Thomas Fanshawe

Tracking Eye Gaze during Interpretation of Endoluminal Three-dimensional CT Colonography: Visual Perception of Experienced and Inexperienced Readers

PURPOSE To identify and compare key stages of the visual process in experienced and inexperienced readers and to examine how these processes are used to search a moving three-dimensional ( 3D three-dimensional ) image and their relationship to false-negative errors. MATERIALS AND METHODS Institutional review board research ethics approval was granted to use anonymized computed tomographic (CT) colonographic data from previous studies and to obtain eye-tracking data from volunteers. Sixty-five radiologists (27 experienced, 38 inexperienced) interpreted 23 endoluminal 3D three-dimensional CT colonographic videos. Eye movements were recorded by using eye tracking with a desk-mounted tracker. Readers indicated when they saw a polyp by clicking a computer mouse. Polyp location and boundary on each video frame were quantified and gaze data were related to the polyp boundary for each individual reader and case. Predefined metrics were quantified and used to describe and compare visual search patterns between experienced and inexperienced readers by using multilevel modeling. RESULTS Time to first pursuit was significantly shorter in experienced readers (hazard ratio, 1.22 [95% confidence interval: 1.04, 1.44]; P = .017) but other metrics were not significantly different. Regardless of expertise, metrics such as assessment, identification period, and pursuit times were extended in videos where polyps were visible on screen for longer periods of time. In 97% (760 of 787) of observations, readers correctly pursued polyps. CONCLUSION Experienced readers had shorter time to first eye pursuit, but many other characteristics of eye tracking were similar between experienced and inexperienced readers. Readers pursued polyps in 97% of observations, which indicated that errors during interpretation of 3D three-dimensional CT colonography in this study occurred in either the discovery or the recognition phase, but rarely in the scanning phase of radiologic image inspection.

Prediction of violent reoffending on release from prison: derivation and external validation of a scalable tool

BACKGROUND More than 30 million people are released from prison worldwide every year, who include a group at high risk of perpetrating interpersonal violence. Because there is considerable inconsistency and inefficiency in identifying those who would benefit from interventions to reduce this risk, we developed and validated a clinical prediction rule to determine the risk of violent offending in released prisoners. METHODS We did a cohort study of a population of released prisoners in Sweden. Through linkage of population-based registers, we developed predictive models for violent reoffending for the cohort. First, we developed a derivation model to determine the strength of prespecified, routinely obtained criminal history, sociodemographic, and clinical risk factors using multivariable Cox proportional hazard regression, and then tested them in an external validation. We measured discrimination and calibration for prediction of our primary outcome of violent reoffending at 1 and 2 years using cutoffs of 10% for 1-year risk and 20% for 2-year risk. FINDINGS We identified a cohort of 47 326 prisoners released in Sweden between 2001 and 2009, with 11 263 incidents of violent reoffending during this period. We developed a 14-item derivation model to predict violent reoffending and tested it in an external validation (assigning 37 100 individuals to the derivation sample and 10 226 to the validation sample). The model showed good measures of discrimination (Harrells c-index 0·74) and calibration. For risk of violent reoffending at 1 year, sensitivity was 76% (95% CI 73-79) and specificity was 61% (95% CI 60-62). Positive and negative predictive values were 21% (95% CI 19-22) and 95% (95% CI 94-96), respectively. At 2 years, sensitivity was 67% (95% CI 64-69) and specificity was 70% (95% CI 69-72). Positive and negative predictive values were 37% (95% CI 35-39) and 89% (95% CI 88-90), respectively. Of individuals with a predicted risk of violent reoffending of 50% or more, 88% had drug and alcohol use disorders. We used the model to generate a simple, web-based, risk calculator (OxRec) that is free to use. INTERPRETATION We have developed a prediction model in a Swedish prison population that can assist with decision making on release by identifying those who are at low risk of future violent offending, and those at high risk of violent reoffending who might benefit from drug and alcohol treatment. Further assessments in other populations and countries are needed. FUNDING Wellcome Trust, the Swedish Research Council, and the Swedish Research Council for Health, Working Life and Welfare.

Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: a systematic review with statistical and cost-effectiveness modelling

BACKGROUND Various lipid measurements in monitoring/screening programmes can be used, alone or in cardiovascular risk scores, to guide treatment for prevention of cardiovascular disease (CVD). Because some changes in lipids are due to variability rather than true change, the value of lipid-monitoring strategies needs evaluation. OBJECTIVE To determine clinical value and cost-effectiveness of different monitoring intervals and different lipid measures for primary and secondary prevention of CVD. DATA SOURCES We searched databases and clinical trials registers from 2007 (including the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the Clinical Trials Register, the Current Controlled Trials register, and the Cumulative Index to Nursing and Allied Health Literature) to update and extend previous systematic reviews. Patient-level data from the Clinical Practice Research Datalink and St Lukes Hospital, Japan, were used in statistical modelling. Utilities and health-care costs were drawn from the literature. METHODS In two meta-analyses, we used prospective studies to examine associations of lipids with CVD and mortality, and randomised controlled trials to estimate lipid-lowering effects of atorvastatin doses. Patient-level data were used to estimate progression and variability of lipid measurements over time, and hence to model lipid-monitoring strategies. Results are expressed as rates of true-/false-positive and true-/false-negative tests for high lipid or high CVD risk. We estimated incremental costs per quality-adjusted life-year. RESULTS A total of 115 publications reported strength of association between different lipid measures and CVD events in 138 data sets. The summary adjusted hazard ratio per standard deviation of total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio was 1.25 (95% confidence interval 1.15 to 1.35) for CVD in a primary prevention population but heterogeneity was high (I(2) = 98%); similar results were observed for non-HDL cholesterol, apolipoprotein B and other ratio measures. Associations were smaller for other single lipid measures. Across 10 trials, low-dose atorvastatin (10 and 20 mg) effects ranged from a TC reduction of 0.92 mmol/l to 2.07 mmol/l, and low-density lipoprotein reduction of between 0.88 mmol/l and 1.86 mmol/l. Effects of 40 mg and 80 mg were reported by one trial each. For primary prevention, over a 3-year period, we estimate annual monitoring would unnecessarily treat 9 per 1000 more men (28 vs. 19 per 1000) and 5 per 1000 more women (17 vs. 12 per 1000) than monitoring every 3 years. However, annual monitoring would also undertreat 9 per 1000 fewer men (7 vs. 16 per 1000) and 4 per 1000 fewer women (7 vs. 11 per 1000) than monitoring at 3-year intervals. For secondary prevention, over a 3-year period, annual monitoring would increase unnecessary treatment changes by 66 per 1000 men and 31 per 1000 women, and decrease undertreatment by 29 per 1000 men and 28 per 1000 men, compared with monitoring every 3 years. In cost-effectiveness, strategies with increased screening/monitoring dominate. Exploratory analyses found that any unknown harms of statins would need utility decrements as large as 0.08 (men) to 0.11 (women) per statin user to reverse this finding in primary prevention. LIMITATION Heterogeneity in meta-analyses. CONCLUSIONS While acknowledging known and potential unknown harms of statins, we find that more frequent monitoring strategies are cost-effective compared with others. Regular lipid monitoring in those with and without CVD is likely to be beneficial to patients and to the health service. Future research should include trials of the benefits and harms of atorvastatin 40 and 80 mg, large-scale surveillance of statin safety, and investigation of the effect of monitoring on medication adherence. STUDY REGISTRATION This study is registered as PROSPERO CRD42013003727. FUNDING The National Institute for Health Research Health Technology Assessment programme.

The Influence of Maternally Derived Antibody and Infant Age at Vaccination on Infant Vaccine Responses : An Individual Participant Meta-analysis.

