzed three annual measurements of two markers (bone alkaline phosphatase [BAP] and cross-linked N-telopeptide of type I collagen [NTX]) from the Fracture Intervention Trial. We compared marker variation among women allocated to alendronate with that among women allocated to placebo to estimate how much variation was due to true between-person differences in response to treatment, and how much was due to random within-person fluctuations unrelated to treatment. For both markers we found that the mean effect of treatment differed by the baseline level of the marker. After allowing for this and other effects, we found large true between-person differences in response to treatment for both markers, with a coefficient of variation (CV) for NTX of 25.1% and for BAP of 21.2%. However, random within-person fluctuation was even larger, with a CV for change in NTX of 42.5% and for change in BAP of 25.8%. Although repeated measurements have the potential to reduce within person variability, even triplicate baseline marker measurements resulted in an averaged value that was only within 31% of the true value with 95% certainty. In summary, although bone turnover markers appear promising for monitoring between-person differences in response to treatment, their use in clinical practice is currently limited by large random within-person variation., (Copyright © 2012 American Society for Bone and Mineral Research.)

Purpose: To develop more evidence-based guidelines for the frequency of patient follow-up after treatment of localized (American Joint Committee on Cancer [AJCC] stage I or II) melanoma., Methods: We used data from Melanoma Institute Australia on an inception cohort of 3,081 consecutive patients first diagnosed with stage I or II melanoma between January 1985 and December 2009. Kaplan-Meier curves and Cox models were used to characterize the time course and predictors for recurrence and new primaries. We modeled the delay in diagnosis of recurrence or new primary as well as the number of monitoring visits required using two monitoring schedules: first, according to 2008 Australian and New Zealand guidelines and, second, with fewer visits, especially for those at lowest risk of recurrence., Results: For every 1,000 patients beginning follow-up, 229 developed recurrence and 61 developed new primary within 10 years. There was only a small difference in modeled delay in diagnosis (extra 44.9 and 9.6 patients per 1,000 for recurrence and new primary, respectively, with delay greater than 2 months) using a schedule that requires far fewer visits (3,000 fewer visits per 1,000 patients) than recommended by current guidelines. AJCC substage was the most important predictor of recurrence, whereas age and date of primary diagnosis were important predictors of developing new primary., Conclusion: By providing less intensive monitoring, more efficient follow-up strategies are possible. Fewer visits with a more focused approach may address the needs of patients and clinicians to detect recurrent or new melanoma.

Background: Colonoscopy is an invasive and costly procedure with a risk of serious complications. It would therefore be useful to prioritise colonoscopies by identifying people at higher risk of either cancer or premalignant adenomas. The aim of this study is to assess a model that identifies people with colorectal cancer, advanced, large and small adenomas., Methods: Patients seen by gastroenterologists and colorectal surgeons between April 2004 and December 2006 completed a validated, structured self-administered questionnaire prior to colonoscopy. Information was collected on symptoms, demographics and medical history. Multinomial logistic regression was used to simultaneously assess factors associated with findings on colonoscopy of cancer, advanced adenomas and adenomas sized 6 -9 mm, and ≤ 5 mm. The area under the curve of ROC curve was used to assess the incremental gain of adding demographic variables, medical history and symptoms (in that order) to a base model that included only age., Results: Sociodemographic variables, medical history and symptoms (from 8,204 patients) jointly provide good discrimination between colorectal cancer and no abnormality (AUC 0.83), but discriminate less well between adenomas and no abnormality (AUC advanced adenoma 0.70; other adenomas 0.67). Age is the dominant risk factor for cancer and adenomas of all sizes. Having a colonoscopy within the last 10 years confers protection for cancers and advanced adenomas., Conclusions: Our models provide guidance about which factors can assist in identifying people at higher risk of disease using easily elicited information. This would allow colonoscopy to be prioritised for those for whom it would be of most benefit.

