Measuring and exploring mental health determinants: a closer look at co-residents' effect using a multilevel structural equations model.

OBJECTIVE: Previous research has demonstrated that individual risk of mental illness is associated with individual, co-resident, and household risk factors. However, modelling the overall effect of these risk factors presents several methodological challenges. In this study we apply a multilevel structural equation model (MSEM) to address some of these challenges and the impact of the different determinants when measuring mental health risk. STUDY DESIGN AND SETTING: Two thousand, one hundred forty-three individuals aged 16 and over from 888 households were analysed based on the Household Survey for England-2014 dataset. We applied MSEM to simultaneously measure and identify psychiatric morbidity determinants while accounting for the dependency among individuals within the same household and the measurement errors. RESULTS: Younger age, female gender, non-working status, headship of the household, having no close relationship with other people, having history of mental illness and obesity were all significant (p < 0.01) individual risk factors for psychiatric morbidity. A previous history of mental illness in the co-residents, living in a deprived household, and a lack of closeness in relationships among residents were also significant predictors. Model fit indices showed a very good model specification (CFI = 0.987, TLI = 0.980, RMSEA = 0.023, GFI = 0.992). CONCLUSION: Measuring and addressing mental health determinants should consider not only an individual's characteristics but also the co-residents and the households in which they live.

Comparing outcomes from tailored meta-analysis with outcomes from a setting specific test accuracy study using routine data of faecal calprotectin testing for inflammatory bowel disease.

BACKGROUND: Meta-analyses of test accuracy studies may provide estimates that are highly improbable in clinical practice. Tailored meta-analysis produces plausible estimates for the accuracy of a test within a specific setting by tailoring the selection of included studies compatible with a specific setting using information from the target setting. The aim of this study was to validate the tailored meta-analysis approach by comparing outcomes from tailored meta-analysis with outcomes from a setting specific test accuracy study. METHODS: A retrospective cohort study of primary care electronic health records provided setting-specific data on the test positive rate and disease prevalence. This was used to tailor the study selection from a review of faecal calprotectin testing for inflammatory bowel disease for meta-analysis using the binomial method and the Mahalanobis distance method. Tailored estimates were compared to estimates from a study of test accuracy in primary care using the same routine dataset. RESULTS: Tailoring resulted in the inclusion of 3/14 (binomial method) and 9/14 (Mahalanobis distance method) studies in meta-analysis. Sensitivity and specificity from tailored meta-analysis using the binomial method were 0.87 (95% CI 0.77 to 0.94) and 0.65 (95% CI 0.60 to 0.69) and 0.98 (95% CI 0.83 to 0.999) and 0.68 (95% CI 0.65 to 0.71), respectively using the Mahalanobis distance method. The corresponding estimates for the conventional meta-analysis were 0.94 (95% CI 0.90 to 0.97) and 0.67 (95% CI 0.57 to 0.76) and for the FC test accuracy study of primary care data 0.93 (95%CI 0.89 to 0.96) and 0.61 (95% CI 0.6 to 0.63) to detect IBD at a threshold of 50 µg/g. Although the binomial method produced a plausible estimate, the tailored estimates of sensitivity and specificity were not closer to the primary study estimates than the estimates from conventional meta-analysis including all 14 studies. CONCLUSIONS: Tailored meta-analysis does not always produce estimates of sensitivity and specificity that lie closer to the estimates derived from a primary study in the setting in question. Potentially, tailored meta-analysis may be improved using a constrained model approach and this requires further investigation.

The incidence and prevalence of inflammatory bowel disease in UK primary care: a retrospective cohort study of the IQVIA Medical Research Database.