Importance The design of infant immunization schedules requires an understanding of the factors that determine the immune response to each vaccine antigen. Data Sources Deidentified individual participant data from GlaxoSmithKline clinical trials were obtained through Clinical Study Data Request. The data were requested on January 2, 2015, and final data were received on April 11, 2016. Study Selection Immunogenicity trials of licensed or unlicensed vaccines administered to infants were included if antibody concentrations in infants were measured prior to the first dose of vaccine. Data Extraction and Synthesis The database was examined; studies that appeared to have appropriate data were reviewed. Main Outcomes and Measures Antigen-specific antibody concentration measured 1 month after priming vaccine doses, before booster vaccination, and 1 month after booster vaccine doses. Results A total of 7630 infants from 32 studies in 17 countries were included. Mean (SD) age at baseline was 9.0 (2.3) weeks; 3906 (51.2%) were boys. Preexisting maternal antibody inhibited infant antibody responses to priming doses for 20 of 21 antigens. The largest effects were observed for inactivated polio vaccine, where 2-fold higher maternal antibody concentrations resulted in 20% to 28% lower postvaccination antibody concentration (geometric mean ratios [GMRs], type 1: 0.80; 95% CI, 0.78-0.83; type 2: 0.72; 95% CI, 0.69-0.74; type 3: 0.78; 95% CI, 0.75-0.82). For acellular pertussis antigens, 2-fold higher maternal antibody was associated with 11% lower postvaccination antibody for pertussis toxoid (GMR, 0.89; 95% CI, 0.87-0.90) and filamentous hemagglutinin (GMR, 0.89; 95% CI, 0.88-0.90) and 22% lower pertactin antibody (GMR, 0.78; 95% CI, 0.77-0.80). For tetanus and diphtheria, these estimates were 13% (GMR, 0.87; 95% CI, 0.86-0.88) and 24% (GMR, 0.76; 95% CI, 0.74-0.77), respectively. The influence of maternal antibody was still evident in reduced responses to booster doses of acellular pertussis, inactivated polio, and diphtheria vaccines at 12 to 24 months of age. Children who were older when first immunized had higher antibody responses to priming doses for 18 of 21 antigens, after adjusting for the effect of maternal antibody concentrations. The largest effect was seen for polyribosylribitol phosphate antibody, where responses were 71% higher per month (GMR, 1.71; 95% CI, 1.52-1.92). Conclusions and Relevance Maternal antibody concentrations and infant age at first vaccination both influence infant vaccine responses. These effects are seen for almost all vaccines contained in global immunization programs and influence immune response for some vaccines even at the age of 24 months. These data highlight the potential for maternal immunization strategies to influence established infant programs.

Multi-Reader Multi-Case Studies Using the Area under the Receiver Operator Characteristic Curve as a Measure of Diagnostic Accuracy: Systematic Review with a Focus on Quality of Data Reporting

Introduction We examined the design, analysis and reporting in multi-reader multi-case (MRMC) research studies using the area under the receiver-operating curve (ROC AUC) as a measure of diagnostic performance. Methods We performed a systematic literature review from 2005 to 2013 inclusive to identify a minimum 50 studies. Articles of diagnostic test accuracy in humans were identified via their citation of key methodological articles dealing with MRMC ROC AUC. Two researchers in consensus then extracted information from primary articles relating to study characteristics and design, methods for reporting study outcomes, model fitting, model assumptions, presentation of results, and interpretation of findings. Results were summarized and presented with a descriptive analysis. Results Sixty-four full papers were retrieved from 475 identified citations and ultimately 49 articles describing 51 studies were reviewed and extracted. Radiological imaging was the index test in all. Most studies focused on lesion detection vs. characterization and used less than 10 readers. Only 6 (12%) studies trained readers in advance to use the confidence scale used to build the ROC curve. Overall, description of confidence scores, the ROC curve and its analysis was often incomplete. For example, 21 (41%) studies presented no ROC curve and only 3 (6%) described the distribution of confidence scores. Of 30 studies presenting curves, only 4 (13%) presented the data points underlying the curve, thereby allowing assessment of extrapolation. The mean change in AUC was 0.05 (−0.05 to 0.28). Non-significant change in AUC was attributed to underpowering rather than the diagnostic test failing to improve diagnostic accuracy. Conclusions Data reporting in MRMC studies using ROC AUC as an outcome measure is frequently incomplete, hampering understanding of methods and the reliability of results and study conclusions. Authors using this analysis should be encouraged to provide a full description of their methods and results.

