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This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To review the effects of bilateral versus single internal mammary artery grafts for coronary bypass grafting.

Objectives The objectives are to describe the disadvantages of the area under the receiver operating characteristic curve (ROC AUC) to measure diagnostic test performance and to propose an alternative based on net benefit. Methods We use a narrative review supplemented by data from a study of computer-assisted detection for CT colonography. Results We identified problems with ROC AUC. Confidence scoring by readers was highly non-normal, and score distribution was bimodal. Consequently, ROC curves were highly extrapolated with AUC mostly dependent on areas without patient data. AUC depended on the method used for curve fitting. ROC AUC does not account for prevalence or different misclassification costs arising from false-negative and false-positive diagnoses. Change in ROC AUC has little direct clinical meaning for clinicians. An alternative analysis based on net benefit is proposed, based on the change in sensitivity and specificity at clinically relevant thresholds. Net benefit incorporates estimates of prevalence and misclassification costs, and it is clinically interpretable since it reflects changes in correct and incorrect diagnoses when a new diagnostic test is introduced. Conclusions ROC AUC is most useful in the early stages of test assessment whereas methods based on net benefit are more useful to assess radiological tests where the clinical context is known. Net benefit is more useful for assessing clinical impact. Key points • The area under the receiver operating characteristic curve (ROC AUC) measures diagnostic accuracy. • Confidence scores used to build ROC curves may be difficult to assign. • False-positive and false-negative diagnoses have different misclassification costs. • Excessive ROC curve extrapolation is undesirable. • Net benefit methods may provide more meaningful and clinically interpretable results than ROC AUC.

BACKGROUND: Obese breast cancer patients have a poorer prognosis than non-obese patients. We examined data from a large prospective cohort study to explore the associations of obesity with tumour pathology, treatment and outcome in young British breast cancer patients receiving modern oncological treatments. PATIENTS AND METHODS: A total of 2956 patients aged ≤40 at breast cancer diagnosis were recruited from 126 UK hospitals from 2001 to 2007. Height and weight were measured at registration. Tumour pathology and treatment details were collected. Follow-up data were collected at 6, 12 months, and annually. RESULTS: A total of 2843 eligible patients (96.2%) had a body mass index (BMI) recorded: 1526 (53.7%) were under/healthy-weight (U/H, BMI

Importance: While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility.Objective: To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders.Design: Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration–registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials.Findings: No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items.Conclusions and Relevance: Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.

The purpose of the INTERGROWTH-21

Background The use of core outcome sets (COS) ensures that researchers measure and report those outcomes that are most likely to be relevant to users of their research. Several hundred COS projects have been systematically identified to date, but there has been no formal quality assessment of these studies. The Core Outcome Set-STAndards for Development (COS-STAD) project aimed to identify minimum standards for the design of a COS study agreed upon by an international group, while other specific guidance exists for the final reporting of COS development studies (Core Outcome Set-STAndards for Reporting [COS-STAR]). Methods and findings An international group of experienced COS developers, methodologists, journal editors, potential users of COS (clinical trialists, systematic reviewers, and clinical guideline developers), and patient representatives produced the COS-STAD recommendations to help improve the quality of COS development and support the assessment of whether a COS had been developed using a reasonable approach. An open survey of experts generated an initial list of items, which was refined by a 2-round Delphi survey involving nearly 250 participants representing key stakeholder groups. Participants assigned importance ratings for each item using a 1–9 scale. Consensus that an item should be included in the set of minimum standards was defined as at least 70% of the voting participants from each stakeholder group providing a score between 7 and 9. The Delphi survey was followed by a consensus discussion with the study management group representing multiple stakeholder groups. COS-STAD contains 11 minimum standards that are the minimum design recommendations for all COS development projects. The recommendations focus on 3 key domains: the scope, the stakeholders, and the consensus process. Conclusions The COS-STAD project has established 11 minimum standards to be followed by COS developers when planning their projects and by users when deciding whether a COS has been developed using reasonable methods., Paula Williamson and colleagues report on the core outcome set standards for development that researchers should use for improving reporting of their research.

Objectives: There is still little evidence to support routine dual antiplatelet therapy (DAPT) with P2Y12 antagonists following coronary artery bypass grafting (CABG). The Arterial Re-vascularization Trial (ART) was designed to compare 10-year survival after bilateral versus single internal thoracic artery grafting. We aimed to get insights into the effect of DAPT (with clopidogrel) following CABG on 1 year outcomes by performing a post-hoc ART anal-ysis. Methods: Among patients enrolled in the ART (n=3102), 609 (21%) and 2308 (79%) were discharged on DAPT or aspirin alone respectively. The primary endpoint was the incidence of major adverse cerebrovascular and cardiac events (MACCE) at 1 year including cardiac death, myocardial infarction, cerebrovascular accident and reintervention; safety endpoint was bleeding requiring hospitalization. Propensity score (PS) matching was used to create comparable groups. Results: Among 609-PS matched pairs, MACCE occurred in 34 (5.6%) and 34 (5.6%) in the DAPT and aspirin alone groups respectively with no significant difference between the two groups (HR 0.97; 95%CI 0.59-1.59; P=0.90). Only 188 (31%) subjects completed 1 year of DAPT and in this subgroup, MACCE rate was 5.8% (HR 1.11; 95%CI 0.53-2.30; P=0.78). In the overall sample, bleeding rate was higher in DAPT group (2.3% versus 1.1%; P=0.02) although this difference was no longer significant after matching (2.3% vs 1.8%; P=0.54). Conclusions: Based on these findings, when compared to aspirin alone, DAPT with clopidogrel prescribed at discharge was not associated with a significant reduction of adverse cardiac and cerebrovascular events at 1 year following CABG.