Objective: In current medical literature, mammography and other cancer screening programs are subject to controversy because of debate about the magnitude and nature of the benefits and harms. This paper discusses the issues around informed choice for women considering breast screening., Method: We discuss qualitative and quantitative studies of women's attitudes to breast screening and informed choice., Results: Women view breast screening as a way of avoiding potential regret, and reassurance from normal results is highly valued. Screening participants acknowledge anxiety about false positives but awareness regarding potential overdetection of indolent breast cancer is minimal, and research is needed to assess how better understanding of screening downsides may affect women's views. In any case, weighing up screening advantages and disadvantages is sensitive to personal preferences., Conclusions: Communicators have an ethical obligation to make balanced information available to women, which is flexible enough to respond to the level of detail and involvement desired by each individual. Many women want to know more and to participate more actively in screening decisions. Techniques have been developed to present balanced information and support individual decision making in ways that are accessible and empowering for the wider community. Evaluations of breast cancer screening must integrate clinical data with evidence on the perspectives of women themselves., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Bowel symptoms are often considered an indication to perform colonoscopy to identify or rule out colorectal cancer or precancerous polyps. Investigation of bowel symptoms for this purpose is recommended by numerous clinical guidelines. However, the evidence for this practice is unclear. The objective of this study is to systematically review the evidence about the association between bowel symptoms and colorectal cancer or polyps., Methods: We searched the literature extensively up to December 2008, using MEDLINE and EMBASE and following references. For inclusion in the review, papers from cross sectional, case control and cohort studies had to provide a 2×2 table of symptoms by diagnosis (colorectal cancer or polyps) or sufficient data from which that table could be constructed. The search procedure, quality appraisal, and data extraction was done twice, with disagreements resolved with another reviewer. Summary ROC analysis was used to assess the diagnostic performance of symptoms to detect colorectal cancer and polyps., Results: Colorectal cancer was associated with rectal bleeding (AUC 0.66; LR+ 1.9; LR- 0.7) and weight loss (AUC 0.67, LR+ 2.5, LR- 0.9). Neither of these symptoms was associated with the presence of polyps. There was no significant association of colorectal cancer or polyps with change in bowel habit, constipation, diarrhoea or abdominal pain. Neither the clinical setting (primary or specialist care) nor study type was associated with accuracy.Most studies had methodological flaws. There was no consistency in the way symptoms were elicited or interpreted in the studies., Conclusions: Current evidence suggests that the common practice of performing colonoscopies to identify cancers in people with bowel symptoms is warranted only for rectal bleeding and the general symptom of weight loss. Bodies preparing guidelines for clinicians and consumers to improve early detection of colorectal cancer need to take into account the limited value of symptoms.

Background: The Rucker 2-stage randomized trial (RCT) design and method allows treatment, preference, and selection effects to be estimated separately in clinical trials., Objective: To understand the effect of patient choice on patient outcomes, the authors applied the Rucker design and analysis method., Design: They used data from a trial of management strategies for women with atypical cells of undetermined significance (ASCUS) detected at routine cervical screening, in which informed choice using a decision aid was compared to no choice., Setting: Women's health clinics across Australia., Patients: Women aged 18 to 70 years (n = 314) with ASCUS., Intervention: Women were randomized to either an informed choice of human papillomavirus (HPV) triage testing or repeat Pap testing or to no choice with random allocation to management by either option., Measurements: Health-related quality of life (SF36) and satisfaction were measured over the course of management and up to 1 year after triage., Results: Using the Rucker analysis, patients who received their choice had higher quality of life scores than those who did not choose (SF36 MCS, 6% higher, 6.0; 95% confidence interval: -0.6 to 12.9; P = 0.07; effect size 0.61 [moderate]). In contrast, the traditional RCT analysis suggested there was little difference in quality of life between the choice and no-choice trial arms., Limitations: The Rucker method assumes that the declared preferences for treatment in the choice arm are representative of the preferences that would have been observed in the no-choice arms if choice was available., Conclusions: The Rucker method should be used to estimate treatment, preference, and selection effects in randomized trials, as it adds to our understanding of the effect of choice on patient outcomes.

