Red flags to screen for vertebral fracture in patients presenting with low-back pain.

EDITORIAL NOTE: See https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD014461.pub2/full for a more recent review that covers this topic and has superseded this review. 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.

Factors Associated With Advanced Colorectal Neoplasia in Patients With CKD.

RATIONALE & OBJECTIVE: The risk of developing colorectal cancer in patients with chronic kidney disease (CKD) is twice that of the general population, but the factors associated with colorectal cancer are poorly understood. The aim of this study was to identify factors associated with advanced colorectal neoplasia in patients with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients with CKD stages 3-5, including those treated with maintenance dialysis or transplantation across 11 sites in Australia, New Zealand, Canada, and Spain, were screened for colorectal neoplasia using a fecal immunochemical test (FIT) as part of the Detecting Bowel Cancer in CKD (DETECT) Study. EXPOSURE: Baseline characteristics for patients at the time of study enrollment were ascertained, including duration of CKD, comorbidities, and medications. OUTCOME: Advanced colorectal neoplasia was identified through a 2-step verification process with colonoscopy following positive FIT and 2-year clinical follow-up for all patients. ANALYTICAL APPROACH: Potential factors associated with advanced colorectal neoplasia were explored using multivariable logistic regression. Sensitivity analyses were performed using grouped LASSO (least absolute shrinkage and selection operator) logistic regression. RESULTS: Among 1,706 patients who received FIT-based screening-791 with CKD stages 3-5 not receiving kidney replacement therapy (KRT), 418 receiving dialysis, and 497 patients with a functioning kidney transplant-117 patients (6.9%) were detected to have advanced colorectal neoplasia (54 with CKD stages 3-5 without KRT, 34 receiving dialysis, and 29 transplant recipients), including 9 colorectal cancers. The factors found to be associated with advanced colorectal neoplasia included older age (OR per year older, 1.05 [95% CI, 1.03-1.07], P<0.001), male sex (OR, 2.27 [95% CI, 1.45-3.54], P<0.001), azathioprine use (OR, 2.99 [95% CI, 1.40-6.37], P=0.005), and erythropoiesis-stimulating agent use (OR, 1.92 [95% CI, 1.22-3.03], P=0.005). Grouped LASSO logistic regression revealed similar associations between these factors and advanced colorectal neoplasia. LIMITATIONS: Unmeasured confounding factors. CONCLUSIONS: Older age, male sex, erythropoiesis-stimulating agents, and azathioprine were found to be significantly associated with advanced colorectal neoplasia in patients with CKD.

QUADAS-C: A Tool for Assessing Risk of Bias in Comparative Diagnostic Accuracy Studies.

Comparative diagnostic test accuracy studies assess and compare the accuracy of 2 or more tests in the same study. Although these studies have the potential to yield reliable evidence regarding comparative accuracy, shortcomings in the design, conduct, and analysis may bias their results. The currently recommended quality assessment tool for diagnostic test accuracy studies, QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), is not designed for the assessment of test comparisons. The QUADAS-C (Quality Assessment of Diagnostic Accuracy Studies-Comparative) tool was developed as an extension of QUADAS-2 to assess the risk of bias in comparative diagnostic test accuracy studies. Through a 4-round Delphi study involving 24 international experts in test evaluation and a face-to-face consensus meeting, an initial version of the tool was developed that was revised and finalized following a pilot study among potential users. The QUADAS-C tool retains the same 4-domain structure of QUADAS-2 (Patient Selection, Index Test, Reference Standard, and Flow and Timing) and comprises additional questions to each QUADAS-2 domain. A risk-of-bias judgment for comparative accuracy requires a risk-of-bias judgment for the accuracy of each test (resulting from QUADAS-2) and additional criteria specific to test comparisons. Examples of such additional criteria include whether participants either received all index tests or were randomly assigned to index tests, and whether index tests were interpreted with blinding to the results of other index tests. The QUADAS-C tool will be useful for systematic reviews of diagnostic test accuracy addressing comparative questions. Furthermore, researchers may use this tool to identify and avoid risk of bias when designing a comparative diagnostic test accuracy study.