Despite its wide use in statistics, the logarithmic transformation can make non-statisticians uncomfortable.1234 This is a shame because logarithms have very useful properties, including a secret not widely known even among statisticians. The two familiar forms of logarithm are common logs, to base 10, and natural logs, to base e .1 Here we focus on natural logs (or “ln” for short), which have the following “natural” interpretation: if we take two numbers a and b , then the difference between their logs, ln( a )−ln( b ), is the fractional difference between a and b . And multiplied by 100—that is, 100×ln( a )−100×ln( b )—it is the percentage difference between a and b .5 This value is slightly different from the conventional percentage difference, …

Background Guidelines for assessing methodological and reporting quality of systematic reviews (SRs) were developed to contribute to implementing evidence-based health care and the reduction of research waste. As SRs assessing a cohort of SRs is becoming more prevalent in the literature and with the increased uptake of SR evidence for decision-making, methodological quality and standard of reporting of SRs is of interest. The objective of this study is to evaluate SR adherence to the Quality of Reporting of Meta-analyses (QUOROM) and PRISMA reporting guidelines and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) and Overview Quality Assessment Questionnaire (OQAQ) quality assessment tools as evaluated in methodological overviews. Methods The Cochrane Library, MEDLINE®, and EMBASE® databases were searched from January 1990 to October 2014. Title and abstract screening and full-text screening were conducted independently by two reviewers. Reports assessing the quality or reporting of a cohort of SRs of interventions using PRISMA, QUOROM, OQAQ, or AMSTAR were included. All results are reported as frequencies and percentages of reports and SRs respectively. Results Of the 20,765 independent records retrieved from electronic searching, 1189 reports were reviewed for eligibility at full text, of which 56 reports (5371 SRs in total) evaluating the PRISMA, QUOROM, AMSTAR, and/or OQAQ tools were included. Notable items include the following: of the SRs using PRISMA, over 85% (1532/1741) provided a rationale for the review and less than 6% (102/1741) provided protocol information. For reports using QUOROM, only 9% (40/449) of SRs provided a trial flow diagram. However, 90% (402/449) described the explicit clinical problem and review rationale in the introduction section. Of reports using AMSTAR, 30% (534/1794) used duplicate study selection and data extraction. Conversely, 80% (1439/1794) of SRs provided study characteristics of included studies. In terms of OQAQ, 37% (499/1367) of the SRs assessed risk of bias (validity) in the included studies, while 80% (1112/1387) reported the criteria for study selection. Conclusions Although reporting guidelines and quality assessment tools exist, reporting and methodological quality of SRs are inconsistent. Mechanisms to improve adherence to established reporting guidelines and methodological assessment tools are needed to improve the quality of SRs. Electronic supplementary material The online version of this article (doi:10.1186/s13643-017-0527-2) contains supplementary material, which is available to authorized users.

OBJECTIVES: To assess a comprehensive package of ultrasound quality control in a large multicentre study of fetal growth - the Fetal Growth Longitudinal Study of the INTERGROWTH-21(st) Project. METHODS: We performed quality control (QC) measures on 20,313 ultrasound scan images taken prospectively from 4,321 fetuses at 14-41 weeks' gestation in eight geographical locations. At the time of each ultrasound examination, three fetal biometric variables were measured in triplicate on separately generated images: head circumference (HC), abdominal circumference (AC) and femur length (FL). All measurements were taken in a blinded fashion. QC had two elements: 1) qualitative QC: visual assessment by sonographers at each study site of their images based on specific criteria with 10% of images being re-assessed at the Oxford-based Ultrasound Quality Unit (compared using an adjusted kappa statistic), and 2) quantitative QC: measurement data were assessed by (a) comparing the first, second and third measurement (intraobserver variability); (b) re-measurement of caliper replacement in 10% (interobserver variability), both by Bland-Altman plots, and (c) plotting frequency histograms of the SDs of triplicate measurements and assessing how many were above or below 2SDs of the expected distribution. The system allowed the sonographers' performance to be regularly monitored. RESULTS: A high level of agreement between the self- and external scoring was demonstrated for all measurements (kappa = 0.99 [95% confidence interval: 0.98, 0.99] for HC, 0.98 [0.97, 0.99] for AC, and 0.96 [0.95, 0.98] for FL. Intraobserver variability (95% limits of agreement (LoA)) of ultrasound measures for HC, AC and FL were ±3%, ±6% and ±6%, respectively; the corresponding values for interobserver variability were ±4%, ±6% and ±6%. The SD distribution of triplicate measurements for all biometric variables showed excessive variability for three of 31 sonographers, allowing prompt identification and retraining. CONCLUSIONS: Qualitative and quantitative QC monitoring was feasible and highly reproducible in a large multicentre research study, which facilitated the production of high-quality ultrasound images. We recommend that the QC system we developed is implemented in future research studies and clinical practice.

Objectives To investigate the application and interpretation of statistical analyses in a cross-section of systematic reviews (SRs) of therapeutic interventions, without restriction by journal, clinical condition, or specialty. Study Design and Setting We evaluated a random sample of SRs assembled previously, which were indexed in MEDLINE® during February 2014, focused on a treatment or prevention question, and reported at least one meta-analysis. The reported statistical methods used in each SR were extracted from articles and online appendices by one author, with a 20% random sample extracted in duplicate. Results We evaluated 110 SRs; 78/110 (71%) were non-Cochrane SRs, and 55/110 (50%) investigated a pharmacological intervention. The SRs presented a median of 13 (interquartile range 5-27) meta-analytic effects. When considering the index (primary or first reported) meta-analysis of each SR, just over half (62/110 [56%]) used the random-effects model, but few (5/62 [8%]) interpreted the meta-analytic effect correctly (as the average of the intervention effects across all studies). A statistical test for funnel plot asymmetry was reported in 17/110 (15%) SRs, however, in only 4/17 (24%) did the test include the recommended number of at least 10 studies of varying size. Subgroup analyses accompanied 42/110 (38%) index meta-analyses, but findings were not interpreted with respect to a test for interaction in 29/42 (69%) cases, and the issue of potential confounding in the subgroup analyses was not raised in any SR. Conclusions There is scope for improvement in the application and interpretation of statistical analyses in SRs of therapeutic interventions. Involvement of statisticians on the SR team, and establishment of partnerships between researchers with specialist expertise in SR methods and journal editors may help overcome these shortcomings.

Editors' Note: This article is the simplified Chinese version of the CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. (Cheng C, Wu T, Shang H, Li, Y, Altman D, Moher D; CONSORT-CHM Formulas 2017 Group. CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration. Ann Intern Med. 2017;167:112-21. [Epub 27 June 2017]. doi:10.7326/M16-2977).

BACKGROUND The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF).OBJECTIVES This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo.METHODS The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization.RESULTS A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p CONCLUSIONS Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm. (C) 2017 by the American College of Cardiology Foundation.