Identification of low risk of violent crime in severe mental illness with a clinical prediction tool (Oxford Mental Illness and Violence tool [OxMIV]): a derivation and validation study

Summary Background Current approaches to stratify patients with psychiatric disorders into groups on the basis of violence risk are limited by inconsistency, variable accuracy, and unscalability. To address the need for a scalable and valid tool to assess violence risk in patients with schizophrenia spectrum or bipolar disorder, we describe the derivation of a score based on routinely collected factors and present findings from external validation. Methods On the basis of a national cohort of 75 158 Swedish individuals aged 15–65 years with a diagnosis of severe mental illness (schizophrenia spectrum or bipolar disorder) with 574 018 patient episodes between Jan 1, 2001, and Dec 31, 2008, we developed predictive models for violent offending (primary outcome) within 1 year of hospital discharge for inpatients or clinical contact with psychiatric services for outpatients (patient episode) through linkage of population-based registers. We developed a derivation model to determine the relative influence of prespecified criminal history and sociodemographic and clinical risk factors, which are mostly routinely collected, and then tested it in an external validation. We measured discrimination and calibration for prediction of violent offending at 1 year using specified risk cutoffs. Findings Of the cohort of 75 158 patients with schizophrenia spectrum or bipolar disorder, we assigned 58 771 (78%) to the derivation sample and 16 387 (22%) to the validation sample. In the derivation sample, 830 (1%) individuals committed a violent offence within 12 months of their patient episode. We developed a 16-item model. The strongest predictors of violent offending within 12 months were conviction for previous violent crime (adjusted odds ratio 5·03 [95% CI 4·23–5·98]; p<0·0001), male sex (2·32 [1·91–2·81]; p<0·0001), and age (0·63 per 10 years of age [0·58–0·67]; p<0·0001). In external validation, the model showed good measures of discrimination (c-index 0·89 [0·85–0·93]) and calibration. For risk of violent offending at 1 year, with a 5% cutoff, sensitivity was 62% (95% CI 55–68) and specificity was 94% (93–94). The positive predictive value was 11% and the negative predictive value was more than 99%. We used the model to generate a simple web-based risk calculator (Oxford Mental Illness and Violence tool [OxMIV]). Interpretation We have developed a prediction score in a national cohort of patients with schizophrenia spectrum or bipolar disorder, which can be used as an adjunct to decision making in clinical practice by identifying those who are at low risk of violent offending. The low positive predictive value suggests that further clinical assessment in individuals at high risk of violent offending is required to establish who might benefit from additional risk management. Further validation in other countries is needed. Funding Wellcome Trust and Swedish Research Council.

Factors Associated with Sequelae of Campylobacter and Non-typhoidal Salmonella Infections: A Systematic Review

Despite the significant global burden of gastroenteritis and resulting sequelae, there is limited evidence on risk factors for sequelae development. We updated and extended previous systematic reviews by assessing the role of antibiotics, proton pump inhibitors (PPI) and symptom severity in the development of sequelae following campylobacteriosis and salmonellosis. We searched four databases, including PubMed, from 1 January 2011 to 29 April 2016. Observational studies reporting sequelae of reactive arthritis (ReA), Reiters syndrome (RS), irritable bowel syndrome (IBS) and Guillain-Barré syndrome (GBS) following gastroenteritis were included. The primary outcome was incidence of sequelae of interest amongst cases of campylobacteriosis and salmonellosis. A narrative synthesis was conducted where heterogeneity was high. Of the 55 articles included, incidence of ReA (n = 37), RS (n = 5), IBS (n = 12) and GBS (n = 9) were reported following campylobacteriosis and salmonellosis. A pooled summary for each sequela was not estimated due to high level of heterogeneity across studies (I2 > 90%). PPI usage and symptoms were sparsely reported. Three out of seven studies found a statistically significant association between antibiotics usage and development of ReA. Additional primary studies investigating risk modifying factors in sequelae of GI infections are required to enable targeted interventions.

