Publications by authors named "Brian H Willis"

29 Publications

  • Page 1 of 1

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

BMC Gastroenterol 2021 Mar 26;21(1):139. Epub 2021 Mar 26.

Warwick Medical School, University of Warwick, Coventry, UK.

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.
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http://dx.doi.org/10.1186/s12876-021-01716-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004426PMC
March 2021

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

BMJ Open 2021 02 22;11(2):e044177. Epub 2021 Feb 22.

Warwick Medical School, University of Warwick, Coventry, UK.

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.
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http://dx.doi.org/10.1136/bmjopen-2020-044177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903095PMC
February 2021

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

Br J Gen Pract 2021 25;71(704):e219-e225. Epub 2021 Feb 25.

Institute of Applied Health Research, University of Birmingham, Birmingham.

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 (<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 (<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.
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http://dx.doi.org/10.3399/bjgp20X714065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888748PMC
February 2021

Clinical scores in primary care.

Br J Gen Pract 2020 06 28;70(695):279. Epub 2020 May 28.

University of Birmingham, Birmingham.

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http://dx.doi.org/10.3399/bjgp20X709985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241919PMC
June 2020

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

Br J Gen Pract 2020 04 26;70(693):e245-e254. Epub 2020 Mar 26.

Institute of Applied Health Research, University of Birmingham, Birmingham.

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 -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.
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http://dx.doi.org/10.3399/bjgp20X708833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065683PMC
April 2020

Long-term impact of giving antibiotics before skin incision versus after cord clamping on children born by caesarean section: protocol for a longitudinal study based on UK electronic health records.

BMJ Open 2019 09 26;9(9):e033013. Epub 2019 Sep 26.

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

Introduction: In the UK, about a quarter of women give birth by caesarean section (CS) and are offered prophylactic broad-spectrum antibiotics to reduce the risk of maternal postpartum infection. In 2011, national guidance was changed from recommending antibiotics after the umbilical cord was cut to giving antibiotics prior to skin incision based on evidence that earlier administration reduces maternal infectious morbidity. Although antibiotics cross the placenta, there are no known short-term harms to the baby. This study aims to address the research gap on longer term impact of these antibiotics on child health.

Methods And Analysis: A controlled interrupted time series study will use anonymised mother-baby linked routine electronic health records for children born during 2006-2018 recorded in UK primary care (The Health Improvement Network, THIN and Clinical Practice Research Datalink, CPRD) and secondary care (Hospital Episode Statistics, HES) databases. The primary outcomes of interest are asthma and eczema, two common allergy-related diseases in childhood. In-utero exposure to antibiotics immediately prior to CS will be compared with no exposure when given after cord clamping. The risk of outcomes in children delivered by CS will also be compared with a control cohort delivered vaginally to account for time effects. We will use all available data from THIN, CPRD and HES with estimated power of 80% and 90% to detect relative increase in risk of asthma of 16% and 18%, respectively at the 5% significance level.

Ethics And Dissemination: Ethical approval has been obtained from the University of Birmingham Ethical Review Committee with scientific approvals obtained from the independent scientific advisory committees from the Medicines and Healthcare products Regulatory Agency for CPRD and the data provider, IQVIA for THIN. The results will be published in peer-reviewed journals, presented at national and international conferences and disseminated to stakeholders.
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http://dx.doi.org/10.1136/bmjopen-2019-033013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773283PMC
September 2019

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

Stat Methods Med Res 2020 04 11;29(4):1197-1211. Epub 2019 Jun 11.

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

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 from the 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 . Based on its performance characteristics the method of profiling is recommended for fitting the bivariate generalised linear mixed model for meta-analysis.
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http://dx.doi.org/10.1177/0962280219853602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221455PMC
April 2020

Cancer as a risk factor for urinary tract calculi: a retrospective cohort study using 'The Health Improvement Network' : Cancer and urinary tract calculi.

Urolithiasis 2019 Dec 16;47(6):541-547. Epub 2019 Mar 16.

Department of Urology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK.

Purpose: Urolithiasis is a common condition that poses significant morbidity to patients. There are similarities in the development of certain cancers and urinary tract calculi (UTC), however, little is known about their temporal relationship. This study aims to identify if cancer is a risk factor for the development of UTC.

Methods: A population-based retrospective cohort study was conducted for the period 1st January 1990 to 1st May 2016. 124,901 exposed patients identified using clinical codes with newly diagnosed cancer were matched to 476,203 unexposed controls by age, gender, BMI, and general practice. The main outcome measure was the risk of developing UTC described by hazard ratios.