Objective To examine how poor reporting and inadequate methods for key methodological features in randomised controlled trials (RCTs) have changed over the past three decades. Design Mapping of trials included in Cochrane reviews. Data sources Data from RCTs included in all Cochrane reviews published between March 2011 and September 2014 reporting an evaluation of the Cochrane risk of bias items: sequence generation, allocation concealment, blinding, and incomplete outcome data. Data extraction For each RCT, we extracted consensus on risk of bias made by the review authors and identified the primary reference to extract publication year and journal. We matched journal names with Journal Citation Reports to get 2014 impact factors. Main outcomes measures We considered the proportions of trials rated by review authors at unclear and high risk of bias as surrogates for poor reporting and inadequate methods, respectively. Results We analysed 20 920 RCTs (from 2001 reviews) published in 3136 journals. The proportion of trials with unclear risk of bias was 48.7% for sequence generation and 57.5% for allocation concealment; the proportion of those with high risk of bias was 4.0% and 7.2%, respectively. For blinding and incomplete outcome data, 30.6% and 24.7% of trials were at unclear risk and 33.1% and 17.1% were at high risk, respectively. Higher journal impact factor was associated with a lower proportion of trials at unclear or high risk of bias. The proportion of trials at unclear risk of bias decreased over time, especially for sequence generation, which fell from 69.1% in 1986-1990 to 31.2% in 2011-14 and for allocation concealment (70.1% to 44.6%). After excluding trials at unclear risk of bias, use of inadequate methods also decreased over time: from 14.8% to 4.6% for sequence generation and from 32.7% to 11.6% for allocation concealment. Conclusions Poor reporting and inadequate methods have decreased over time, especially for sequence generation and allocation concealment. But more could be done, especially in lower impact factor journals.

Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases., The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis. Here authors show that trehalose, an mTOR-independent autophagy inducer, alleviates the pathological phenotypes in a mouse model of neurodegenerative disease. Trehalose acts by inhibiting Akt, which normally suppresses TFEB via an mTORC1-independent mechanism.

Policy makers have clearly indicated – through heavy investment in the Patient Centered Outcomes Research Institute – that reporting outcomes that are meaningful to patients is crucial for improvement in healthcare delivery and cost reduction. Better interpretation and generalizability of clinical research results that incorporate patient-centered outcomes research can be achieved by accelerating the development and uptake of core outcome sets (COS). COS provide a standardized minimum set of the outcomes that should be measured and reported in all clinical trials of a specific condition. The level of activity around COS has increased significantly over the past decade, with substantial progress in several clinical domains. However, there are many important clinical conditions for which high-quality COS have not been developed and there are limited resources and capacity with which to develop them. We believe that meaningful progress toward the goals behind the significant investments in patient-centered outcomes research and comparative effectiveness research will depend on a serious effort to address these issues.

PURPOSE: To determine the maximum rate of false-positive diagnoses that patients and health care professionals were willing to accept in exchange for detection of extracolonic malignancy by using computed tomographic (CT) colonography for colorectal cancer screening. MATERIALS AND METHODS: After obtaining ethical approval and informed consent, 52 patients and 50 health care professionals undertook two discrete choice experiments where they chose between unrestricted CT colonography that examined intra- and extracolonic organs or CT colonography restricted to the colon, across different scenarios. The first experiment detected one extracolonic malignancy per 600 cases with a false-positive rate varying across scenarios from 0% to 99.8%. One experiment examined radiologic follow-up generated by false-positive diagnoses while the other examined invasive follow-up. Intracolonic performance was identical for both tests. The median tipping point (maximum acceptable false-positive rate for extracolonic findings) was calculated overall and for both groups by bootstrap analysis. RESULTS: The median tipping point for radiologic follow-up occurred at a false-positive rate greater than 99.8% (interquartile ratio [IQR], 10 to >99.8%). Participants would tolerate at least a 99.8% rate of unnecessary radiologic tests to detect an additional extracolonic malignancy. The median tipping-point for invasive follow-up occurred at a false-positive rate of 10% (IQR, 2 to >99.8%). Tipping points were significantly higher for patients than for health care professionals for both experiments (>99.8 vs 40% for radiologic follow-up and >99.8 vs 5% for invasive follow-up, both P < .001). CONCLUSION: Patients and health care professionals are willing to tolerate high rates of false-positive diagnoses with CT colonography in exchange for diagnosis of extracolonic malignancy. The actual specificity of screening CT colonography for extracolonic findings in clinical practice is likely to be highly acceptable to both patients and health care professionals. Online supplemental material is available for this article.

Artículo original: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6:e1000097.The original authors have not revised and verified the Spanish translation, and not necessary endorse it. Los autores originales no han revisado ni verificado la traducción del manuscrito al español, y no necesariamente están de acuerdo con su contenido.Publicación del artículo original: 21 Julio 2009 Derechos: © 2009 Moher et al. Este es un artículo de acceso abierto distribuido bajo las condiciones de The Creative Commons Attribution License, que permite el uso ilimitado, su distribución y reproducción en cualquier medio, siempre y cuando se acredite el autor y su fuente original.Procedencia: No comisionado; revisión científica externa. Para promover la publicación de la Declaración PRISMA, el artículo se ha publicado como acceso abierto y se puede encontrar en la página web de PLoS Medicine (http://medicine.plosjournals.org/) y también se ha publicado en Annals of Internal Medicine, BMJ, Journal of Clinical Epidemiology, y Open Medicine. Los autores tienen unánimemente los derechos de este artículo. Para más detalles de su uso ver la página web de PRISMA (http://www.prisma-statement.org/).Traducción y adaptación al español: Mercedes Sotos-Prieto, Johana Prieto, Maria Manera, Eduard Baladia, Rodrigo Martínez-Rodríguez y Julio Basulto.Autor de correspondencia de la traducción: Mercedes Sotos-Prieto (merchesotosprieto@gmail.com)

Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(+) T cell and antibody response, which was maintained by both regiments at similar levels. However, CD8(+) T cell responses were significantly boosted in 3 out of 18 patients in Arm A after the first rF-NY-ESO-1 injection and such responses were maintained until the end of the trial, while no patients in Arm B showed similar CD8(+) T cell responses. In addition, our results clearly identified immunodominant regions in the NY-ESO-1 protein: NY-ESO-179-102 and NY-ESO-1115-138 for CD4+ T cells and NY-ESO-185-108 for CD8+ T cells in a large proportion of vaccinated patients. These regions of NY-ESO-1 protein should be considered in future clinical trials as immunodominant epitopes.