Correction to: Estimation of treatment preference effects in clinical trials when some participants are indifferent to treatment choice.

In the original publication of this article [1], the number "- 0.49" in the below sentence in the Results section should be changed to "-3.23", and this typo does not affect the wider conclusions.

One-Time Fecal Immunochemical Screening for Advanced Colorectal Neoplasia in Patients with CKD (DETECT Study).

BACKGROUND: In patients with CKD, the risk of developing colorectal cancer is high and outcomes are poor. Screening using fecal immunochemical testing (FIT) is effective in reducing mortality from colorectal cancer, but performance characteristics of FIT in CKD are unknown. METHODS: To determine the detection rates and performance characteristics of FIT for advanced colorectal neoplasia (ACN) in patients with CKD, we used FIT to prospectively screen patients aged 35-74 years with CKD (stages 3-5 CKD, dialysis, and renal transplant) from 11 sites in Australia, New Zealand, Canada, and Spain. All participants received clinical follow-up at 2 years. We used a two-step reference standard approach to estimate disease status. RESULTS: Overall, 369 out of 1706 patients who completed FIT (21.6%) tested positive; 323 (87.5%) underwent colonoscopies. A total of 1553 (91.0%) completed follow-up; 82 (4.8%) had died and 71 (4.2%) were lost. The detection rate of ACN using FIT was 6.0% (5.6%, 7.4%, and 5.6% for stages 3-5 CKD, dialysis, and transplant). Sensitivity, specificity, and positive and negative predictive values of FIT for ACN were 0.90, 0.83, 0.30, and 0.99, respectively. Of participants who underwent colonoscopy, five (1.5%) experienced major colonoscopy-related complications, including bowel perforation and major bleeding. CONCLUSIONS: FIT appears to be an accurate screening test for patients with CKD, such that a negative test may rule out the diagnosis of colorectal cancer within 2 years. However, the risk of major complications from work-up colonoscopy are at least ten-fold higher than in the general population.

Optimising the two-stage randomised trial design when some participants are indifferent in their treatment preferences.

Outcomes in a clinical trial can be affected by any underlying preferences that its participants have for the treatments under comparison and by whether they actually receive their preferred treatment. These effects cannot be evaluated in standard trial designs but are estimable in the alternative two-stage randomised trial design, in which some patients can choose their treatment, while the rest are randomly assigned. We have previously shown that, when all two-stage trial participants have a preferred treatment, the preference effects can be evaluated, in addition to the usual direct effect of treatment. We also determined criteria by which to optimise how many participants should be given a choice of treatment vs being randomised. More recently, we extended our methodology to allow for participants who are unable or unwilling to express a treatment preference if they are assigned to the choice group. In this paper, we show how to optimise the two-stage design when some participants are undecided about their treatment. We demonstrate that the undecided group should be regarded as distinct in the analysis, to obtain valid estimates of the preference effects. We derive the optimal proportion of participants who should be offered a choice of treatment, which in many cases will be close to 50%. More generally, the optima depend on the preference rates for treatments and the proportion of undecided participants, and the parameters of primary interest. We discuss some advantages and disadvantages of the two-stage trial design in this situation and describe a practical example.

Pilot trial of digital breast tomosynthesis (3D mammography) for population-based screening in BreastScreen Victoria.