BACKGROUND: Our knowledge of the incidence and prevalence of inflammatory bowel disease (IBD) is uncertain. Recent studies reported an increase in prevalence. However, they excluded a high proportion of ambiguous cases from general practice. Estimates are needed to inform health care providers who plan the provision of services for IBD patients. We aimed to estimate the IBD incidence and prevalence in UK general practice. METHODS: We undertook a retrospective cohort study of routine electronic health records from the IQVIA Medical Research Database covering 14 million patients. Adult patients from 2006 to 2016 were included. IBD was defined as an IBD related Read code or record of IBD specific medication. Annual incidence and 12-month period prevalence were calculated. RESULTS: The prevalence of IBD increased between 2006 and 2016 from 106.2 (95% CI 105.2-107.3) to 142.1 (95% CI 140.7-143.5) IBD cases per 10,000 patients which is a 33.8% increase. Incidence varied across the years. The incidence across the full study period was 69.5 (95% CI 68.6-70.4) per 100,000 person years. CONCLUSIONS: In this large study we found higher estimates of IBD incidence and prevalence than previously reported. Estimates are highly dependent on definitions of disease and previously may have been underestimated.

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

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

Visual and radiographic caries detection: a tailored meta-analysis for two different settings, Egypt and Germany.

BACKGROUND: Diagnostic meta-analyses on caries detection methods should assist practitioners in their daily practice. However, conventional meta-analysis estimates may be inapplicable due to differences in test conduct, applied thresholds and assessed population between settings. Our aim was to demonstrate the impact of tailored meta-analysis of visual and radiographic caries detection to different settings using setting-specific routine data. METHODS: Published systematic reviews and meta-analyses on the accuracy of visual and radiographic caries detection were used. In two settings (a private practice in Germany and a public health clinic in Egypt), routine data of a total of 100 (n = 50/practice) consecutive 12-14 year-olds were collected. Test-positive rates of visual and radiographic detection for initial and advanced carious lesions on occlusal or proximal surfaces of molars were used to tailor meta-analyses. If prevalence data were available, these were also used for tailoring. RESULTS: From the original reviews, 210 and 100 heterogeneous studies on visual and radiographic caries detection were included in our meta-analyses. For radiographic detection, sensitivity and specificity estimates derived from conventional and tailored meta-analysis were similar. For visual detection of advanced occlusal carious lesions, the conventional meta-analysis yielded a sensitivity and specificity (95% CI) of 64.6% (57-71) and 90.9% (88-93), whereas the tailored estimates for Egypt were 75.1% (70-81) and 84.9% (82-89), respectively, and 43.7% (37-51) and 96.5% (95-97) for Germany, respectively. CONCLUSION: Conventional test accuracy meta-analyses may yield aggregate estimates which are inapplicable to specific settings. Routine data may be used to produce a meta-analysis estimate which is tailored to the setting and thereby improving its applicability.

Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study.

AIMS/HYPOTHESIS: The aim of this research was to explore the relationship between incident epilepsy and type 1 diabetes in British participants. METHODS: Using The Health Improvement Network database, we conducted a retrospective, open-cohort study. Patients who were newly diagnosed with type 1 diabetes mellitus at the age of ≤40 years were identified and followed-up from 1 January 1990 to 15 September 2015. These patients, identified as not suffering from epilepsy at the time of diagnosis, were randomly matched with up to four individuals without type 1 diabetes mellitus, based on age, sex and participating general practice. A Cox regression analysis was subsequently performed using Townsend deprivation index, cerebral palsy, head injury and learning disabilities as model covariates. RESULTS: The study population consisted of a total of 24,610 individuals (4922 with type 1 diabetes and 19,688 controls). These individuals were followed up for a mean of 5.4 years (approximately 132,000 person-years of follow up). Patients with type 1 diabetes were significantly more likely to be diagnosed with epilepsy during the observation period compared with controls (crude HR [95% CI]: 3.02 [1.95, 4.69]). The incidence rate was estimated to be 132 and 44 per 100,000 person-years in patients and controls, respectively. This finding persisted after adjusting for model covariates (adjusted HR [95% CI]: 3.01 [1.93, 4.68]) and was also robust to sensitivity analysis, excluding adult-onset type 1 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Patients with type 1 diabetes are at approximately three-times greater risk of developing epilepsy compared with matched controls without type 1 diabetes. This should be considered when investigating seizure-related disorders in patients with type 1 diabetes mellitus.

Measuring the statistical validity of summary meta-analysis and meta-regression results for use in clinical practice.