Evidence shows the quality of reporting of randomised controlled trials is not optimal. The lack of transparent reporting impedes readers from judging the reliability and validity of trial findings, prevents researchers from extracting information for systematic reviews, and results in research waste. The Consolidated Standards of Reporting Trials (CONSORT) statement was developed to improve the reporting of randomised controlled trials. The primary focus of the statement was on parallel group trials with two treatment groups. Crossover trials are a particular type of trial for chronic conditions in which participants are randomised to a sequence of interventions. They are a useful and efficient design because participants act as their own control. However, the reporting of crossover trials has been variable and incomplete, which hinders their use in clinical decision making and by future researchers. We present the CONSORT extension to randomised crossover trials, which aims to facilitate better reporting of crossover trials. The CONSORT 2010 checklist is revised for crossover designs, and introduces a modified flowchart and baseline table to enhance transparency. Examples of good reporting and evidence based rationale for CONSORT crossover checklist items are provided.

I reflect on the evolution of meta-analysis in clinical research over 35 years since I first encountered the key ideas in the late 1970s.

Background & Aims We studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators. Methods We created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors ("vascular pattern", "bleeding", and "erosions and ulcers") comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores. Results There was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details. Conclusions The UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details.

OBJECTIVES: To assess the feasibility, accuracy and reproducibility of manipulating three-dimensional (3D) volume sets in order to reconstruct optimal two-dimensional (2D) planes for fetal biometry throughout gestation and compare them with those derived from real-time 2D scanning. METHODS: Sixty-five fetuses were evaluated at a gestational age of 14-41 weeks. For each fetus a duplicate set of seven standard fetal measurements was taken by an experienced operator using 2D ultrasound and then 20 intentionally suboptimal 3D volumes from different predefined angles were captured and stored. These were manipulated and measured. The time taken to complete a full scan, with both 2D and 3D ultrasound, was recorded. All measurement differences were expressed as gestational age-specific Z-scores. For all comparisons Bland-Altman plots were used and limits of agreement were calculated. The means and variances of the measurements were tested with a paired t-test and Pitman's test for differences in variance, respectively. The difference between the time taken to perform a 2D and a 3D scan was tested using the Wilcoxon signed-ranks test. RESULTS: Mean agreement between 2D and 3D ultrasound measurements was good, with no statistically significant differences (i.e. no systematic error) unless the head was facing anteroposteriorly, or the long axis of the femur was at 60-90° to the transducer. The variance (random error) for 3D measurements was similar to that for 2D measurements. Planes from some volumes could not be extracted (7% for head circumference, 9% for abdominal circumference and 11% for femur length). The median time required to perform a full fetal biometric scan was significantly higher for 3D than for 2D (3:04 min vs 1:57 min, respectively; P

An antidote to inadequate reporting of research > “It is the responsibility of everyone involved to ensure that the published record is an unbiased, accurate representation of research.”1 The research record is often manipulated for short term gain but at the risk of harm to patients. The medical research community needs to implement changes to ensure that readers obtain the truth about all research, especially reports of randomised trials, which hold a special place in answering what works best for patients. Failure to publish the findings of all studies, especially randomised trials, seriously distorts the evidence base for clinical decision making. A recent systematic review of reboxetine for treating depression found that almost three quarters of included patients were in unpublished trials.2 Of 904 completed trials of interventions for acute ischaemic stroke (1955-2008), a fifth were not properly published, “several of which may be large enough to influence clinical practice and the findings of systematic reviews and meta-analyses.”3 Bad as non-publication is, incomplete or misleading publications cause greater problems. Results of clinical trials published in peer reviewed publications may differ from what was previously submitted to regulatory agencies,4 5 6 with the published data being more positive. The primary outcome often differs from what the researchers had stated in the trial protocol7 8 or …

Background Despite its rarity, the prognosis of pancreatic cancer is very poor and it is a major cause of cancer mortality; being ranked fourth in the world, it has one of the worst survival rates of any cancer. Aim To evaluate the performance of QCancer ® (Pancreas) for predicting the absolute risk of pancreatic cancer in an independent UK cohort of patients, from general practice records. Design and setting Prospective cohort study to evaluate the performance QCancer (Pancreas) prediction models in 364 practices from the UK, contributing to The Health Improvement Network (THIN) database. Method Records were extracted from the THIN database for 2.15 million patients registered with a general practice surgery between 1 January 2000 and 30 June 2008, aged 30–84 years (3.74 million person-years), with 618 pancreatic cancer cases. Pancreatic cancer was defined as incident diagnosis of pancreatic cancer during the 2 years after study entry. Results The results from this independent and external validation of QCancer (Pancreas) demonstrated good performance data on a large cohort of general practice patients. QCancer (Pancreas) had very good discrimination properties, with areas under the receiver operating characteristic curve of 0.89 and 0.92 for females and males respectively. QCancer (Pancreas) explained 60% and 67% of the variation in females and males respectively. QCancer (Pancreas) over-predicted risk in both females and males, notably in older patients. Conclusion QCancer (Pancreas) is potentially useful for identifying undetected cases of pancreatic cancer in primary care in the UK.