Results: There were 512 incident UTC events in the cancer group compared to 1787 in the unexposed controls. This translated to an adjusted hazard ratio of 1.26 (95% CI 1.14-1.39; p < 0.001). A sub-analysis assessing cancer-specific effects demonstrated increased risks for 10 out of 12 common cancers, most significantly in bladder, colorectal and prostate cancer.

Conclusion: This study demonstrated a 26% increased risk of UTC in cancer patients suggesting wider recognition of this risk amongst clinicians could improve diagnosis and prevention of UTC, as well as encourage further research exploring this association.
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http://dx.doi.org/10.1007/s00240-019-01127-zDOI Listing
December 2019

Faecal calprotectin to detect inflammatory bowel disease: a systematic review and exploratory meta-analysis of test accuracy.

BMJ Open 2019 03 8;9(3):e027428. Epub 2019 Mar 8.

Warwick Medical School, University of Warwick, Coventry, UK.

Objective: Test accuracy of faecal calprotectin (FC) testing in primary care is inconclusive. We aimed to assess the test accuracy of FC testing in primary care and compare it to secondary care estimates for the detection of inflammatory bowel disease (IBD).

Methods: Systematic review and meta-analysis of test accuracy using a bivariate random effects model. We searched MEDLINE, EMBASE, Cochrane Library and Web of Science until 31 May 2017 and included studies from auto alerts up until 31 January 2018. Eligible studies measured FC levels in stool samples to detect IBD in adult patients with chronic (at least 6-8 weeks) abdominal symptoms in primary or secondary care. Risk of bias and applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 criteria. We followed the protocol registered as PROSPERO CRD 42012003287.

Results: 38 out of 2168 studies were eligible including five from primary care. Comparison of test accuracy by setting was precluded by extensive heterogeneity. Overall, summary estimates of sensitivity and specificity were not recorded. At a threshold of 50 µg/g, sensitivity from separate meta-analysis of four assay types ranged from 0.85 (95% CI 0.75 to 0.92) to 0.94 (95% CI 0.75 to 0.90) and specificity from 0.67 (95% CI 0.56 to 0.76) to 0.88 (95% CI 0.77 to 0.94). Across three different definitions of disease, sensitivity ranged from 0.80 (95% CI 0.76 to 0.84) to 0.97 (95% CI 0.91 to 0.99) and specificity from 0.67 (95% CI 0.58 to 0.75) to 0.76 (95% CI 0.66 to 0.84). Sensitivity appears to be lower in primary care and is further reduced at a revised threshold of 100 µg/g.

Conclusions: Conclusive estimates of sensitivity and specificity of FC testing in primary care for the detection of IBD are still missing. There is insufficient evidence in the published literature to support the decision to introduce FC testing in primary care. Studies evaluating FC testing in an appropriate primary care setting are needed.
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http://dx.doi.org/10.1136/bmjopen-2018-027428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429840PMC
March 2019

Tailored meta-analysis: an investigation of the correlation between the test positive rate and prevalence.

J Clin Epidemiol 2019 02 29;106:1-9. Epub 2018 Sep 29.

Institute of Applied Health Research, University of Birmingham, UK; Department of Applied Statistics, Helwan University, Cairo, Egypt.

Background And Objective: Meta-analysis may produce estimates that are unrepresentative of a test's performance in practice. Tailored meta-analysis (TMA) circumvents this by deriving an applicable region for the practice and selecting the studies compatible with the region. It requires the test positive rate, r and prevalence, p being estimated for the setting but previous studies have assumed their independence. The aim is to investigate the effects a correlation between r and p has on estimating the applicable region and how this affects TMA.

Methods: Six methods for estimating 99% confidence intervals (CI) for r and p were investigated: Wilson's ± Bonferroni correction, Clopper-Pearson's ± Bonferroni correction, and Hotelling's T statistic ± continuity correction. These were analyzed in terms of the coverage probability using simulation trials over different correlations, sample sizes, and values for r and p. The methods were then applied to two published meta-analyses with associated practice data, and the effects on the applicable region, studies selected, and summary estimates were evaluated.

Results: Hotelling's T statistic with a continuity correction had the highest median coverage (0.9971). This and the Clopper-Pearson method with a Bonferroni correction both had coverage consistently above 0.99. The coverage of Hotelling's CI's varied the least across different correlations. For both meta-analyses, the number of studies selected was largest when Hotelling's T statistic was used to derive the applicable region. In one instance, this increased the sensitivity by over 4% compared with TMA estimates using other methods.