Context: Women with a personal history of breast cancer (PHBC) are at risk of developing another breast cancer and are recommended for screening mammography. Few high-quality data exist on screening performance in PHBC women., Objective: To examine the accuracy and outcomes of mammography screening in PHBC women relative to screening of similar women without PHBC., Design and Setting: Cohort of PHBC women, mammogram matched to non-PHBC women, screened through facilities (1996-2007) affiliated with the Breast Cancer Surveillance Consortium., Participants: There were 58,870 screening mammograms in 19,078 women with a history of early-stage (in situ or stage I-II invasive) breast cancer and 58,870 matched (breast density, age group, mammography year, and registry) screening mammograms in 55,315 non-PHBC women., Main Outcome Measures: Mammography accuracy based on final assessment, cancer detection rate, interval cancer rate, and stage at diagnosis., Results: Within 1 year after screening, 655 cancers were observed in PHBC women (499 invasive, 156 in situ) and 342 cancers (285 invasive, 57 in situ) in non-PHBC women. Screening accuracy and outcomes in PHBC relative to non-PHBC women were cancer rates of 10.5 per 1000 screens (95% CI, 9.7-11.3) vs 5.8 per 1000 screens (95% CI, 5.2-6.4), cancer detection rate of 6.8 per 1000 screens (95% CI, 6.2-7.5) vs 4.4 per 1000 screens (95% CI, 3.9-5.0), interval cancer rate of 3.6 per 1000 screens (95% CI, 3.2-4.1) vs 1.4 per 1000 screens (95% CI, 1.1-1.7), sensitivity 65.4% (95% CI, 61.5%-69.0%) vs 76.5% (95% CI, 71.7%-80.7%), specificity 98.3% (95% CI, 98.2%-98.4%) vs 99.0% (95% CI, 98.9%-99.1%), abnormal mammogram results in 2.3% (95% CI, 2.2%-2.5%) vs 1.4% (95% CI, 1.3%-1.5%) (all comparisons P < .001). Screening sensitivity in PHBC women was higher for detection of in situ cancer (78.7%; 95% CI, 71.4%-84.5%) than invasive cancer (61.1%; 95% CI, 56.6%-65.4%), P < .001; lower in the initial 5 years (60.2%; 95% CI, 54.7%-65.5%) than after 5 years from first cancer (70.8%; 95% CI, 65.4%-75.6%), P = .006; and was similar for detection of ipsilateral cancer (66.3%; 95% CI, 60.3%-71.8%) and contralateral cancer (66.1%; 95% CI, 60.9%-70.9%), P = .96. Screen-detected and interval cancers in women with and without PHBC were predominantly early stage., Conclusion: Mammography screening in PHBC women detects early-stage second breast cancers but has lower sensitivity and higher interval cancer rate, despite more evaluation and higher underlying cancer rate, relative to that in non-PHBC women.

Previously, we showed that in randomised experiments, correction for measurement error in a baseline variable induces bias in the estimated treatment effect, and conversely that ignoring measurement error avoids bias. In observational studies, non-zero baseline covariate differences between treatment groups may be anticipated. Using a graphical approach, we argue intuitively that if baseline differences are large, failing to correct for measurement error leads to a biased estimate of the treatment effect. In contrast, correction eliminates bias if the true and observed baseline differences are equal. If this equality is not satisfied, the corrected estimator is also biased, but typically less so than the uncorrected estimator. Contrasting these findings, we conclude that there must be a threshold for the true baseline difference, above which correction is worthwhile. We derive expressions for the bias of the corrected and uncorrected estimators, as functions of the correlation of the baseline variable with the study outcome, its reliability, the true baseline difference, and the sample sizes. Comparison of these expressions defines a theoretical decision threshold about whether to correct for measurement error. The results show that correction is usually preferred in large studies, and also in small studies with moderate baseline differences. If the group sample sizes are very disparate, correction is less advantageous. If the equivalent balanced sample size is less than about 25 per group, one should correct for measurement error if the true baseline difference is expected to exceed 0.2-0.3 standard deviation units. These results are illustrated with data from a cohort study of atherosclerosis., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To estimate the accuracy of monitoring cholesterol concentration for detecting non-adherence to lipid lowering treatment., Design: Secondary analysis of data on cholesterol concentration in the LIPID (long term intervention with pravastatin in ischaemic disease) study by using three measures of non-adherence: discontinuation of treatment, allocation to placebo arm, less than 80% of pills taken., Setting: Randomised placebo controlled trial in Australia and New Zealand., Participants: 9014 patients with previous coronary heart disease., Interventions: Pravastatin 40 mg or placebo daily., Main Outcome Measures: Sensitivity, specificity, area under the receiver operating characteristics (ROC) curve, post-test probability., Results: Monitoring of cholesterol concentration had modest ability for detecting complete non-adherence. One year after the start of treatment, half (1957/3937) of the non-adherent patients and 6% (253/3944) of adherent patients had a rise in concentration of low density lipoprotein cholesterol. Accuracy was reasonable (area under the curve 0.89). Cholesterol monitoring, however, had weak ability for detecting partial non-adherence. One year after the start of treatment, 16% (34/213) of partially adherent and 4% (155/3585) of fully adherent patients had a rise in concentration of low density lipoprotein cholesterol. Accuracy was poor (area under the curve 0.65). For typical pre-test probabilities of non-adherence ranging from low (25%) to high (75%), the post-test probabilities indicate continuing uncertainty after lipid testing. A patient with no change in low density lipoprotein cholesterol concentration has a post-test probability of being completely non-adherent of between 67% and 95% and a post-test probability of being partially non-adherent of between 48% and 89%. A patient with a decrease in concentration of 1.0 mmol/L has a post-test probability of being completely non-adherent of between 7% and 40% and a post-test probability of being partially non-adherent of between 21% and 71%., Conclusions: Monitoring concentration of low density lipoprotein (or total) cholesterol has modest ability to detect complete non-adherence or non-persistence with pravastatin treatment and weak ability to detect partial non-adherence. Results of monitoring should be considered as no more than an adjunct to careful discussion with patients about adherence.