© 2013 Cancer Research UK. All rights reserved. 1.1 Introduction: The breast cancer screening programmes in the United Kingdom currently invite women aged 50-70 years for screening mammography every 3 years. Since the time the screening programmes were established, there has been debate, at times sharply polarised, over the magnitude of their benefit and harm, and the balance between them. The expected major benefit is reduction in mortality from breast cancer. The major harm is overdiagnosis and its consequences; overdiagnosis refers to the detection of cancers on screening, which would not have become clinically apparent in the woman's lifetime in the absence of screening. Professor Sir Mike Richards, National Cancer Director, England, and Dr Harpal Kumar, Chief Executive Officer of Cancer Research UK, asked Professor Sir Michael Marmot to convene and chair an independent panel to review the evidence on benefits and harms of breast screening in the context of the UK breast screening programmes. The panel, authors of this report, reviewed the extensive literature and heard testimony from experts in the field who were the main contributors to the debate. The nature of information communicated to the public, which too has sparked debate, was not part of the terms of reference of the panel, which are listed in Appendix 1. 1.2 Relative mortality benefit: The purpose of screening is to advance the time of diagnosis so that prognosis can be improved by earlier intervention. A consequence of earlier diagnosis is that it increases the apparent incidence of breast cancer in a screened population and extends the average time from diagnosis to death, even if screening were to confer no benefit. The appropriate measure of benefit, therefore, is reduction in mortality from breast cancer in women offered screening compared with women not offered screening. In the panel's judgement, the best evidence for the relative benefit of screening on mortality reduction comes from 11 randomised controlled trials (RCTs) of breast screening. Meta-analysis of these trials with 13 years of follow-up estimated a 20% reduction in breast cancer mortality in women invited for screening. The relative reduction in mortality will be higher for women actually attending screening, but by how much is difficult to say because women who do not attend are likely to have a different background risk. Three types of uncertainties surround this estimate of 20% reduction in breast cancer mortality. The first is statistical: the 95% confidence interval (CI) around the relative risk (RR) reduction of 20% was 11-27%. The second is bias: there are a number of potential sources of distortion in the trials that have been widely discussed in the literature ranging from suboptimal randomisation to problems in adjudicating cause of death. The third is the relevance of these old trials to the current screening programmes. The panel acknowledged these uncertainties, but concluded that a 20% reduction is still the most reasonable estimate of the effect of the current UK screening programmes on breast cancer mortality. Most other reviews of the RCTs have yielded similar estimates of relative benefit. The RCTs were all conducted at least 20-30 years ago. More contemporary estimates of the benefit of breast cancer screening come from observational studies. The panel reviewed three types of observational studies. The first were ecological studies comparing areas, or time periods, when screening programmes were and were not in place. These have generated diverse findings, partly because of the major advances in treatment of breast cancer, which have a demonstrably larger influence on mortality trends than does screening, and partly because of the difficulty of excluding imbalances in other factors that could affect breast cancer mortality. The panel did not consider these studies helpful in estimating the effect of screening on mortality. The other two types of studies, case-control studies and incidence-based mortality studies, showed breast screening to confer a greater benefit than did the trials. Although these studies, in general, attempted to control for non-comparability of screened and unscreened women, the panel was concerned that residual bias could inflate the estimate of benefit. However, the panel notes that these studies' findings are in the same direction as the trials. 1.3 Absolute mortality benefit: Estimates of absolute benefit of screening have varied from one breast cancer death avoided for 2000 women invited to screening to 1 avoided for about 100 women screened, about a 20-fold difference. Major determinants of that large variation are the age of women screened, and the durations of screening and follow-up. The age of the women invited is important, as mortality from breast cancer increases markedly with age. The panel therefore applied the relative mortality reduction of 20% to achieve the observed cumulative absolute risk of breast cancer mortality over the ages 55-79 years for women in the United Kingdom, assuming that women who began screening at 50 years would gain no benefit in the first 5 years, but that the mortality reduction would continue for 10 years after screening ended. This yielded the estimate that for every 235 women invited to screening, one breast cancer death would be prevented; correspondingly 180 women would need to be screened to prevent one breast cancer death. Uncertainties in the figure of a 20% RR reduction would carry through to these estimates of absolute mortality benefit. Nonetheless, the panel's estimate of benefit is in the range of one breast cancer death prevented for B250 women invited, rather than the range of 1 in 2000. 1.4 Overdiagnosis: The major harm of screening considered by the panel was that of overdiagnosis. Given the definition of an overdiagnosed cancer, either invasive or non-invasive, as one diagnosed by screening, which would not otherwise have come to attention in the woman's lifetime, there is need for a long follow-up to assess the frequency of overdiagnosis. In the view of the panel, some cancers detected by screening will be overdiagnosed, but the uncertainty surrounding the extent of overdiagnosis is greater than that for the estimate of mortality benefit because there are few sources of reliable data. The issue for the UK screening programmes is the magnitude of overdiagnosis in women who have been in a screening programme from age 50 to 70, then followed for the rest of their lives. There are no data to answer this question directly. Any estimate will therefore be, at best, provisional. Although the definition of an overdiagnosed case, and thus the numerator in a ratio, is clear, the choice of denominator has been the source of further variability in published estimates. Different studies have used: only the cancers found by screening; cancers found during the whole screening period, both screen-detected and interval; cancers diagnosed during the screening period and for the remainder of the women's lifetime. The panel focused on two estimates: the first from a population perspective using as the denominator the number of breast cancers, both invasive and ductal carcinoma in situ (DCIS), diagnosed throughout the rest of a woman's lifetime after the age that screening begins, and the second from the perspective of a woman invited to screening using the total number of breast cancers diagnosed during the screening period as the denominator. The panel thought that the best evidence came from three RCTs that did not systematically screen the control group at the end of the screening period and followed these women for several more years. The frequency of overdiagnosis was of the order of 11% from a population perspective, and about 19% from the perspective of a woman invited to screening. Trials that included systematic screening of the control group at the end of the active part of the trial were not considered to provide informative estimates of the frequency of overdiagnosis. Information from observational studies was also considered. One method that has been used is investigation of time trends in incidence rates of breast cancer for different age groups over the period that population screening was introduced. The published results of these studies varied greatly and have been interpreted as providing either reassurance or cause for alarm. So great was the variation in results that the panel conducted an exercise by varying the assumptions and statistical methods underlying these studies, using the same data sets; estimates of overdiagnosis rates were found to vary across the range of 0-36% of invasive breast cancers diagnosed during the screening period. The panel had no reason to favour one set of estimates over another, and concluded that this method could give no reliable estimate of the extent of overdiagnosis. Were it possible to distinguish at screening those cancers that would not otherwise have come to attention from those that, untreated, would lead to death, the overdiagnosis problem could be much reduced, at least in terms of unnecessary worry and treatment. Currently this is not possible, so neither the woman nor her doctor can know whether a screen-detected cancer is an 'overdiagnosed' case or not. In particular, DCIS, most often diagnosed at screening, does not inevitably equate to overdiagnosis - screen-detected DCIS, after wide local excision (WLE) only, is associated with subsequent development of invasive breast cancer in 10% of women within 10 years. The consequences of overdiagnosis matter, women are turned into patients unnecessarily, surgery and other forms of cancer treatment are undertaken, and quality of life and psychological well being are adversely affected.