An important question for clinicians appraising a meta-analysis is: are the findings likely to be valid in their own practice-does the reported effect accurately represent the effect that would occur in their own clinical population? To this end we advance the concept of statistical validity-where the parameter being estimated equals the corresponding parameter for a new independent study. Using a simple ('leave-one-out') cross-validation technique, we demonstrate how we may test meta-analysis estimates for statistical validity using a new validation statistic, Vn, and derive its distribution. We compare this with the usual approach of investigating heterogeneity in meta-analyses and demonstrate the link between statistical validity and homogeneity. Using a simulation study, the properties of Vn and the Q statistic are compared for univariate random effects meta-analysis and a tailored meta-regression model, where information from the setting (included as model covariates) is used to calibrate the summary estimate to the setting of application. Their properties are found to be similar when there are 50 studies or more, but for fewer studies Vn has greater power but a higher type 1 error rate than Q. The power and type 1 error rate of Vn are also shown to depend on the within-study variance, between-study variance, study sample size, and the number of studies in the meta-analysis. Finally, we apply Vn to two published meta-analyses and conclude that it usefully augments standard methods when deciding upon the likely validity of summary meta-analysis estimates in clinical practice. © 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

Summarising and validating test accuracy results across multiple studies for use in clinical practice.

Following a meta-analysis of test accuracy studies, the translation of summary results into clinical practice is potentially problematic. The sensitivity, specificity and positive (PPV) and negative (NPV) predictive values of a test may differ substantially from the average meta-analysis findings, because of heterogeneity. Clinicians thus need more guidance: given the meta-analysis, is a test likely to be useful in new populations, and if so, how should test results inform the probability of existing disease (for a diagnostic test) or future adverse outcome (for a prognostic test)? We propose ways to address this. Firstly, following a meta-analysis, we suggest deriving prediction intervals and probability statements about the potential accuracy of a test in a new population. Secondly, we suggest strategies on how clinicians should derive post-test probabilities (PPV and NPV) in a new population based on existing meta-analysis results and propose a cross-validation approach for examining and comparing their calibration performance. Application is made to two clinical examples. In the first example, the joint probability that both sensitivity and specificity will be >80% in a new population is just 0.19, because of a low sensitivity. However, the summary PPV of 0.97 is high and calibrates well in new populations, with a probability of 0.78 that the true PPV will be at least 0.95. In the second example, post-test probabilities calibrate better when tailored to the prevalence in the new population, with cross-validation revealing a probability of 0.97 that the observed NPV will be within 10% of the predicted NPV.

Philosophy of science and the diagnostic process.

This is an overview of the principles that underpin philosophy of science and how they may provide a framework for the diagnostic process. Although philosophy dates back to antiquity, it is only more recently that philosophers have begun to enunciate the scientific method. Since Aristotle formulated deduction, other modes of reasoning including induction, inference to best explanation, falsificationism, theory-laden observations and Bayesian inference have emerged. Thus, rather than representing a single overriding dogma, the scientific method is a toolkit of ideas and principles of reasoning. Here we demonstrate that the diagnostic process is an example of science in action and is therefore subject to the principles encompassed by the scientific method. Although a number of the different forms of reasoning are used readily by clinicians in practice, without a clear understanding of their pitfalls and the assumptions on which they are based, it leaves doctors open to diagnostic error. We conclude by providing a case example from the medico-legal literature in which diagnostic errors were made, to illustrate how applying the scientific method may mitigate the chance for diagnostic error.

Clustering functional data using forward search based on functional spatial ranks with medical applications.

Cluster analysis of functional data is finding increasing application in the field of medical research and statistics. Here we introduce a functional version of the forward search methodology for the purpose of functional data clustering. The proposed forward search algorithm is based on the functional spatial ranks and is a data-driven non-parametric method. It does not require any preprocessing functional data steps, nor does it require any dimension reduction before clustering. The Forward Search Based on Functional Spatial Rank (FSFSR) algorithm identifies the number of clusters in the curves and provides the basis for the accurate assignment of each curve to its cluster. We apply it to three simulated datasets and two real medical datasets, and compare it with six other standard methods. Based on both simulated and real data, the FSFSR algorithm identifies the correct number of clusters. Furthermore, when compared with six standard methods used for clustering and classification, it records the lowest misclassification rate. We conclude that the FSFSR algorithm has the potential to cluster and classify functional data.