Purpose: There is no consensus on what constitutes adequate negative margins in breast-conserving therapy (BCT). We review the evidence on surgical margins in BCT for early-stage invasive breast cancer., Methods: Meta-analysis of studies reporting local recurrence (LR) relative to quantified final microscopic margin status and the threshold distance for negative margins. The proportion of LR was modelled using random effects logistic meta-regression., Results: Based on 21 studies (LR in 1,026 of 14,571 subjects) the odds of LR were associated with margin status [model 1: odds ratio (OR) = 2.02 for positive/close versus negative; model 2: OR = 1.80 for close versus negative, 2.42 for positive versus negative (P<0.001 both models)] but not with margin distance [1mm versus 2mm versus 5mm (P > 0.10 both models)], adjusting for median follow-up time. However, there was weak evidence in both models that the odds of LR decreased as the threshold distance for declaring negative margins increased. This bordered significance in model 2 [OR for 1mm, 2mm, 5mm: 1.0, 0.75, 0.51 (P = 0.097 for trend)], and was not significant in model 1 [OR for 1mm, 2mm, 5mm: 1.0, 0.85, 0.58 (P = 0.11 for trend)] but was evident when one study (of women ≤ 40 years) was excluded from this model [OR for 1mm, 2mm, 5mm: 1.0, 0.72, 0.52 (P = 0.058 for trend)]: this trend was rendered insignificant by adjustment for the proportion of subjects receiving a radiation boost or the proportion of subjects receiving endocrine therapy., Conclusions: Margin status has a prognostic effect in all women treated for invasive breast cancer; increasing the threshold distance for declaring negative margins is weakly associated with reduced odds of LR, however adjustment for covariates (adjuvant therapy) removes the significance of this effect. Adoption of wider margins, relative to narrower widths, for declaring negative margins is unlikely to a have substantial additional benefit for long-term local control in BCT., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

After starting antihypertensives, blood pressure is monitored for several reasons, including assessment of adherence. We aimed to estimate the accuracy of blood pressure monitoring for detecting early nonadherence. We conducted a secondary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a large randomized trial of blood pressure lowering to reduce the risk of recurrent stroke. We compared change in blood pressure 3 months after randomization in people who had discontinued treatment (nonadherent) with those who stayed on treatment (adherent). We also used an indirect method, assessing whether change in blood pressure discriminated between active (adherent) and placebo (nonadherent) groups. Both methods gave similar results. For the 3433 subjects, the mean (SD) of the change in systolic blood pressure was -15.8 mm Hg (SD 18.7 mm Hg) in the adherent group and -4.2 mm Hg (SD 18.1 mm Hg) in the nonadherent group. After recalibration of the mean change in the nonadherent group to 0 mm Hg and in the adherent group to -11.6 mm Hg, the absence of a fall in systolic blood pressure at 3 months had a sensitivity of 50% and a specificity of 80% for detecting nonadherence (50% of nonadherent patients and 20% of adherent patients had a rise in blood pressure). Discriminatory power was modest over the range of cutoffs (area under the receiver-operator curve 0.67). Monitoring blood pressure is poor at detecting nonadherence to blood pressure-lowering treatment. Further research should look at other methods of assessing adherence.