BACKGROUND: Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group. METHODS: Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided. RESULTS: Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years. CONCLUSIONS: These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease.

INTERGROWTH-21(st) is a multicentre, multiethnic, population-based project, being conducted in eight geographical areas (Brazil, China, India, Italy, Kenya, Oman, UK and USA), with technical support from four global specialised units, to study growth, health and nutrition from early pregnancy to infancy. It aims to produce prescriptive growth standards, which conceptually extend the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) to cover fetal and newborn life. The new international standards will describe: (1) fetal growth assessed by clinical and ultrasound measures; (2) postnatal growth of term and preterm infants up to 2 years of age; and (3) the relationship between birthweight, length and head circumference, gestational age and perinatal outcomes. As the project has selected healthy cohorts with no obvious risk factors for intrauterine growth restriction, these standards will describe how all fetuses and newborns should grow, as opposed to traditional charts that describe how some have grown at a given place and time. These growth patterns will be related to morbidity and mortality to identify levels of perinatal risk. Additional aims include phenotypic characterisation of the preterm and impaired fetal growth syndromes and development of a prediction model, based on multiple ultrasound measurements, to estimate gestational age for use in pregnant women without access to early/frequent antenatal care.

Control for confounding is crucial in causal observational studies. However, the modelling of continuous confounders has not received much attention. This is probably because in causal research the focus is on a single factor (i.e., the exposure of interest), and confounders are merely considered as

© 2017 Elsevier Inc. Background Well-written and transparent case reports (1) reveal early signals of potential benefits, harms, and information on the use of resources; (2) provide information for clinical research and clinical practice guidelines, and (3) inform medical education. High-quality case reports are more likely when authors follow reporting guidelines. During 2011–2012, a group of clinicians, researchers, and journal editors developed recommendations for the accurate reporting of information in case reports that resulted in the CARE (CAse REport) Statement and Checklist. They were presented at the 2013 International Congress on Peer Review and Biomedical Publication, have been endorsed by multiple medical journals, and translated into nine languages. Objectives This explanation and elaboration document has the objective to increase the use and dissemination of the CARE Checklist in writing and publishing case reports. Article Design and Setting Each item from the CARE Checklist is explained and accompanied by published examples. The explanations and examples in this document are designed to support the writing of high-quality case reports by authors and their critical appraisal by editors, peer reviewers, and readers. Results and Conclusion This article and the 2013 CARE Statement and Checklist, available from the CARE website [www.care-statement.org] and the EQUATOR Network [www.equator-network.org], are resources for improving the completeness and transparency of case reports.

The study protocol, publications, full study report detailing all analyses, and participant-level dataset constitute the main documentation of methods and results for health research. However, journal publications are available for only half of all studies and are plagued by selective reporting of methods and results. The protocol, full study report, and participant-level dataset are rarely available. The quality of information provided in study protocols and reports is variable and often incomplete. Inaccessibility of full information for the vast majority of studies wastes billions of dollars, introduces bias, and has a detrimental impact on patient care and research. To help improve this situation at a systemic level, three main actions are warranted. Firstly, it is important that academic institutions and funders reward investigators who fully disseminate their research protocols, reports, and participant-level datasets. Secondly, standards for the content of protocols, full study reports, and data sharing practices should be rigorously developed and adopted for all types of health research. Finally, journals, funders, sponsors, research ethics committees, regulators, and legislators should implement and enforce policies supporting study registration and availability of journal publications, full study reports, and participant-level datasets.

Fetal growth assessment is important to identify fetuses with abnormal fetal growth that are at increased risk of perinatal morbidity and mortality. Serial measurement of symphysis-fundal height (SFH) is the recommended, inexpensive, and first-level screening tool in both low- and high-risk pregnancies. However, SFH measurements show a wide range of sensitivities for detecting small for gestational age (SGA) owing to the different measurement methods, charts, and thresholds used to perform an ultrasound scan and the use of uncorroborated menstrual dates that can cause errors in dating and can lead to overestimating the length of gestation. A prospective longitudinal observational study, the Fetal Growth Longitudinal Study, one of the main components of the INTERGROWTH-21st Project, was conducted on healthy, well-nourished women to develop international SFH standards to improve antenatal care. Of the 13,108 women screened in the first trimester, 4607 met study criteria, and of these, 4321 (93.8%) delivered live singletons without congenital malformations or complications. The median number of SFH measurements in all women was 5.0 (range, 1–7); 3976 (92.0%) women had 4 or more measurements. Analysis of the duplicate SFH measurements obtained from all women showed that the 95% limits of agreement were approximately 1.5 cm. The international standards developed through this study overcome many of the methodological limitations of SFH measurement by reducing the wide range in sensitivity for the detection of SGA and should reduce the risk of failing to diagnose restricted and excessive fetal growth and help in comparisons across populations. The new international SFH standards in combination with standardized measurement methodology are recommended to improve clinical practice.

Diagnostic accuracy studies are, like other clinical studies, at risk of bias due to shortcomings in design and conduct, and the results of a diagnostic accuracy study may not apply to other patient groups and settings. Readers of study reports need to be informed about study design and conduct, in sufficient detail to judge the trustworthiness and applicability of the study findings. The STARD statement (Standards for Reporting of Diagnostic Accuracy Studies) was developed to improve the completeness and transparency of reports of diagnostic accuracy studies. STARD contains a list of essential items that can be used as a checklist, by authors, reviewers and other readers, to ensure that a report of a diagnostic accuracy study contains the necessary information. STARD was recently updated. All updated STARD materials, including the checklist, are available at http://www.equator-network.org/reporting-guidelines/stard. Here, we present the STARD 2015 explanation and elaboration document. Through commented examples of appropriate reporting, we clarify the rationale for each of the 30 items on the STARD 2015 checklist, and describe what is expected from authors in developing sufficiently informative study reports. Present article is Russian-language translation of the original manuscript edited by Doctor of Medicine R.T. Saygitov.Present translation was first published in Digital Diagnostics. doi: 10.17816/DD71031. It is published with minor changes related to the literary editing of the translation itself.

