Publications by authors named "Christopher Cheyne"

16 Publications

  • Page 1 of 1

Performance of the Innova SARS-CoV-2 antigen rapid lateral flow test in the Liverpool asymptomatic testing pilot: population based cohort study.

BMJ 2021 07 6;374:n1637. Epub 2021 Jul 6.

Institute of Population Health Sciences, University of Liverpool, Liverpool, UK.

Objective: To assess the performance of the SARS-CoV-2 antigen rapid lateral flow test (LFT) versus polymerase chain reaction testing in the asymptomatic general population attending testing centres.

Design: Observational cohort study.

Setting: Community LFT pilot at covid-19 testing sites in Liverpool, UK.

Participants: 5869 asymptomatic adults (≥18 years) voluntarily attending one of 48 testing sites during 6-29 November 2020.

Interventions: Participants were tested using both an Innova LFT and a quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) test based on supervised self-administered swabbing at testing sites.

Main Outcome Measures: Sensitivity, specificity, and predictive values of LFT compared with RT-qPCR in an epidemic steady state of covid-19 among adults with no classic symptoms of the disease.

Results: Of 5869 test results, 22 (0.4%) LFT results and 343 (5.8%) RT-qPCR results were void (that is, when the control line fails to appear within 30 minutes). Excluding the void results, the LFT versus RT-qPCR showed a sensitivity of 40.0% (95% confidence interval 28.5% to 52.4%; 28/70), specificity of 99.9% (99.8% to 99.99%; 5431/5434), positive predictive value of 90.3% (74.2% to 98.0%; 28/31), and negative predictive value of 99.2% (99.0% to 99.4%; 5431/5473). When the void samples were assumed to be negative, a sensitivity was observed for LFT of 37.8% (26.8% to 49.9%; 28/74), specificity of 99.6% (99.4% to 99.8%; 5431/5452), positive predictive value of 84.8% (68.1% to 94.9%; 28/33), and negative predictive value of 93.4% (92.7% to 94.0%; 5431/5814). The sensitivity in participants with an RT-qPCR cycle threshold (Ct) of <18.3 (approximate viral loads >10 RNA copies/mL) was 90.9% (58.7% to 99.8%; 10/11), a Ct of <24.4 (>10 RNA copies/mL) was 69.4% (51.9% to 83.7%; 25/36), and a Ct of >24.4 (<10 RNA copies/mL) was 9.7% (1.9% to 23.7%; 3/34). LFT is likely to detect at least three fifths and at most 998 in every 1000 people with a positive RT-qPCR test result with high viral load.

Conclusions: The Innova LFT can be useful for identifying infections among adults who report no symptoms of covid-19, particularly those with high viral load who are more likely to infect others. The number of asymptomatic adults with lower Ct (indicating higher viral load) missed by LFT, although small, should be considered when using single LFT in high consequence settings. Clear and accurate communication with the public about how to interpret test results is important, given the chance of missing some cases, even at high viral loads. Further research is needed to understand how infectiousness is reflected in the viral antigen shedding detected by LFT versus the viral loads approximated by RT-qPCR.
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http://dx.doi.org/10.1136/bmj.n1637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259455PMC
July 2021

Evaluating social and spatial inequalities of large scale rapid lateral flow SARS-CoV-2 antigen testing in COVID-19 management: An observational study of Liverpool, UK (November 2020 to January 2021).

Lancet Reg Health Eur 2021 Jul 12;6:100107. Epub 2021 May 12.

Chair in Public Health and Clinical Informatics, Department of Public Health and Policy, University of Liverpool, Liverpool, UK.

Background: Large-scale asymptomatic testing of communities in Liverpool (UK) for SARS-CoV-2 was used as a public health tool for containing COVID-19. The aim of the study is to explore social and spatial inequalities in uptake and case-detection of rapid lateral flow SARS-CoV-2 antigen tests (LFTs) offered to people without symptoms of COVID-19.

Methods: Linked pseudonymised records for asymptomatic residents in Liverpool who received a LFT for COVID-19 between 6th November 2020 to 31st January 2021 were accessed using the Combined Intelligence for Population Health Action resource. Bayesian Hierarchical Poisson Besag, York, and Mollié models were used to estimate ecological associations for uptake and positivity of testing.