OBJECTIVES: To estimate detection measures for tomosynthesis and standard mammography; to assess the feasibility of using tomosynthesis in population-based screening for breast cancer. DESIGN, SETTING: Prospective pilot trial comparing tomosynthesis (with synthesised 2D images) and standard mammography screening of women attending Maroondah BreastScreen, a BreastScreen Victoria service in the eastern suburbs of Melbourne. PARTICIPANTS: Women at least 40 years of age who presented for routine breast screening between 18 August 2017 and 8 November 2018. MAIN OUTCOME MEASURES: Cancer detection rate (CDR); proportion of screens that led to recall for further assessment. RESULTS: 5018 tomosynthesis and 5166 standard mammography screens were undertaken in 10 146 women; 508 women (5.0% of screens) opted not to undergo tomosynthesis screening. With tomosynthesis, 49 cancers (40 invasive, 9 in situ) were detected (CDR, 9.8 [95% CI, 7.2-13] per 1000 screens); with standard mammography, 34 cancers (30 invasive, 4 in situ) were detected (CDR, 6.6 [95% CI, 4.6-9.2] per 1000 screens). The estimated difference in CDR was 3.2 more detections (95% CI, -0.32 to 6.8) per 1000 screens with tomosynthesis; the difference was greater for repeat screens and for women aged 60 years or more. The recall rate was greater for tomosynthesis (4.2%; 95% CI, 3.6-4.8%) than standard mammography (3.0%; 95% CI, 2.6-3.5%; estimated difference, 1.2%; 95% CI, 0.46-1.9%). The median screen reading time for tomosynthesis was 67 seconds (interquartile range [IQR] 46-105 seconds); for standard mammography, 16 seconds (IQR, 10-29 seconds). CONCLUSIONS: Breast cancer detection, recall for assessment, and screen reading time were each higher for tomosynthesis than for standard mammography. Our preliminary findings could form the basis of a large scale comparative evaluation of tomosynthesis and standard mammography for breast screening in Australia. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617000947303.

Comparison of breast cancers detected in the Verona screening program following transition to digital breast tomosynthesis screening with cancers detected at digital mammography screening.

BACKGROUND: The Verona population-based breast cancer (BC) screening program provides biennial mammography to women aged 50-69 years. Based on emerging evidence of enhanced detection, the program transitioned to digital breast tomosynthesis (DBT) screening. METHODS: This is a prospective pilot evaluation of DBT with synthesised 2D mammography screening implemented during April 2015-March 2017; the rate and characteristics of cancers detected at DBT screening were compared with those detected at the preceding digital mammography (DM) screening round (April 2013-March 2015) in the same screening program. Distribution of imaging and tumour characteristics were compared. RESULTS: Amongst 34,071 women screened in the Verona DBT pilot, 315 BCs were detected; 153 BCs were detected amongst 29,360 women in the DM screening round. Estimated CDRs were 9.2/1000 (95% CI 8.3-10.3) DBT screens versus 5.2/1000 (95% CI 4.4-6.1) DM screens, P < 0.001. Statistically significant differences were found in the distribution of whether recall by one/both screen readers (more BCs recalled by both readers at DBT than DM); whether detected on one/two views (higher proportion detected on only one view at DBT than DM); type of radiological lesions; tumour stage, pT and histological categories (lower proportion of DCIS/pTis, higher proportions of pT1a and pT1b, and higher proportion of invasive cancers of special types, at DBT than DM); and tumour grade (higher proportion of grade I at DBT than DM). There were no differences in distributions of nodal and hormone receptor (ER/PR) status. CONCLUSIONS: Our findings provide early insights into the extent that transitioning to DBT screening may modify the characteristics of screen-detected breast cancer to inform discussion regarding pros and cons of DBT screening; although our data provide some reassurance that DBT does not increase the proportion of screen-detected DCIS, they highlight mixed findings on comparative tumour characteristics, suggesting a potential for enhancing screening benefit and possibly also over-diagnosis from DBT screening.

The Validity of Drug Effects on Proteinuria, Albuminuria, Serum Creatinine, and Estimated GFR as Surrogate End Points for ESKD: A Systematic Review.