Effects of empathic and positive communication in healthcare consultations: a systematic review and meta-analysis:

Background Practitioners who enhance how they express empathy and create positive expectations of benefit could improve patient outcomes. However, the evidence in this area has not been recently synthesised. Objective To estimate the effects of empathy and expectations interventions for any clinical condition. Design Systematic review and meta-analysis of randomised trials. Data sources Six databases from inception to August 2017. Study selection Randomised trials of empathy or expectations interventions in any clinical setting with patients aged 12 years or older. Review methods Two reviewers independently screened citations, extracted data, assessed risk of bias and graded quality of evidence using GRADE. Random effects model was used for meta-analysis. Results We identified 28 eligible (n = 6017). In seven trials, empathic consultations improved pain, anxiety and satisfaction by a small amount (standardised mean difference −0.18 [95% confidence interval −0.32 to −0.03]). Twenty-two trials tested the effects of positive expectations. Eighteen of these (n = 2014) reported psychological outcomes (mostly pain) and showed a modest benefit (standardised mean difference −0.43 [95% confidence interval −0.65 to −0.21]); 11 (n = 1790) reported physical outcomes (including bronchial function/ length of hospital stay) and showed a small benefit (standardised mean difference −0.18 [95% confidence interval −0.32 to −0.05]). Within 11 trials (n = 2706) assessing harms, there was no evidence of adverse effects (odds ratio 1.04; 95% confidence interval 0.67 to 1.63). The risk of bias was low. The main limitations were difficulties in blinding and high heterogeneity for some comparisons. Conclusions Greater practitioner empathy or communication of positive messages can have small patient benefits for a range of clinical conditions, especially pain. Protocol registration Cochrane Database of Systematic Reviews (protocol) DOI: 10.1002/14651858.CD011934.pub2.

Associations between circadian rhythm instability, appraisal style and mood in bipolar disorder

BACKGROUND Internal appraisal styles, in addition to circadian and social rhythm instability, have been implicated in the development of mood experiences in bipolar disorder (BD), yet potential interactions between these variables remain under researched. METHODS This study used online questionnaires to examine relationships between social and circadian rhythm instability, appraisal style and mood within populations at varying vulnerability for BD. RESULTS Participants with BD (n=51), and those at behavioural high-risk (BHR; n=77), exhibited poor sleep quality and a stronger tendency to form internal appraisals of both positive and negative experiences compared to non-clinical controls (n=498) and participants with fibromyalgia (n=80). Participants with BD also exhibited a stronger tendency to adopt an internal, negative appraisal style compared to individuals at BHR. Sleep disturbance and internal appraisal styles were significantly associated with low mood in BD. LIMITATIONS Sleep quality and social rhythm stability were assessed using self-report measures only, which may differ from objective measures. Causal relationships between constructs could not be examined due to the cross-sectional design. CONCLUSIONS The findings suggest the importance of attending to internal appraisal styles and sleep quality when working therapeutically with individuals diagnosed with BD. Potential differences in the effect of appraisal style at the state and trait level warrant further exploration.

Assessing sex-differences and the effect of timing of vaccination on immunogenicity, reactogenicity and efficacy of vaccines in young children: study protocol for an individual participant data meta-analysis of randomised controlled trials

Introduction Disease incidence differs between males and females for some infectious or inflammatory diseases. Sex-differences in immune responses to some vaccines have also been observed, mostly to viral vaccines in adults. Little evidence is available on whether sex-differences occur in response to immunisation in infancy even though this is the age group in which most vaccines are administered. Factors other than sex, such as timing or coadministration of other vaccines, can also influence the immune response to vaccination. Methods and analysis Individual participant data meta-analysis of randomised controlled trials of vaccines in healthy infants and young children will be conducted. Fully anonymised data from ∼170 randomised controlled trials of vaccines for diphtheria, tetanus, Bordetella pertussis, polio, Haemophilus influenzae type B, hepatitis B, Streptococcus pneumoniae, Neisseria meningitidis, measles, mumps, rubella, varicella and rotavirus will be combined for analysis. Outcomes include measures of immunogenicity (immunoglobulins), reactogenicity, safety and disease-specific clinical efficacy. Data from trials of vaccines containing similar components will be combined in hierarchical models and the effect of sex and timing of vaccinations estimated for each outcome separately. Ethics and dissemination Systematic reviews of published estimates of sex-differences cannot adequately answer questions in this field since such comparisons are never the main purpose of a clinical trial, thus a large degree of reporting bias exists in the published literature. Recent improvements in the widespread availability of individual participant data from randomised controlled trials makes it feasible to conduct extensive individual participant data meta-analyses which were previously impossible, thereby reducing the effect of publication or reporting bias on the understanding of the infant immune response. Preliminary results will be available in 2016 with final results available in 2019. No ethics review is required for secondary analyses of anonymised data.