Findings: 214 525 residents (43%) received a LFT identifying 5192 individuals as positive cases of COVID-19 (1.3% of tests were positive). Uptake was highest in November when there was military assistance. High uptake was observed again in the week preceding Christmas and was sustained into a national lockdown. Overall uptake were lower among males (e.g. 40% uptake over the whole period), Black Asian and other Minority Ethnic groups (e.g. 27% uptake for 'Mixed' ethnicity) and in the most deprived areas (e.g. 32% uptake in most deprived areas). These population groups were also more likely to have received positive tests for COVID-19. Models demonstrated that uptake and repeat testing were lower in areas of higher deprivation, areas located further from test sites and areas containing populations less confident in the using Internet technologies. Positive tests were spatially clustered in deprived areas.

Interpretation: Large-scale voluntary asymptomatic community testing saw social, ethnic, digital and spatial inequalities in uptake. COVID-19 testing and support to isolate need to be more accessible to the vulnerable communities most impacted by the pandemic, including non-digital means of access.

Funding: Department of Health and Social Care (UK) and Economic and Social Research Council.
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http://dx.doi.org/10.1016/j.lanepe.2021.100107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114854PMC
July 2021

Changes in in-hospital mortality in the first wave of COVID-19: a multicentre prospective observational cohort study using the WHO Clinical Characterisation Protocol UK.

Lancet Respir Med 2021 07 14;9(7):773-785. Epub 2021 May 14.

Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK; Department of Respiratory Medicine, Alder Hey Children's Hospital, Liverpool, UK.

Background: Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.

Methods: In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.

Findings: Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8-32·7) in March 9 to April 26, 2020, to 16·4% (15·0-17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65-0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94-0·95) of the reduction in in-hospital mortality.

Interpretation: The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.

Funding: National Institute for Health Research and the Medical Research Council.
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http://dx.doi.org/10.1016/S2213-2600(21)00175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121531PMC
July 2021

Metformin, A Potential Role in Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

Ophthalmol Ther 2021 Jun 12;10(2):245-260. Epub 2021 Apr 12.

Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, L7 8TX, UK.

Background: Currently, no generally approved medical treatment can delay the onset of age-related macular degeneration (AMD) or slow the progression of degenerative changes. Repurposing drugs with beneficial effects on AMD pathophysiology offers a route to new treatments which is faster, cost-effective, and safer for patients. Recent studies indicate a potential role for metformin in delaying AMD development and progression. In this context, we conducted a systematic review and meta-analysis to look for beneficial associations between metformin and AMD.

Methods: We systematically searched Medline and Embase (via Ovid), Web of Science, and ClinicalTrials.gov databases for clinical studies in humans that examined the associations between metformin treatment and AMD published from inception to February 2021. We calculated pooled odds ratio (OR) with 95% confidence interval (CI) considering a random effect model in the meta-analysis.

Results: Five retrospective studies met the inclusion criteria. There are no prospective studies that have reported the effect of metformin in AMD. The meta-analysis showed that people taking metformin were less likely to have AMD although statistical significance was not met (pooled adjusted OR = 0.80, 95% CI 0.54-1.05, I = 98.8%). Subgroup analysis of the association between metformin and early and late AMD could not be performed since the data was not available from the included studies.

Conclusions: Analysis of retrospective data suggests a signal that metformin may be associated with decreased risk of any AMD. It should be interpreted with caution because of the failure to meet statistical significance, the small number of studies, and the limitation of routine record data. However prospective studies are warranted in generalizable populations without diabetes, of varied ethnicities, and AMD stages. Clinical trials are needed to determine if metformin has efficacy in treating early and late-stage AMD.
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http://dx.doi.org/10.1007/s40123-021-00344-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079568PMC
June 2021

Incidence of sight-threatening diabetic retinopathy in an established urban screening programme: An 11-year cohort study.

Diabet Med 2021 Sep 9;38(9):e14583. Epub 2021 Jun 9.

Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool, UK.

Aims: Systematic annual screening to detect sight-threatening diabetic retinopathy (STDR) is established in the United Kingdom. We designed an observational cohort study to provide up-to-date data for policy makers and clinical researchers on incidence of key screening endpoints in people with diabetes attending one screening programme running for over 30 years.

Methods: All people with diabetes aged ≥12 years registered with general practices in the Liverpool health district were offered inclusion. Data sources comprised: primary care (demographics, systemic risk factors), Liverpool Diabetes Eye Screening Programme (retinopathy grading), Hospital Eye Services (slit lamp biomicroscopy assessment of screen positives).