RATIONALE & OBJECTIVE: Proteinuria, albuminuria, and serum creatinine level are widely used as surrogate end point measures of end-stage kidney disease (ESKD). We evaluated the correlation between antihypertensive drug effects on surrogate renal end points and ESKD. STUDY DESIGN: Systematic review. SETTING & PARTICIPANTS: Randomized controlled trials of blood pressure-lowering therapy. SELECTION CRITERIA FOR STUDIES: Trials of pharmacological blood pressure-lowering strategies reporting drug effects on albuminuria, proteinuria, or serum creatinine level and ESKD through March 26, 2018. ANALYTICAL APPROACH: Bayesian bivariate meta-analysis to calculate correlations between drug effects on surrogate end points and drug effects on ESKD. Risks of bias were adjudicated using the Cochrane tool. RESULTS: 22 randomized controlled trials involving 69,642 participants were eligible. Risks of bias in the included trials were frequently unclear due to incomplete reporting. Relative risk for ESKD was statistically significant in 1 of 29 (3.4%) treatment comparisons. There appeared to be little or no correlation between antihypertensive drug effects on serum creatinine level, albuminuria, proteinuria, and the corresponding effects on ESKD. All correlations had wide 95% credible intervals that included the null effect. LIMITATIONS: Low power due to infrequent outcomes of ESKD and incomplete data reporting in primary trials. CONCLUSIONS: The association between antihypertensive drug effects on doubling of serum creatinine level and albuminuria or proteinuria with ESKD in treatment trials is not sufficiently certain to enable the confident use of these markers to guide clinical or regulatory decision making.

Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement.

Importance: Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy. Objective: To develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews. Design: Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group. Findings: The systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted. Conclusions and Relevance: The 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.

Diagnostic Accuracy of Noninvasive Fibrosis Scores in a Population of Individuals With a Low Prevalence of Fibrosis.

BACKGROUND & AIMS: Noninvasive scoring systems for fibrosis are increasingly used in the clinic and in research because of their ease of use, accessibility, and low cost. However, test performance characteristics were established in groups of patients with a high prevalence of advanced fibrosis; little is known about diagnostic accuracy in low-risk populations. METHODS: In a cross-sectional study, 922 members of a general ambulatory population in Hong Kong (randomly selected; 18-70 years old) underwent clinical assessment from May 2008 through December 2010. All participants completed a standard questionnaire that collected information on age, sex, and history of smoking and alcohol use. Results of fasting blood tests and transient elastography were used as the reference standard to identify patients with advanced fibrosis. We assessed performance characteristics of 3 noninvasive fibrosis scoring systems: the nonalcoholic fatty liver disease fibrosis scoring system, the Fibrosis-4 scoring system, and aspartate transaminase to platelet ratio index, using standard thresholds. To calculate diagnostic test characteristics, we constructed a 2-by-2 table with the presence or absence of advanced fibrosis according to the transient elastography reading against the presence or absence of advanced fibrosis according to the scoring systems. Area under the receiver operating curve was calculated to assess overall diagnostic accuracy. RESULTS: Of the 922 individuals evaluated by transient elastography, 749 had a valid reading and 15 had advanced fibrosis (2%). The specificity of noninvasive scores in detection of advanced fibrosis approximated 100% (95% confidence interval [CI], 99%-100%), with a negative predictive value of 98% (95% CI, 97%-99%) for all systems. However, the scoring systems detected fibrosis with a low level of sensitivity, ranging from 7% (95% CI, 0%-32%) to 13% (95% CI, 2%-40%). Positive predictive values ranged from 50% (95% CI, 7%-93%) to 67% (95% CI, 9%-99%). Their negative likelihood ratios ranged from 0.87 (95% CI, 0.71%-1.06%) to 0.93 (95% CI, 0.82%-1.07%); positive likelihood ratios were uninformative because of the small number of people with positive scores. CONCLUSIONS: In low-risk populations, negative results from noninvasive scoring systems reliably exclude advanced fibrosis, without requirements for further tests. Positive test results are often a false-positive result and should prompt further testing.

Elevated Liver Enzymes and Mortality in Older Individuals: A Prospective Cohort Study.