Conclusion: TMA returns estimates that are tailored to practice providing the applicable region is accurately defined. This is most likely when the CI for r and p are estimated using Hotelling's T statistic with a continuity correction. Potentially, the applicable region may be obtained using routine electronic health data.
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http://dx.doi.org/10.1016/j.jclinepi.2018.09.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355317PMC
February 2019

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

BMC Oral Health 2018 06 8;18(1):105. Epub 2018 Jun 8.

Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

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.
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http://dx.doi.org/10.1186/s12903-018-0561-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993995PMC
June 2018

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

JAMA 2018 01;319(4):388-396

University of Birmingham, Birmingham, England.

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.
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http://dx.doi.org/10.1001/jama.2017.19163DOI Listing
January 2018

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

Stat Med 2017 Sep 15;36(21):3283-3301. Epub 2017 Jun 15.

Research Institute for Primary Care and Health Sciences, Keele University, U.K.

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.
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http://dx.doi.org/10.1002/sim.7372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575530PMC
September 2017

All-Cause Mortality in Patients With Diabetes Under Treatment With Dapagliflozin: A Population-Based, Open-Cohort Study in The Health Improvement Network Database.

J Clin Endocrinol Metab 2017 05;102(5):1719-1725

Institute of Applied Health Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.

Context: Empagliflozin was found to decrease mortality in patients with type 2 diabetes mellitus (T2DM) and a prior cardiovascular disease (CVD) event.

Objectives: To establish whether these benefits can be replicated in a real-world setting, should be expected with the use of dapagliflozin, and apply to T2DM patients at low risk of CVD.

Design: General practice, population-based, retrospective cohort study (January 2013 to September 2015).

Setting: The Health Improvement Network database.

Participants: A total of 22,124 T2DM patients (4444 exposed to dapagliflozin; 17,680 unexposed T2DM patients) matched for age, sex, body mass index, T2DM duration, and smoking.

Main Outcome Measures: The primary outcome was all-cause mortality (high and low risk for CVD) in the total study population, expressed as the adjusted incidence rate ratio (aIRR) with 95% confidence intervals (CIs). As a secondary analysis in the low-risk population, all-cause mortality and incident CVD were considered.

Results: Patients with T2DM exposed to dapagliflozin were significantly less likely to die of any cause (aIRR: 0.50; 95% CI: 0.33 to 0.75; P = 0.001). Similarly, in low-risk patients, death from any cause was significantly lower in the cohort exposed to dapagliflozin (aIRR: 0.44; 95% CI: 0.25 to 0.78; P = 0.002). The difference in the risk of incident CVD did not reach statistical significance between groups in low-risk patients (aIRR: 0.89; 95% CI: 0.61 to 1.31; P = 0.546).

Conclusions: Patients with T2DM who were exposed to dapagliflozin had a lower risk of death from any cause irrespective of baseline CVD status.
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http://dx.doi.org/10.1210/jc.2016-3446DOI Listing
May 2017

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

Diabetologia 2017 02 31;60(2):258-261. Epub 2016 Oct 31.

Institute of Applied Health Research, University of Birmingham, Birmingham, UK.

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.
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http://dx.doi.org/10.1007/s00125-016-4142-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518067PMC
February 2017

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

Stat Med 2015 Jun 20;34(13):2081-103. Epub 2015 Mar 20.

Research Institute of Primary Care and Health Sciences, Keele University, Staffordshire, ST5 5BG, U.K.

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.
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http://dx.doi.org/10.1002/sim.6471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973708PMC
June 2015

What is the test's accuracy in my practice population? Tailored meta-analysis provides a plausible estimate.

J Clin Epidemiol 2015 Aug 3;68(8):847-54. Epub 2014 Dec 3.

Institute of Health Research, University of Exeter Medical School, The Veysey Building, Salmon Pool lane, Exeter, EX2 4SG, UK.

Objectives: Diagnostic test accuracy studies and meta-analyses may, in some cases, provide estimates that are highly improbable in practice; tailored meta-analysis provides a potential solution. To investigate the utility of tailored meta-analysis in synthesizing estimates of a test's accuracy compared with conventional meta-analysis for three case examples.

Study Design And Setting: MEDLINE, Embase, and CINAHL were searched for relevant studies, and routine data were collected on the test positive rate and disease prevalence from the case settings to define an applicable region for each setting. Three cases were evaluated: mammography in the NHS Breast Screening Programme, Patient Health Questionnaire-9 to screen for depression in general practice, and Centor's criteria used to diagnose group A β-hemolytic streptococcus in general practice. For conventional meta-analysis, studies were selected using standard systematic review methods; for tailored meta-analysis, this selection was refined to those with results compatible with the applicable region for the setting.