Background We aimed to describe newborn body composition and identify which anthropometric ratio (weight/length; BMI; or ponderal index, PI) best predicts fat mass (FM) and fat-free mass (FFM). Methods Air-displacement plethysmography (PEA POD) was used to estimate FM, FFM, and body fat percentage (BF%). Associations between FFM, FM, and BF% and weight/length, BMI, and PI were evaluated in 1,019 newborns using multivariate regression analysis. Charts for FM, FFM, and BF% were generated using a prescriptive subsample (n=247). Standards for the best-predicting anthropometric ratio were calculated utilizing the same population used for the INTERGROWTH-21st Newborn Size Standards (n=20,479). Results FFM and FM increased consistently during late pregnancy. Differential FM, BF%, and FFM patterns were observed for those born preterm (34+0−36+6 weeks’ gestation) and with impaired intrauterine growth. Weight/length by gestational age (GA) was a better predictor of FFM and FM (adjusted R2=0.92 and 0.71, respectively) than BMI or PI, independent of sex, GA, and timing of measurement. Results were almost identical when only preterm newborns were studied. We present sex-specific centiles for weight/length ratio for GA. Conclusions Weight/length best predicts newborn FFM and FM. There are differential FM, FFM, and BF% patterns by sex, GA, and size at birth.

Background Core outcome sets (COS) can enhance the relevance of research by ensuring that outcomes of importance to health service users and other people making choices about health care in a particular topic area are measured routinely. Over 200 COS to date have been developed, but the clarity of these reports is suboptimal. COS studies will not achieve their goal if reports of COS are not complete and transparent. Methods and Findings In recognition of these issues, an international group that included experienced COS developers, methodologists, journal editors, potential users of COS (clinical trialists, systematic reviewers, and clinical guideline developers), and patient representatives developed the Core Outcome Set–STAndards for Reporting (COS-STAR) Statement as a reporting guideline for COS studies. The developmental process consisted of an initial reporting item generation stage and a two-round Delphi survey involving nearly 200 participants representing key stakeholder groups, followed by a consensus meeting. The COS-STAR Statement consists of a checklist of 18 items considered essential for transparent and complete reporting in all COS studies. The checklist items focus on the introduction, methods, results, and discussion section of a manuscript describing the development of a particular COS. A limitation of the COS-STAR Statement is that it was developed without representative views of low- and middle-income countries. COS have equal relevance to studies conducted in these areas, and, subsequently, this guideline may need to evolve over time to encompass any additional challenges from developing COS in these areas. Conclusions With many ongoing COS studies underway, the COS-STAR Statement should be a helpful resource to improve the reporting of COS studies for the benefit of all COS users., Paula Williamson and colleagues present reporting standards for studies that report core outcome sets for health research.

Non-randomized studies of the effects of interventions are critical to many areas of health care evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomized Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomization to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomized studies.

Objective: Most healthcare interventions provide modest benefits, but occasionally trials report very large improvements over existing treatments or inactive controls. This often leads to speculation that further trials may be unnecessary. We examined whether a very large effect (VLE, relative risk (RR) of ≤0.2 or ≥5) in a randomised trial could be an empirical marker that subsequent trials are unnecessary. Design: Meta-epidemiological assessment of existing published data on randomised trials Data sources: Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7) with data on subsequent large trials updated to CDSR 2015, issue 12. Eligibility criteria for selecting forest plots:: All binary-outcome forest plots which: (i) contained an index randomised trial with a VLE that was nominally statistically significant (P Results: 3,082 reviews yielded 85,002 forest plots, of which only 44 (0.05%) satisfied the inclusion criteria. Index trials were generally small with a median sample of 99 (median 14 events). Few index trials were rated at low risk of bias (9 of 44; 20%). The relative risk was closer to the null in the subsequent large trials in 43 of 44 cases. Subsequent large trial data failed to find a statistically significant (pConclusions: The frequency of very large effects followed by a large trial is vanishingly small, and where they occur they do not appear to be a reliable marker for a benefit that is reproducible and directly actionable. An empirical rule using a very large effect in an RCT as a marker that further trials are unnecessary would be neither practical nor useful. Caution should be taken when interpreting small studies with very large treatment effects.

Objective To quantify the association between atrial fibrillation and cardiovascular disease, renal disease, and death. Design Systematic review and meta-analysis. Data sources Medline and Embase. Eligibility criteria Cohort studies examining the association between atrial fibrillation and cardiovascular disease, renal disease, and death. Two reviewers independently extracted study characteristics and the relative risk of outcomes associated with atrial fibrillation: specifically, all cause mortality, cardiovascular mortality, major cardiovascular events, any stroke, ischaemic stroke, haemorrhagic stroke, ischaemic heart disease, sudden cardiac death, congestive heart failure, chronic kidney disease, and peripheral arterial disease. Estimates were pooled with inverse variance weighted random effects meta-analysis. Results 104 eligible cohort studies involving 9 686 513 participants (587 867 with atrial fibrillation) were identified. Atrial fibrillation was associated with an increased risk of all cause mortality (relative risk 1.46, 95% confidence interval 1.39 to 1.54), cardiovascular mortality (2.03, 1.79 to 2.30), major cardiovascular events (1.96, 1.53 to 2.51), stroke (2.42, 2.17 to 2.71), ischaemic stroke (2.33, 1.84 to 2.94), ischaemic heart disease (1.61, 1.38 to 1.87), sudden cardiac death (1.88, 1.36 to 2.60), heart failure (4.99, 3.04 to 8.22), chronic kidney disease (1.64, 1.41 to 1.91), and peripheral arterial disease (1.31, 1.19 to 1.45) but not haemorrhagic stroke (2.00, 0.67 to 5.96). Among the outcomes examined, the highest absolute risk increase was for heart failure. Associations between atrial fibrillation and included outcomes were broadly consistent across subgroups and in sensitivity analyses. Conclusions Atrial fibrillation is associated with an increased risk of death and an increased risk of cardiovascular and renal disease. Interventions aimed at reducing outcomes beyond stroke are warranted in patients with atrial fibrillation.