AIM OF THE STUDY: The aim of the study was to determine the excess risk of all-cause and cardiovascular mortality in older people with elevated liver enzymes [alanine transaminase (ALT) and gamma glutamyltransferase (GGT)]. METHODS: We utilized data from a large, prospective, population based study of 2061 people aged 50 to 99 years with linkage to a National Death Registry. Participants were categorized as having elevated liver enzymes using standard thresholds (for males, GGT>51 and ALT>40 IU/L, and GGT>33 and ALT>31 IU/L for females). Adjusted Cox proportional hazards models assessed the association of elevated liver enzymes and mortality with long duration follow-up. RESULTS: Over a median follow-up of 10 years (20,145 person years), 701 people died, including 203 (34%) from cardiovascular disease. Cox regression models adjusted for sex, age, smoking, and alcohol intake indicated that people with elevated liver enzymes had an increased risk of all-cause mortality that was modified by age (test for interaction P=0.01). Age-stratified analyses demonstrated no increased risk at younger ages [age 59 y and below; hazard ratio (HR): 0.46; 95% confidence interval, 0.06-3.49], but increased risk with age; age 60 to 69, HR: 1.05 (0.53-2.07), age 70 to 79 years, HR: 1.54 (0.81 to 2.93), and age 80 years and above, HR: 3.53 (1.55 to 8.04). Similarly, the risk of cardiovascular mortality with elevated liver enzymes was also modified by, and increased with age (test for interaction P=0.02); age 70 to 79, HR: 3.15 (1.37 to 7.23), age 80 years and above, HR: 6.86 (2.44 to 19.30). CONCLUSIONS: In community-dwelling elderly persons, an elevation in both ALT and GGT are associated with an excess risk of all-cause and cardiovascular mortality which increases with age.

Estimation of treatment preference effects in clinical trials when some participants are indifferent to treatment choice.

BACKGROUND: In the two-stage randomised trial design, a randomly sampled subset of study participants are permitted to choose their own treatment, while the remaining participants are randomised to treatment in the usual way. Appropriate analysis of the data from both arms of the study allows investigators to estimate the impact on study outcomes of treatment preferences that patients may have, in addition to evaluating the usual direct effect of treatment. In earlier work, we showed how to optimise this design by making a suitable choice of the proportion of participants who should be assigned to the choice arm of the trial. However, we ignored the possibility of some participants being indifferent to the treatments under study. In this paper, we extend our earlier work to consider the analysis of two-stage randomised trials when some participants have no treatment preference, even if they are assigned to the choice arm and allowed to choose. METHODS: We compare alternative characterisations of the response profiles of the indifferent or undecided participants, and derive estimates of the treatment and preference effects on study outcomes. We also present corresponding test statistics for these parameters. The methods are illustrated with data from a clinical trial contrasting medical and surgical interventions. RESULTS: Expressions are obtained to estimate and test the impact of treatment choices on study outcomes, as well as the impact of the actual treatment received. Contrasts are defined between patients with stated treatment preferences and those with no preference. Alternative assumptions concerning the outcomes of undecided participants are described, and an approach leading to unbiased estimation and testing is identified. CONCLUSIONS: Use of the two-stage design can provide important insights into determinants of study outcomes that are not identifiable with other designs. The design can remain attractive even in the presence of participants with no stated treatment preference.

Prevalence of elevated alanine transaminase in Australia and its relationship to metabolic risk factors: A cross-sectional study of 9,447 people.