Most clinicians monitor blood pressure to estimate a patient's response to blood pressure-lowering therapy. However, the apparent change may not actually reflect the effect of the treatment, because a person's blood pressure varies considerably even without the administration of drug therapy. We estimated random background within-person variation, apparent between-person variation, and true between-person variation in blood pressure response to angiotensin-converting enzyme inhibitors after 3 months. We used meta-analytic mixed models to analyze individual patient data from 28 281 participants in 7 randomized, controlled trials from the Blood Pressure Lowering Trialists Collaboration. The apparent between-person variation in response was large, with SDs for change in systolic blood pressure/diastolic blood pressure of 15.2/8.5 mm Hg. Within-person variation was also large, with SDs for change in systolic blood pressure/diastolic blood pressure of 14.9/8.45 mm Hg. The true between-person variation in response was small, with SDs for change in systolic blood pressure/diastolic blood pressure of 2.6/1.0 mm Hg. The proportion of the apparent between-person variation in response that was attributed to true between-person variation was only 3% for systolic blood pressure and 1% for diastolic blood pressure. In conclusion, most of the apparent variation in response is not because of true variation but is a consequence of background within-person fluctuation in day-to-day blood pressure levels. Instead of monitoring an individual's blood pressure response, a better approach may be to simply assume the mean treatment effect.

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.)

Background: Many bodies advise that people with bowel symptoms undergo colonoscopy to detect colorectal cancer., Aim: To determine which bowel symptoms predict cancer on colonoscopy., Methods: Information was collected on symptoms, demographics and medical history from patients subsequently undergoing colonoscopy. Multiple logistic regression modelling was used to identify predictors of colorectal cancer. An ROC curve was estimated for each model, and the area under the curve (AUC) was computed., Results: Cancer was found in 159 patients and no cancer or adenoma in 7577 patients. Bowel symptoms that predicted cancer were rectal bleeding, change in bowel habit and rectal mucus. Prediction was the strongest in patients who had symptoms at least weekly and commencing within the previous 12 months; abdominal pain was predictive only in such patients. The odds ratios never exceeded 4.27. A model based on age, gender, and medical history was highly predictive (AUC = 0.79). Adding symptoms to this model increased the AUC to 0.85., Conclusions: This model predicts patients in whom colonoscopy will have the highest yield. Conversely, colonoscopy can be avoided in people at low risk: in our study, 95% of cancers could have been detected by doing only 60% of the colonoscopies.

Objectives: To evaluate current processes by which young children presenting with a febrile illness but suspected of having serious bacterial infection are diagnosed and treated, and to develop and test a multivariable model to distinguish serious bacterial infections from self limiting non-bacterial illnesses. Design Two year prospective cohort study. Setting The emergency department of The Children's Hospital at Westmead, Westmead, Australia., Participants: Children aged less than 5 years presenting with a febrile illness between 1 July 2004 and 30 June 2006., Intervention: A standardised clinical evaluation that included mandatory entry of 40 clinical features into the hospital's electronic record keeping system was performed by physicians. Serious bacterial infections were confirmed or excluded using standard radiological and microbiological tests and follow-up. Main outcome measures Diagnosis of one of three key types of serious bacterial infection (urinary tract infection, pneumonia, and bacteraemia), and the accuracy of both our clinical decision making model and clinician judgment in making these diagnoses., Results: We had follow-up data for 93% of the 15 781 instances of febrile illnesses recorded during the study period. The combined prevalence of any of the three infections of interest (urinary tract infection, pneumonia, or bacteraemia) was 7.2% (1120/15 781, 95% confidence interval (CI) 6.7% to 7.5%), with urinary tract infection the diagnosis in 543 (3.4%) cases of febrile illness (95% CI 3.2% to 3.7%), pneumonia in 533 (3.4%) cases (95% CI 3.1% to 3.7%), and bacteraemia in 64 (0.4%) cases (95% CI 0.3% to 0.5%). Almost all (>94%) of the children with serious bacterial infections had the appropriate test (urine culture, chest radiograph, or blood culture). Antibiotics were prescribed acutely in 66% (359/543) of children with urinary tract infection, 69% (366/533) with pneumonia, and 81% (52/64) with bacteraemia. However, 20% (2686/13 557) of children without bacterial infection were also prescribed antibiotics. On the basis of the data from the clinical evaluations and the confirmed diagnosis, a diagnostic model was developed using multinomial logistic regression methods. Physicians' diagnoses of bacterial infection had low sensitivity (10-50%) and high specificity (90-100%), whereas the clinical diagnostic model provided a broad range of values for sensitivity and specificity., Conclusions: Emergency department physicians tend to underestimate the likelihood of serious bacterial infection in young children with fever, leading to undertreatment with antibiotics. A clinical diagnostic model could improve decision making by increasing sensitivity for detecting serious bacterial infection, thereby improving early treatment.