Background and study aims Terminal digit preference bias for “pleasing” numbers has been described in many areas of medicine. The aim of this study was to determine whether endoscopists, radiologists, and pathologists exhibit such bias when measuring colorectal polyp diameters. Methods Colorectal polyp diameters measured at endoscopy, computed tomographic colonography (CTC), and histopathology were collated from a colorectal cancer screening program and two parallel multicenter randomized trials. Smoothing models were fitted to the data to estimate the expected number of polyps at 1-mm increments, assuming no systematic measurement bias. The difference between the expected and observed numbers of polyps was calculated for each terminal digit using statistical modeling. The impact of measurement bias on per-patient detection rates of polyps ≥10 mm was estimated for each modality. Results A total of 92 124 individual polyps were measured by endoscopy (91 670 screening and 454 from trials), 2 385 polyps were measured by CTC (1664 screening, 721 trials), and 79 272 were measured by histopathology (78 783 screening, 489 trials). Clustering of polyp diameter measurements at 5-mm intervals was demonstrated for all modalities, both in the screening program and the trials. The statistical models estimated that per-patient detection rates of polyps ≥10 mm were over-inflated by 2.4% for endoscopy, 3.1% for CTC, and 3.3% for histopathology in the screening program, with similar trends in the randomized trials. Conclusions Endoscopists, radiologists, and pathologists all exhibit terminal digit preference when measuring colorectal polyps. This will bias trial data, referral rates for further testing, adenoma surveillance regimens, and comparisons between tests.

Background Many journals prohibit the use of declarative titles that state study findings, yet a few journals encourage or even require them. We compared the effects of a declarative versus a descriptive title on readers’ perceptions about the strength of evidence in a research abstract describing a randomized trial. Methods Study participants (medical or dental students or doctors attending lectures) read two abstracts describing studies of a fictitious treatment (Anticox) for a fictitious condition (Green’s syndrome). The first abstract (A1) described an uncontrolled, 10-patient, case series, and the second (A2) described a randomized, placebocontrolled trial involving 48 patients. All participants rated identical A1 abstracts (with a descriptive title) to provide baseline ratings and thus reduce the effects of inter-individual variability. Participants were randomized so that half rated a version of A2 with a descriptive title and half with a declarative title. For each abstract, participants indicated their agreement with the statement “Anticox is an effective treatment for pain in Green’s syndrome” using 100 mm visual analogue scales (VAS) ranging from “disagree completely” to “agree completely.” VAS scores were measured by an investigator who was unaware of group allocation. Results One hundred forty-four participants from four centres completed the study. There was no significant difference between the declarative and the descriptive title groups’ confidence in the study conclusions as expressed on VAS scales—in fact, the mean difference between A1 and A2 was smaller for the declarative title group than that for the descriptive title group (32.6 mm, SD 27.4 vs. 39.8 mm, SD 22.6, respectively, p = 0.09). Conclusions We found no evidence that the use of a declarative title affected readers’ perceptions about study conclusions. This suggests that editors’ fears that declarative titles might unduly influence readers’ judgements about study conclusions may be unfounded, at least in relation to reports of randomized trials. However, our study design had several limitations, and our findings may not be generalizable to other situations.

Objective Although crossover trials enjoy wide use, standards for analysis and reporting have not been established. We reviewed methodological aspects and quality of reporting in a representative sample of published crossover trials. Methods We searched MEDLINE for December 2000 and identified all randomized crossover trials. We abstracted data independently, in duplicate, on 14 design criteria, 13 analysis criteria, and 14 criteria assessing the data presentation. Results We identified 526 randomized controlled trials, of which 116 were crossover trials. Trials were drug efficacy (48%), pharmacokinetic (28%), and nonpharmacologic (30%). The median sample size was 15 (interquartile range 8–38). Most (72%) trials used 2 treatments and had 2 periods (64%). Few trials reported allocation concealment (17%) or sequence generation (7%). Only 20% of trials reported a sample size calculation and only 31% of these considered pairing of data in the calculation. Carry-over issues were addressed in 29% of trial's methods. Most trials reported and defended a washout period (70%). Almost all trials (93%) tested for treatment effects using paired data and also presented details on by-group results (95%). Only 29% presented CIs or SE so that data could be entered into a meta-analysis. Conclusion Reports of crossover trials frequently omit important methodological issues in design, analysis, and presentation. Guidelines for the conduct and reporting of crossover trials might improve the conduct and reporting of studies using this important trial design.

The identification and assessment of prognostic markers constitutes one of the major tasks in clinical research. Despite huge research effort, the prognostic value of most traditional factors under discussion is uncertain and the usefulness of many specific markers, prognostic indices, and classification schemes is still unproven. Results from different studies are often contradictory, and a general assessment of the usefulness of a specific marker is very difficult. One reason is that systematic reviews of prognostic marker studies have received rather little attention in the literature. It is obvious that a clinically useful and sensible systematic review of a prognostic marker is only possible if the published studies reflect the true nature of the marker and if sufficient details are given in each report. An important goal of a systematic review is to produce a quantitative summary of an effect of interest by a meta-analysis, a statistical approach that combines the results of individual primary studi...

BACKGROUND: First published in 2001, STRICTA (STandards for Reporting Interventions in Controlled Trials of Acupuncture) was designed to expand on the reporting of one item within the CONSORT (Consolidated Standards of Reporting Trials) Statement checklist, the item relating to the intervention. Two recent reviews had found that STRICTA was highly regarded in the field and that there was a need for minor revisions. OBJECTIVE: To revise STRICTA within the CONSORT family of reporting guidelines. DESIGN: A collaborative effort involving the STRICTA Group, the CONSORT Group and the Chinese Cochrane Centre was agreed. A consultation process with 47 international experts provided detailed feedback on an initial draft of a revised checklist. These data, along with the two review studies, comprised the documentation for a consensus meeting in Freiburg, Germany in October 2008. A total of 21 participants attended the meeting, bringing their expertise as research methodologists, reporting guideline developers, acupuncturists, physicians and journal editors. RESULTS: At the workshop, a revised draft checklist was agreed. There was general consensus that STRICTA should continue to function as a stand-alone guideline as well as an extension to CONSORT. It was agreed that STRICTA should be sufficiently broad to cover all type of clinical studies, from case reports through uncontrolled studies to randomised controlled trials. It was also decided that explanations and examples, as with other CONSORT reporting guidelines, would provide a useful way of supporting the uptake to the new recommendations when published. DISCUSSION: The checklist will be subjected to further revision processes in order to further its impact and support wider dissemination. Journals that regularly publish acupuncture trials will be encouraged to adopt the revised STRICTA, include it in their guidelines for authors, and promote the adoption of its recommendations for clinical studies of acupuncture.