BACKGROUND AND AIM: Elevated alanine transaminase (ALT) is a strong predictor of metabolic syndrome, but there are few data from the Australian population. We aimed to determine the prevalence of elevated ALT and association with metabolic risk factors. METHODS: In this cross-sectional study including adult participants (N = 9,447) from a nationwide, population-based survey, we assessed the prevalence of elevated ALT [defined as ≥ 40 IU/L (men) and ≥ 30 IU/L (women) as baseline, and ALT as ≥ 30 IU/L (men) and ≥ 19 IU/L (women) as lower threshold], distribution of metabolic risk factors, and independent predictors of elevated ALT in logistic regression models. Analyses were weighted to the population with population weights. RESULTS: Elevated ALT levels were found in 11.2% of the Australian population. People with elevated ALT were younger (43 vs 46 yrs) with more truncal adiposity (100 vs 91 cm), higher pro-atherogenic lipids and glucose and exercised less (120 vs 160 min per week, P < 0.05 for all analyses). Regression analyses indicated that younger age, male sex, diabetes, triglycerides, apolipoprotein B, and waist circumference were independent predictors of elevated ALT. The population attributable fraction of elevated ALT due to truncal obesity was estimated at 47%. CONCLUSION: These data demonstrate a high prevalence of elevated ALT in the general population that is closely associated with metabolic risk factors. Individuals with elevated ALT should be evaluated for co-existent metabolic disorders.

Beginning the trajectory to ESKD in adult life: albuminuria in Australian aboriginal children and adolescents.

BACKGROUND: Globally, disadvantaged populations suffer a high burden of chronic kidney disease (CKD). The trajectory to CKD during childhood and adolescence remains unclear due to a paucity of longitudinal studies. METHODS: This was a prospective, population-based cohort study in which since 2002 we have followed 3418 children (1469 non-Aboriginal and 1949 Aboriginal) attending participating schools across New South Wales (NSW), Australia. The albumin:creatinine ratio was measured by dipstick every 2 years together with the body mass index (BMI) and blood pressure. We used multivariable logistic generalised estimating equation models to examine whether Aboriginal children had a higher prevalence of albuminuria compared with non-Aboriginal children with increasing age and to identify potential risk factors. RESULTS: The mean age at enrolment was 10.6 years, at which time 14.2 % of the children were obese and 16.0 % overweight, with 11.5 % found to have albuminuria. Over 8 years (11,387 participant-years) of follow-up the prevalence of albuminuria increased to 18.5 %, overweight to 16.1 % and obesity to 17.2 %. The BMI standard deviation score (SDS) was found to have a differential effect on the risk of albuminuria in Aboriginal and non-Aboriginal children (P interaction < 0.01). The prevalence of albuminuria decreased as the BMI SDS increased in both groups of children, but it increased more in non-Aboriginal children, leading to a 2.5 % higher prevalence of albuminuria in overweight Aboriginal children (95 % confidence interval 1.0-4.2 %). CONCLUSION: Compared with non-Aboriginal children, Aboriginal children are of higher risk of albuminuria when overweight or obese. We hypothesise that overweight and obesity are key contributors to the development of adult onset CKD among Aboriginal Australians, which needs further exploration in future studies.

Diagnostic accuracy of the Ottawa Ankle and Midfoot Rules: a systematic review with meta-analysis.

OBJECTIVE: To review the diagnostic accuracy of the Ottawa Ankle and Midfoot Rules and explore if clinical features and/or methodological quality of the study influence diagnostic accuracy estimates. DESIGN: Systematic review with meta-analysis. DATA SOURCES: MEDLINE, EMBASE, CINAHL, SPORTDiscus and Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Primary diagnostic studies reporting the accuracy of the Rules in people with ankle and/or midfoot injury were retrieved. Diagnostic accuracy estimates, overall and for subgroups (patient's age, profession of the assessor and setting of application), were made. Sensitivity analyses included studies with a low risk of bias and studies where all patients received radiographs. RESULTS: 66 studies were included. Ankle and Midfoot Rules presented similar accuracies, which were homogeneous and high for sensitivity and negative likelihood ratios and poor and heterogeneous for specificity and positive likelihood ratios (mean, 95% CI pooled sensitivity of Ankle Rules: 99.4%, 97.9% to 99.8%; specificity: 35.3%, 28.8% to 42.3%). Sensitivity of the Ankle Rules was higher in adults than in children, but the profession of the assessor did not appear to influence accuracy. Specificity was higher for Midfoot than for Ankle Rules. There were not enough studies to allow comparison according to setting of application. Studies with a low risk of bias and where all patients received radiographs provided lower accuracy estimates. Specificity heterogeneity was not explained by assessor training, use of imaging in all patients and low risk of bias. CONCLUSIONS: Study features and the methodological quality influence estimates of the diagnostic accuracy of the Ottawa Ankle and Midfoot Rules.