Risk of developing gallbladder cancer in patients with gallbladder polyps detected on transabdominal ultrasound: a systematic review and meta-analysis.

OBJECTIVE: To estimate the risk of malignancy in gallbladder polyps of incremental sizes detected during transabdominal ultrasound (TAUS). METHODS: We searched databases including MEDLINE, Embase, and Cochrane Library for eligible studies recording the polyp size from which gallbladder malignancy developed, confirmed following cholecystectomy, or by subsequent follow-up. Primary outcome was the risk of gallbladder cancer in patients with polyps. Secondary outcome was the effect of polyp size as a prognostic factor for cancer. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Bayesian meta-analysis estimated the median cancer risk according to polyp size. This study is registered with PROSPERO (CRD42020223629). RESULTS: 82 studies published since 1990 reported primary data for 67,837 patients. 67,774 gallbladder polyps and 889 cancers were reported. The cumulative median cancer risk of a polyp measuring 10 mm or less was 0.60% (99% credible range 0.30-1.16%). Substantial heterogeneity existed between studies (I2 = 99.95%, 95% credible interval 99.86-99.98%). Risk of bias was generally high and overall confidence in evidence was low. 13 studies (15.6%) were graded with very low certainty, 56 studies (68.3%) with low certainty, and 13 studies (15.6%) with moderate certainty. In studies considered moderate quality, TAUS monitoring detected 4.6 cancers per 10,000 patients with polyps less than 10 mm. CONCLUSION: Malignant risk in gallbladder polyps is low, particularly in polyps less than 10 mm, however the data are heterogenous and generally low quality. International guidelines, which have not previously modelled size data, should be informed by these findings. ADVANCES IN KNOWLEDGE: This large systematic review and meta-analysis has shown that the mean cumulative risk of small gallbladder polyps is low, but heterogeneity and missing data in larger polyp sizes (>10 mm) means the risk is uncertain and may be higher than estimated.Studies considered to have better methodological quality suggest that previous estimates of risk are likely to be inflated.

Long-term impact of pre-incision antibiotics on children born by caesarean section: a longitudinal study based on UK electronic health records.

BACKGROUND: Since changes in the national guidance in 2011, prophylactic antibiotics for women undergoing caesarean section are recommended prior to skin incision, rather than after the baby's umbilical cord has been clamped. Evidence from randomised controlled trials conducted outside the UK has shown that this reduces maternal infectious morbidity; however, the prophylactic antibiotics also cross the placenta, meaning that babies are exposed to them around the time of birth. Antibiotics are known to affect the gut microbiota of the babies, but the long-term effects of exposure to high-dose broad-spectrum antibiotics around the time of birth on allergy and immune-related diseases are unknown. OBJECTIVES: We aimed to examine whether or not in-utero exposure to antibiotics immediately prior to birth compared with no pre-incisional antibiotic exposure increases the risk of (1) asthma and (2) eczema in children born by caesarean section. DESIGN: This was a controlled interrupted time series study. SETTING: The study took place in primary and secondary care. PARTICIPANTS: Children born in the UK during 2006-18 delivered by caesarean section were compared with a control cohort delivered vaginally. INTERVENTIONS: In-utero exposure to antibiotics immediately prior to birth. MAIN OUTCOME MEASURES: Asthma and eczema in children in the first 5 years of life. Additional secondary outcomes, including other allergy-related conditions, autoimmune diseases, infections, other immune system-related diseases and neurodevelopmental conditions, were also assessed. DATA SOURCES: The Health Improvement Network (THIN) and the Clinical Practice Research Datalink (CPRD) primary care databases and the Hospital Episode Statistics (HES) database. Previously published linkage strategies were adapted to link anonymised data on mothers and babies in these databases. Duplicate practices contributing to both THIN and the CPRD databases were removed to create a THIN-CPRD data set. RESULTS: In the THIN-CPRD and HES data sets, records of 515,945 and 3,945,351 mother-baby pairs were analysed, respectively. The risk of asthma was not significantly higher in children born by caesarean section exposed to pre-incision antibiotics than in children whose mothers received post-cord clamping antibiotics, with an incidence rate ratio of 0.91 (95% confidence interval 0.78 to 1.05) for diagnosis of asthma in primary care and an incidence rate ratio of 1.05 (95% confidence interval 0.99 to 1.11) for asthma resulting in a hospital admission. We also did not find an increased risk of eczema, with an incidence rate ratio of 0.98 (95% confidence interval 0.94 to1.03) and an incidence rate ratio of 0.96 (95% confidence interval 0.71 to 1.29) for diagnosis in primary care and hospital admissions, respectively. LIMITATIONS: It was not possible to ascertain the exposure to pre-incision antibiotics at an individual level. The maximum follow-up of children was 5 years. CONCLUSIONS: There was no evidence that the policy change from post-cord clamping to pre-incision prophylactic antibiotics for caesarean sections during 2006-18 had an impact on the incidence of asthma and eczema in early childhood in the UK. FUTURE WORK: There is a need for further research to investigate if pre-incision antibiotics have any impact on developing asthma and other allergy and immune-related conditions in older children. STUDY REGISTRATION: This study is registered as researchregistry3736. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 30. See the NIHR Journals Library website for further project information.