Results: In each example, studies were excluded as a result of incorporating an applicable region for the setting. Comparing tailored with conventional meta-analysis, the positive likelihood ratios (with 95% confidence intervals in brackets) were 36.5 (23.0, 57.9) and 19.8 (12.8, 30.9), respectively, for mammography and 4.89 (2.02, 11.8) and 2.35 (1.51, 3.67), respectively, for Centor's criteria. This had the effect of increasing the positive predictive value from 17% to 27% for mammography and 23% to 38% for Centor's criteria.

Conclusion: Tailored meta-analysis has the potential to provide a plausible estimate for a test's accuracy, which is specific to the practice setting. When compared with conventional meta-analysis, the difference may, in some cases, be sufficient to lead to different decisions on patient management.
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http://dx.doi.org/10.1016/j.jclinepi.2014.10.002DOI Listing
August 2015

Estimating a test's accuracy using tailored meta-analysis-How setting-specific data may aid study selection.

J Clin Epidemiol 2014 May 18;67(5):538-46. Epub 2014 Jan 18.

Public Health and Epidemiology, University of Exeter, The Veysey Building, Salmon Pool Lane, Exeter, UK.

Objectives: To determine a plausible estimate for a test's performance in a specific setting using a new method for selecting studies.

Study Design And Setting: It is shown how routine data from practice may be used to define an "applicable region" for studies in receiver operating characteristic space. After qualitative appraisal, studies are selected based on the probability that their study accuracy estimates arose from parameters lying in this applicable region. Three methods for calculating these probabilities are developed and used to tailor the selection of studies for meta-analysis. The Pap test applied to the UK National Health Service (NHS) Cervical Screening Programme provides a case example.

Results: The meta-analysis for the Pap test included 68 studies, but at most 17 studies were considered applicable to the NHS. For conventional meta-analysis, the sensitivity and specificity (with 95% confidence intervals) were estimated to be 72.8% (65.8, 78.8) and 75.4% (68.1, 81.5) compared with 50.9% (35.8, 66.0) and 98.0% (95.4, 99.1) from tailored meta-analysis using a binomial method for selection. Thus, for a cervical intraepithelial neoplasia (CIN) 1 prevalence of 2.2%, the post-test probability for CIN 1 would increase from 6.2% to 36.6% between the two methods of meta-analysis.

Conclusion: Tailored meta-analysis provides a method for augmenting study selection based on the study's applicability to a setting. As such, the summary estimate is more likely to be plausible for a setting and could improve diagnostic prediction in practice.
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http://dx.doi.org/10.1016/j.jclinepi.2013.10.016DOI Listing
May 2014

Opt-out organ donation: on evidence and public policy.

J R Soc Med 2014 Feb 24;107(2):56-60. Epub 2013 Oct 24.

School of Health and Population Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

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http://dx.doi.org/10.1177/0141076813507707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914429PMC
February 2014

Philosophy of science and the diagnostic process.

Fam Pract 2013 Oct 1;30(5):501-5. Epub 2013 Jul 1.

Primary Care Clinical Sciences, University of Birmingham, Birmingham, UK.

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.
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http://dx.doi.org/10.1093/fampra/cmt031DOI Listing
October 2013

Empirical evidence that disease prevalence may affect the performance of diagnostic tests with an implicit threshold: a cross-sectional study.

Authors:
Brian H Willis

BMJ Open 2012 3;2(1):e000746. Epub 2012 Feb 3.

Department of Biostatistics, University of Manchester, Manchester, UK.

Objective: To investigate the effects that prevalence has on the diagnostic performance of junior doctors in interpreting x-rays.

Design: Two-armed cross-sectional design using systematic sampling.

Setting: Emergency department in the UK.

Participants: From a sample of 2593 patients (1434 men and 1159 women) taken from an unselected attending cohort between January and April 2002, 967 x-rays were analysed. The sex distribution was 558 men and 409 women, and the mean age of those receiving an x-ray was 34.6.

Interventions: The interpretation of x-rays by junior doctors after their triage into high- and low-prevalence populations by radiographers.

Main Outcome Measures: Sensitivity, specificity, likelihood ratios, diagnostic odds ratios and receiver operator characteristic curve.