Breast cancer screening with tomosynthesis (3D mammography) with acquired or synthetic 2D mammography compared with 2D mammography alone (STORM-2): a population-based prospective study.

BACKGROUND: Breast tomosynthesis (pseudo-3D mammography) improves breast cancer detection when added to 2D mammography. In this study, we examined whether integrating 3D mammography with either standard 2D mammography acquisitions or with synthetic 2D images (reconstructed from 3D mammography) would detect more cases of breast cancer than 2D mammography alone, to potentially reduce the radiation burden from the combination of 2D plus 3D acquisitions. METHODS: The Screening with Tomosynthesis Or standard Mammography-2 (STORM-2) study was a prospective population-based screening study comparing integrated 3D mammography (dual-acquisition 2D-3D mammography or 2D synthetic-3D mammography) with 2D mammography alone. Asymptomatic women aged 49 years or older who attended population-based screening in Trento, Italy were recruited for the study. All participants underwent digital mammography with 2D and 3D mammography acquisitions, with the use of software that allowed synthetic 2D mammographic images to be reconstructed from 3D acquisitions. Mammography screen-reading was done in two parallel double-readings conducted sequentially for 2D acquisitions followed by integrated acquisitions. Recall based on a positive mammography result was defined as recall at any screen read. Primary outcome measures were a comparison between integrated (2D-3D or 2D synthetic-3D) mammography and 2D mammography alone of the number of cases of screen-detected breast cancer, the cancer detection rate per 1000 screens, the incremental cancer detection rate, and the number and percentage of false-positive recalls. FINDINGS: Between May 31, 2013, and May 29, 2015, 10 255 women were invited to participate, of whom 9672 agreed to participate and were screened. In these 9672 participants (median age 58 years [IQR 53-63]), screening detected 90 cases of breast cancer, including 74 invasive breast cancers, in 85 women (five women had bilateral breast cancer). To account for these bilateral cancers in cancer detection rate estimates, the number of screens used for analysis was 9677. Both 2D-3D mammography (cancer detection rate 8·5 per 1000 screens [82 cancers detected in 9677 screens]; 95% CI 6·7-10·5) and 2D synthetic-3D mammography (8·8 per 1000 [85 in 9677]; 7·0-10·8) had significantly higher rates of breast cancer detection than 2D mammography alone (6·3 per 1000 [61 in 9677], 4·8-8·1; p<0·0001 for both comparisons). The cancer detection rate did not differ significantly between 2D-3D mammography and 2D synthetic-3D mammography (p=0·58). Compared with 2D mammography alone, the incremental cancer detection rate from 2D-3D mammography was 2·2 per 1000 screens (95% CI 1·2-3·3) and that from 2D synthetic-3D mammography was 2·5 per 1000 (1·4-3·8). Compared with the proportion of false-positive recalls from 2D mammography alone (328 of 9587 participants not found to have cancer at assessment) [3·42%; 95% CI 3·07-3·80]), false-positive recall was significantly higher for 2D-3D mammography (381 of 9587 [3·97%; 3·59-4·38], p=0·00063) and for 2D synthetic-3D mammography (427 of 9587 [4·45%; 4·05-4·89], p<0·0001). INTERPRETATION: Integration of 3D mammography (2D-3D or 2D synthetic-3D) detected more cases of breast cancer than 2D mammography alone, but increased the percentage of false-positive recalls in sequential screen-reading. These results should be considered in the context of the trade-off between benefits and harms inherent in population breast cancer screening, including that significantly increased breast cancer detection from integrating 3D mammography into screening has the potential to augment screening benefit and also possibly contribute to overdiagnosis. FUNDING: None.

Meta-analysis of breast cancer mortality benefit and overdiagnosis adjusted for adherence: improving information on the effects of attending screening mammography.