WHAT WAS THE QUESTION?: Women giving birth by caesarean section are at risk of developing infections (such as wound infections) and are offered antibiotics at the time of their operation to reduce this risk. In 2011, the national guidelines changed from recommending antibiotics after cord clamping to giving them before the operation to further reduce the risk of maternal infection. During birth, the newborn gut is colonised by microbes. Antibiotics given to the mother before caesarean section can reach the baby through the placenta and disrupt the normal microbes that colonise the gut. These microbes are believed to play a role in the development of the immune system and altering the normal development of these microbes has been linked to children developing allergic conditions, such as asthma and eczema. This study investigated whether or not giving antibiotics before the caesarean section had a longer-term impact on children's health. WHAT DID WE DO?: We used routine NHS information already collected by hospitals and general practitioners about women who gave birth in the UK between 2006 and 2018, and their children. We compared the risk of asthma, eczema and other health conditions in the first 5 years after birth in children born by caesarean section before and after the change in hospital policies. We also compared their health with children born vaginally. WHAT DID WE FIND?: We found that there was no increased risk of asthma or eczema for children born by caesarean section after the policy decision in 2011 to give the mother antibiotics before the operation. WHAT DOES THIS MEAN?: The study findings provide further evidence for the current recommendation to give preventative antibiotics to women shortly before the caesarean section to reduce the overall risk of infections after birth.

Long term impact of prophylactic antibiotic use before incision versus after cord clamping on children born by caesarean section: longitudinal study of UK electronic health records.

OBJECTIVE: To investigate the impact on child health up to age 5 years of a policy to use antibiotic prophylaxis for caesarean section before incision compared with after cord clamping. DESIGN: Observational controlled interrupted time series study. SETTING: UK primary and secondary care. PARTICIPANTS: 515 945 children born in 2006-18 with linked maternal records and registered with general practices contributing to two UK primary care databases (The Health Improvement Network and Clinical Practice Research Datalink), and 7 147 884 children with linked maternal records in the Hospital Episode Statistics database covering England, of which 3 945 351 were linked to hospitals that reported the year of policy change to administer prophylactic antibiotics for caesarean section before incision rather than after cord clamping. INTERVENTION: Fetal exposure to antibiotics shortly before birth (using pre-incision antibiotic policy as proxy) compared with no exposure. MAIN OUTCOME MEASURES: The primary outcomes were incidence rate ratios of asthma and eczema in children born by caesarean section when pre-incision prophylactic antibiotics were recommended compared with those born when antibiotics were administered post-cord clamping, adjusted for temporal changes in the incidence rates in children born vaginally. RESULTS: Prophylactic antibiotics administered before incision for caesarean section compared with after cord clamping were not associated with a significantly higher risk of asthma (incidence rate ratio 0.91, 95% confidence interval 0.78 to 1.05) or eczema (0.98, 0.94 to 1.03), including asthma and eczema resulting in hospital admission (1.05, 0.99 to 1.11 and 0.96, 0.71 to 1.29, respectively), up to age 5 years. CONCLUSIONS: This study found no evidence of an association between pre-incision prophylactic antibiotic use and risk of asthma and eczema in early childhood in children born by caesarean section.