Objective: To assess which of three triage strategies for women with borderline abnormal cervical smear results in the best psychosocial outcomes., Design: Pragmatic, non-blinded, multicentre, randomised controlled trial., Setting: 18 family planning clinics across Australia, covering both urban and rural areas, between January 2004 and October 2006., Participants: Women aged 16-70 years (n=314) who attended routine cervical screening and received a borderline cervical smear., Interventions: Patients were randomly assigned to human papillomavirus (HPV) DNA testing (n=104), a repeat smear test at six months (n=106), or the patient's informed choice of either test supported by a decision aid (n=104). Psychosocial outcomes were assessed at multiple time points over 12 months by postal questionnaire., Main Outcome Measures: We assessed health related quality of life (SF36 mental health subscale), cognitive effects (such as perceived risk of cervical cancer, intrusive thoughts), affective outcomes (general anxiety [state-trait anxiety inventory]), specific anxiety about an abnormal smear (cervical screening questionnaire), and behavioural outcomes (sexual health behaviour and visits to the doctor) over 12 months of follow-up., Results: At two weeks, some psychosocial outcomes were worse for women allocated to HPV testing compared with those in the smear testing group (SF36 vitality subscale: t=-1.63, df=131, P=0.10; intrusive thoughts chi(2)=8.14, df=1, P<0.01). Over 12 months, distress about the abnormal smear was lowest in women allocated to HPV testing and highest in the repeat smear testing group (t=-2.89, df=135, P<0.01). Intrusive thoughts were highest in patients allocated to HPV testing (25%, compared with 13% in the informed choice group; difference=12%, 95% CI -1.1% to 25.1%). Women in the HPV DNA group and the informed choice group were more satisfied with their care than women allocated to repeat smear testing., Conclusions: Although the psychosocial effect was initially worse for women allocated to HPV triage, over the full year of follow-up this intervention was better for women's psychosocial health than repeat smear testing. Offering informed choice could have a small advantage for cognitive outcomes, but in view of the additional effort and logistical complexity that this intervention requires, HPV testing alone can be justified for most women., Trial Registration: actr.org.au Identifier: 12605000111673.

Purpose: To estimate the extent of overdiagnosis of invasive breast cancer associated with screening in New South Wales, Australia, a population with a well-established mammography screening program which has achieved full geographic coverage., Methods: We calculated overdiagnosis as the observed annual incidence of invasive breast cancer in NSW in 1999-2001 (a screened population) minus the expected annual incidence in this population at the same time, as a percentage of the expected incidence. We estimated expected incidence without screening in 1999-2001 from the incidence of invasive breast cancer in: (1) women in unscreened age groups (interpolation method); and (2) women in all age groups prior to the implementation of screening (extrapolation method). We then adjusted these estimates for trends in major risk factors for breast cancer that may have coincided with the introduction of mammography screening: increasing obesity, use of hormone replacement therapy (HRT) and nulliparity. Finally, we adjusted for lead time to produce estimates of expected incidence in 1999-2001. These were compared with the observed incidence in 1999-2001 to calculate overdiagnosis of breast cancer associated with screening., Results: Overdiagnosis of invasive breast cancer among 50-69 year NSW women was estimated to be 42 and 30% using the interpolation and extrapolation methods, respectively., Conclusion: Overdiagnosis of invasive breast cancer attributable to mammography screening appears to be substantial. Our estimates are similar to recent estimates from other screening programmes. Overdiagnosis merits greater attention in research and in clinical and public health policy making.