BACKGROUND: Women require information about the impact of regularly attending screening mammography on breast cancer mortality and overdiagnosis to make informed decisions. To provide this information we aimed to meta-analyse randomised controlled trials adjusted for adherence to the trial protocol. METHODS: Nine screening mammography trials used in the Independent UK Breast Screening Report were selected. Extending an existing approach to adjust intention-to-treat (ITT) estimates for less than 100% adherence rates, we conducted a random-effects meta-analysis. This produced a combined deattenuated prevented fraction and a combined deattenuated percentage risk of overdiagnosis. RESULTS: In women aged 39-75 years invited to screen, the prevented fraction of breast cancer mortality at 13-year follow-up was 0.22 (95% CI 0.15-0.28) and it increased to 0.30 (95% CI 0.18-0.42) with deattenuation. In women aged 40-69 years invited to screen, the ITT percentage risk of overdiagnosis during the screening period was 19.0% (95% CI 15.2-22.7%), deattenuation increased this to 29.7% (95% CI 17.8-41.5%). CONCLUSIONS: Adjustment for nonadherence increased the size of the mortality benefit and risk of overdiagnosis by up to 50%. These estimates are more appropriate when developing quantitative information to support individual decisions about attending screening mammography.

The Association of Surgical Margins and Local Recurrence in Women with Ductal Carcinoma In Situ Treated with Breast-Conserving Therapy: A Meta-Analysis.

PURPOSE: There is no consensus on adequate negative margins in breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS). We systematically reviewed the evidence on margins in BCS for DCIS. METHODS: A study-level meta-analysis of local recurrence (LR), microscopic margin status and threshold distance for negative margins. LR proportion was modeled using random-effects logistic meta-regression (frequentist) and network meta-analysis (Bayesian) that allows for multiple margin distances per study, adjusting for follow-up time. RESULTS: Based on 20 studies (LR: 865 of 7883), odds of LR were associated with margin status [logistic: odds ratio (OR) 0.53 for negative vs. positive/close (p < 0.001); network: OR 0.45 for negative vs. positive]. In logistic meta-regression, relative to >0 or 1 mm, ORs for 2 mm (0.51), 3 or 5 mm (0.42) and 10 mm (0.60) showed comparable significant reductions in the odds of LR. In the network analysis, ORs relative to positive margins for 2 (0.32), 3 (0.30) and 10 mm (0.32) showed similar reductions in the odds of LR that were greater than for >0 or 1 mm (0.45). There was weak evidence of lower odds at 2 mm compared with >0 or 1 mm [relative OR (ROR) 0.72, 95 % credible interval (CrI) 0.47-1.08], and no evidence of a difference between 2 and 10 mm (ROR 0.99, 95 % CrI 0.61-1.64). Adjustment for covariates, and analyses based only on studies using whole-breast radiotherapy, did not change the findings. CONCLUSION: Negative margins in BCS for DCIS reduce the odds of LR; however, minimum margin distances above 2 mm are not significantly associated with further reduced odds of LR in women receiving radiation.

Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): explanation and elaboration.

The TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) Statement includes a 22-item checklist, which aims to improve the reporting of studies developing, validating, or updating a prediction model, whether for diagnostic or prognostic purposes. The TRIPOD Statement aims to improve the transparency of the reporting of a prediction model study regardless of the study methods used. This explanation and elaboration document describes the rationale; clarifies the meaning of each item; and discusses why transparent reporting is important, with a view to assessing risk of bias and clinical usefulness of the prediction model. Each checklist item of the TRIPOD Statement is explained in detail and accompanied by published examples of good reporting. The document also provides a valuable reference of issues to consider when designing, conducting, and analyzing prediction model studies. To aid the editorial process and help peer reviewers and, ultimately, readers and systematic reviewers of prediction model studies, it is recommended that authors include a completed checklist in their submission. The TRIPOD checklist can also be downloaded from www.tripod-statement.org.