Uptake of newer methodological developments and the deployment of meta-analysis in diagnostic test research: a systematic review.

BACKGROUND: The last decade has seen a number of methodological developments in meta-analysis of diagnostic test studies. However, it is unclear whether such developments have permeated the wider research community and on which applications they are being deployed. The objective was to assess the uptake and deployment of the main methodological developments in the meta-analysis of diagnostic tests, and identify the tests and target disorders most commonly evaluated by meta-analysis. METHODS: Design--systematic review. Data Sources--Medline, EMBASE, CINAHL, Cochrane, PsychInfo, Global health, HMIC, and AMED were searched for studies published before 31st December 2008. Selection criteria--studies were included if they satisfied all of the following: evaluated a diagnostic test; measured test performance; searched two or more databases; stated search terms and inclusion criteria; used a statistical method to summarise performance. Data extraction--included the following data items: year; test; reference standard; target disorder; setting; statistical and quality methods. RESULTS: 236 studies were included. Over the last 5 years the number of meta-analyses published has increased, but the uptake of new statistical methods lags behind. Pooling the sensitivity and specificity and using the SROC remain the preferred methods for analysis in 70% of studies, with the bivariate random effects and HSROC model being used in only 22% and 5% of studies respectively. In contrast, between 2006 and 2008 the QUADAS tool was used in 40% of studies. Broadly, radiological imaging was the most frequent category of tests analysed (36%), with cancer (22%) and infection (21%) being the most common categories of target disorder. Nearly 80% of tests analysed were those normally used in specialist settings. CONCLUSION: Although quality assessment in meta-analyses has improved with the introduction of QUADAS, uptake of the newer statistical methods is still lagging behind. Furthermore, the focus of secondary research seems to be in evaluating specialist tests in specialist settings, in contrast to the more routine tests and settings encountered in the majority of clinical practice.

The assessment of the quality of reporting of meta-analyses in diagnostic research: a systematic review.

BACKGROUND: Over the last decade there have been a number of guidelines published, aimed at improving the quality of reporting in published studies and reviews. In systematic reviews this may be measured by their compliance with the PRISMA statement. This review aims to evaluate the quality of reporting in published meta-analyses of diagnostic tests, using the PRISMA statement and establish whether there has been a measurable improvement over time. METHODS: Eight databases were searched for reviews published prior to 31(st) December 2008. Studies were selected if they evaluated a diagnostic test, measured performance, searched two or more databases, stated the search terms and inclusion criteria, and used a statistical method to summarise a test's performance. Data were extracted on the review characteristics and items of the PRISMA statement. To measure the change in the quality of reporting over time, PRISMA items for two periods of equal duration were compared. RESULTS: Compliance with the PRISMA statement was generally poor: none of the reviews completely adhered to all 27 checklist items. Of the 236 meta-analyses included following selection: only 2(1%) reported the study protocol; 59(25%) reported the searches used; 76(32%) reported the results of a risk of bias assessment; and 82(35%) reported the abstract as a structured summary. Only 11 studies were published before 2000. Thus, the impact of QUOROM on the quality of reporting was not evaluated. However, the periods 2001-2004 and 2005-2008 (covering 93% of studies) were compared using relative risks (RR). There was an increase in the proportion of reviews reporting on five PRISMA items: eligibility criteria (RR 1.13, 95% CI 1.00 - 1.27); risk of bias across studies (methods) (RR 1.81, 95% CI 1.34 - 2.44); study selection results (RR 1.48, 95% CI 1.05 - 2.09); results of individual studies (RR 1.37, 95% CI 1.09 - 1.72); risk of bias across studies (results) (RR 1.65, 95% CI 1.20 - 2.25). CONCLUSION: Although there has been an improvement in the quality of meta-analyses in diagnostic research, there are still many deficiencies in the reporting which future reviewers need to address if readers are to trust the validity of the reported findings.