Results: There were statistically significant differences in the performance characteristics of junior doctors when interpreting high-probability and low-probability x-rays. For the high- and low-probability populations, respectively, the sensitivities were 95.8% (95% CI 91.1% to 98.1%) and 78.3% (95% CI 65.7% to 87.2%) and the specificities were 56.0% (95% CI 41.9% to 69.2%) and 92.3% (95% CI 90.0% to 94.2%). Hierarchical logistic regression showed that the sensitivity did depend on the type of x-ray being interpreted but the diagnostic odds ratios did not vary significantly with prevalence, suggesting that doctors were changing their implicit threshold between the two populations along a common receiver operator characteristic curve.

Conclusions: This study provides evidence on how the prevalence may affect the performance of diagnostic tests with an implicit threshold and potentially includes the clinical history and examination. This has implications both for clinicians applying research findings to their practice and the design of future studies.
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http://dx.doi.org/10.1136/bmjopen-2011-000746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274715PMC
October 2012

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

BMC Med Res Methodol 2011 Dec 9;11:163. Epub 2011 Dec 9.

Biostatistics, University of Manchester, Manchester, M13 9PL, United Kingdom.

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.
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http://dx.doi.org/10.1186/1471-2288-11-163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258221PMC
December 2011

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

BMC Med Res Methodol 2011 Mar 14;11:27. Epub 2011 Mar 14.

Biostatistics, University of Manchester, Jean McFarlane building, Oxford Road, Manchester M13 9PL, UK.

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.
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http://dx.doi.org/10.1186/1471-2288-11-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065444PMC
March 2011

Spectrum bias--why clinicians need to be cautious when applying diagnostic test studies.

Authors:
Brian H Willis

Fam Pract 2008 Oct 1;25(5):390-6. Epub 2008 Sep 1.

Health Methodology Group, University of Manchester, Manchester, UK.

When applying study results to their practice, the clinician is constrained by a number of factors, perhaps none more important than spectrum bias, which describes the effect a change in patient case mix may have on the performance of a test. Although the literature contains notable examples of spectrum bias, the emphasis has been to demonstrate its existence and its implications on study design rather than how it affects the clinician. Here a definition is proposed before considering it from a GP's perspective. As a patient's probability of disease is in part determined by the test's result, having reliable estimates of a test's performance is imperative to making good decisions on patient management. Knowing how the test performs on a patient usually means knowing its performance within a particular subgroup. Unfortunately, studies tend to report weighted average estimates of performance across broad populations. Such estimates may be inaccurate at an individual level and at a population level with the overall performance of the test in practice varying significantly from the average estimate reported, owing to differing case mixes. To avert such problems, investigators should design studies to evaluate tests over all relevant subgroups, and where this is not possible, to be explicit about the case mix in the study sample. Furthermore, GPs should endeavour to know both individual patients and practice populations as a whole in terms of demographics and co-morbidities before applying study results to their patients.
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http://dx.doi.org/10.1093/fampra/cmn051DOI Listing
October 2008

How good are emergency department Senior House Officers at interpreting X-rays following radiographers' triage?

Eur J Emerg Med 2007 Feb;14(1):6-13

Emergency Department, Horton Hospital, Oxford Radcliffe Hospitals NHS Trust, Oxon, UK.

Objective: To assess the accuracy of Senior House Officers at interpreting plain X-rays following their triage by radiographers in an emergency department.

Method: We collected 2593 patients' records by systematic sampling of all those seen by emergency physicians between January 2002 and April 2002 (ca 10 000 patients) in a UK emergency department. The variables recorded included evidence of X-ray investigations and, when present, the Senior House Officer's diagnosis, the presence (abnormal) or absence of a radiographers red dot and the reference standard diagnosis. A separate category of uncertain (inconclusive) was applied to the Senior House Officer and reference standard diagnosis where appropriate. Diagnostic performance was measured by likelihood ratios with associated pre-test and post-test probabilities.

Results: Including the uncertain category as abnormal gave the following results: there were 967 X-rays and those with a red dot had a probability of an abnormality of 80%. Although a further opinion of abnormal by a Senior House Officer increased this probability to 89% when they overrode the red dot opinion of the radiographer, it was incorrect in 26% of cases.

Conclusion: Currently, the Senior House Officer contributes to the red dot system by improving on the radiographer in rates of diagnosis of both abnormal and normal X-rays. Further reductions in error rates, however, are unlikely to be achieved until there is a change to the existing system. This may ultimately involve removing some of the responsibility of X-ray interpretation from the Senior House Officer. Any future research should consider the methodological issues highlighted by this study.
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http://dx.doi.org/10.1097/01.mej.0000224438.74493.faDOI Listing
February 2007