Factors predicting statin prescribing for primary prevention: a historical cohort study.

BACKGROUND: Initiation of statins for the primary prevention of cardiovascular disease (CVD) should be based on CVD risk estimates, but their use is suboptimal. AIM: To investigate the factors influencing statin prescribing when clinicians code and do not code estimated CVD risk (QRISK2). DESIGN AND SETTING: A historical cohort of patients who had lipid tests in a database (IQVIA Medical Research Data) of UK primary care records. METHOD: The cohort comprised 686 560 entries (lipid test results) between 2012 and 2016 from 383 416 statin-naive patients without previous CVD. Coded QRISK2 scores were extracted, with variables used in calculating QRISK2 and factors that might influence statin prescribing. If a QRISK2 score was not coded, it was calculated post hoc. The outcome was initiation of a statin within 60 days of the lipid test result. RESULTS: Of the entries, 146 693 (21.4%) had a coded QRISK2 score. Statins were initiated in 6.6% (95% confidence interval [CI] = 6.4% to 6.7%) of those with coded and 4.1% (95% CI = 4.0% to 4.1%) of uncoded QRISK2 (P<0.001). Statin initiations were consistent with National Institute for Health and Care Excellence guideline recommendations in 85.0% (95% CI = 84.2% to 85.8%) of coded and 44.2% (95% CI = 43.5% to 44.9%) of uncoded QRISK2 groups (P<0.001). When coded, QRISK2 score was the main predictor of statin initiation, but total cholesterol was the main predictor when a QRISK2 score was not coded. CONCLUSION: When a QRISK2 score is coded, prescribing is more consistent with guidelines. With no QRISK2 score, prescribing is mainly based on total cholesterol. Using QRISK2 is associated with statin prescribing that is more likely to benefit patients. Promoting the routine CVD risk estimation is essential to optimise decision making.

Faecal calprotectin testing in UK general practice: a retrospective cohort study using The Health Improvement Network database.

BACKGROUND: Faecal calprotectin (FC) testing to detect inflammatory bowel disease (IBD) was recommended for use in UK general practice in 2013. The actual use of FC testing following the national recommendations is unknown. AIM: To characterise the use of FC testing for IBD in UK general practice. DESIGN AND SETTING: A retrospective cohort study of routine electronic patient records from The Health Improvement Network database from UK general practice. METHOD: The study included 6 965 853 adult patients (aged ≥18 years), between 2006 and 2016. FC test uptake, the patients tested, and patient management following testing were characterised. RESULTS: A total of 17 027 patients had 19 840 FC tests recorded. The mean age of tested patients was 44.2 years. The first FC tests were documented in 2009. FC test use was still increasing in 2016. By 2016, 66.8% (n = 493/738) of practices had started FC testing. About one-fifth (20.7%, n = 1253/6051) of tests were carried out in patients aged ≥60 years. Only 7.8% (n = 473/6051) of the FC test records were preceded by symptoms eligible for FC testing. Only 3.1% (n = 1720/55 477) of patients with eligible symptoms have received FC testing since the national recommendations were published. There was only a small number of patients with symptoms, FC test, and a IBD diagnosis. In total, 71.3% (n = 1416/1987) of patients with a positive and 47.7% (n = 1337/2805) with a negative FC test were referred or further investigated. CONCLUSION: Uptake of FC testing in clinical practice has been slow and inconsistent. The indication of non-compliance with national recommendations may suggest that these recommendations lack applicability to the general practice context.

Test accuracy of faecal calprotectin for inflammatory bowel disease in UK primary care: a retrospective cohort study of the IMRD-UK data.

OBJECTIVE: To estimate the test accuracy of faecal calprotectin (FC) for inflammatory bowel disease (IBD) in the primary care setting using routine electronic health records. DESIGN: Retrospective cohort test accuracy study. SETTING: UK primary care. PARTICIPANTS: 5970 patients (≥18 years) without a previous IBD diagnosis and with a first FC test between 1 January 2006 and 31 December 2016. We excluded multiple tests and tests without numeric results in units of µg/g. INTERVENTION: FC testing for the diagnosis of IBD. Disease status was confirmed by a recorded diagnostic code and/or a drug code of an IBD-specific medication at three time points after the FC test date. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values for the differential of IBD versus non-IBD and IBD versus irritable bowel syndrome (IBS) at the 50 and 100 µg/g thresholds. RESULTS: 5970 patients met the inclusion criteria and had at least 6 months of follow-up data after FC testing. 1897 had an IBS diagnosis, 208 had an IBD diagnosis, 31 had a colorectal cancer diagnosis, 80 had more than one diagnosis and 3754 had no subsequent diagnosis. Sensitivity, specificity, and positive and negative predictive values were 92.9% (88.6% to 95.6%), 61.5% (60.2% to 62.7%), 8.1% (7.1% to 9.2%) and 99.6% (99.3% to 99.7%), respectively, at the threshold of 50 µg/g. Raising the threshold to 100 µg/g missed less than 7% additional IBD cases. Longer follow-up had no effect on test accuracy. Overall, uncertainty was greater for specificity than sensitivity. General practitioners' (GPs') referral decisions did not follow the anticipated clinical pathways in national guidance. CONCLUSIONS: GPs can be confident in excluding IBD on the basis of a negative FC test in a population with low pretest risk but should interpret a positive test with caution. The applicability of national guidance to general practice needs to be improved.

Comparison of Centor and McIsaac scores in primary care: a meta-analysis over multiple thresholds.

BACKGROUND: Centor and McIsaac scores are both used to diagnose group A beta-haemolytic streptococcus (GABHS) infection, but have not been compared through meta-analysis. AIM: To compare the performance of Centor and McIsaac scores at diagnosing patients with GABHS presenting to primary care with pharyngitis. DESIGN AND SETTING: A meta-analysis of diagnostic test accuracy studies conducted in primary care was performed using a novel model that incorporates data at multiple thresholds. METHOD: MEDLINE, EMBASE, and PsycINFO were searched for studies published between January 1980 and February 2019. Included studies were: cross-sectional; recruited patients with sore throats from primary care; used the Centor or McIsaac score; had GABHS infection as the target diagnosis; used throat swab culture as the reference standard; and reported 2 × 2 tables across multiple thresholds. Selection and data extraction were conducted by two independent reviewers. QUADAS-2 was used to assess study quality. Summary receiver operating characteristic (SROC) curves were synthesised. Calibration curves were used to assess the transferability of results into practice. RESULTS: Ten studies using the Centor score and eight using the McIsaac score were included. The prevalence of GABHS ranged between 4% and 44%. The areas under the SROC curves for McIsaac and Centor scores were 0.7052 and 0.6888, respectively. The P-value for the difference (0.0164) was 0.419, suggesting the SROC curves for the tests are equivalent. Both scores demonstrated poor calibration. CONCLUSION: Both Centor and McIsaac scores provide only fair discrimination of those with and without GABHS, and appear broadly equivalent in performance. The poor calibration for a positive test result suggests other point-of-care tests are required to rule in GABHS; however, with both Centor and McIsaac scores, a score of ≤0 may be sufficient to rule out infection.

Maximum likelihood estimation based on Newton-Raphson iteration for the bivariate random effects model in test accuracy meta-analysis.

A bivariate generalised linear mixed model is often used for meta-analysis of test accuracy studies. The model is complex and requires five parameters to be estimated. As there is no closed form for the likelihood function for the model, maximum likelihood estimates for the parameters have to be obtained numerically. Although generic functions have emerged which may estimate the parameters in these models, they remain opaque to many. From first principles we demonstrate how the maximum likelihood estimates for the parameters may be obtained using two methods based on Newton-Raphson iteration. The first uses the profile likelihood and the second uses the Observed Fisher Information. As convergence may depend on the proximity of the initial estimates to the global maximum, each algorithm includes a method for obtaining robust initial estimates. A simulation study was used to evaluate the algorithms and compare their performance with the generic generalised linear mixed model function glmer from the lme4 package in R before applying them to two meta-analyses from the literature. In general, the two algorithms had higher convergence rates and coverage probabilities than glmer. Based on its performance characteristics the method of profiling is recommended for fitting the bivariate generalised linear mixed model for meta-analysis.