Results: 133,366 screening episodes occurred in 28,384 people over 11 years. Overall incidences were: screen positive 6.7% (95% CI 6.5-6.8), screen positive for retinopathy 3.1% (3.0-3.1), unassessable images 2.6% (2.5-2.7), other significant eye diseases 1.0% (1.0-1.1). 1.6% (1.6-1.7) had sight-threatening retinopathy confirmed by slit lamp biomicroscopy. The annual incidence of screen positive and screen positive for retinopathy showed consistent declines from 8.8%-10.6% and 4.4%-4.6% in 2007/09 to 4.4%-6.8% and 2.3%-2.9% in 2013/17, respectively. Rates of STDR (true positive) were consistently below 2% after 2008/09. Screen positive rates were higher in first time attenders (9.9% [9.4-10.2] vs. 6.1% [6.0-6.2]) in part due to ungradeable images (4.1% vs. 2.3%) and other eye disease (2.4% vs. 0.8%). 4.5% (3.9-5.2) of previous non-attenders had sight-threatening retinopathy. Compared with people with type 2 diabetes, those with type 1 disease demonstrated higher rates of screen positive (11.9% vs. 6.0%) and STDR (6.4% vs. 1.2%). Overall prevalence of any retinopathy was 27.2% (27.0-27.4).

Conclusions: In an established screening programme with a stable population screen, positive rates show a consistent fall over time to a low level. Of those who are screen positive, fewer than 50% are screen positive for diabetic retinopathy. Most are due to sight threatening maculopathy. The annual incidence of STDR is under 2% suggesting future work on redefining screen positive and supporting extended intervals for people at low risk. Higher rates of screen positive and STDR are seen in first time attenders. Those who have never attended for screening should be specifically targeted.
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http://dx.doi.org/10.1111/dme.14583DOI Listing
September 2021

Safety and cost-effectiveness of individualised screening for diabetic retinopathy: the ISDR open-label, equivalence RCT.

Diabetologia 2021 01 4;64(1):56-69. Epub 2020 Nov 4.

Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners, Liverpool, UK.

Aims/hypothesis: Using variable diabetic retinopathy screening intervals, informed by personal risk levels, offers improved engagement of people with diabetes and reallocation of resources to high-risk groups, while addressing the increasing prevalence of diabetes. However, safety data on extending screening intervals are minimal. The aim of this study was to evaluate the safety and cost-effectiveness of individualised, variable-interval, risk-based population screening compared with usual care, with wide-ranging input from individuals with diabetes.

Methods: This was a two-arm, parallel-assignment, equivalence RCT (minimum 2 year follow-up) in individuals with diabetes aged 12 years or older registered with a single English screening programme. Participants were randomly allocated 1:1 at baseline to individualised screening at 6, 12 or 24 months for those at high, medium and low risk, respectively, as determined at each screening episode by a risk-calculation engine using local demographic, screening and clinical data, or to annual screening (control group). Screening staff and investigators were observer-masked to allocation and interval. Data were collected within the screening programme. The primary outcome was attendance (safety). A secondary safety outcome was the development of sight-threatening diabetic retinopathy. Cost-effectiveness was evaluated within a 2 year time horizon from National Health Service and societal perspectives.

Results: A total of 4534 participants were randomised. After withdrawals, there were 2097 participants in the individualised screening arm and 2224 in the control arm. Attendance rates at first follow-up were equivalent between the two arms (individualised screening 83.6%; control arm 84.7%; difference -1.0 [95% CI -3.2, 1.2]), while sight-threatening diabetic retinopathy detection rates were non-inferior in the individualised screening arm (individualised screening 1.4%, control arm 1.7%; difference -0.3 [95% CI -1.1, 0.5]). Sensitivity analyses confirmed these findings. No important adverse events were observed. Mean differences in complete case quality-adjusted life-years (EuroQol Five-Dimension Questionnaire, Health Utilities Index Mark 3) did not significantly differ from zero; multiple imputation supported the dominance of individualised screening. Incremental cost savings per person with individualised screening were £17.34 (95% CI 17.02, 17.67) from the National Health Service perspective and £23.11 (95% CI 22.73, 23.53) from the societal perspective, representing a 21% reduction in overall programme costs. Overall, 43.2% fewer screening appointments were required in the individualised arm.

Conclusions/interpretation: Stakeholders involved in diabetes care can be reassured by this study, which is the largest ophthalmic RCT in diabetic retinopathy screening to date, that extended and individualised, variable-interval, risk-based screening is feasible and can be safely and cost-effectively introduced in established systematic programmes. Because of the 2 year time horizon of the trial and the long time frame of the disease, robust monitoring of attendance and retinopathy rates should be included in any future implementation.

Trial Registration: ISRCTN 87561257 FUNDING: The study was funded by the UK National Institute for Health Research. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05313-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716929PMC
January 2021

Individualised screening for diabetic retinopathy: the ISDR study-rationale, design and methodology for a randomised controlled trial comparing annual and individualised risk-based variable-interval screening.

BMJ Open 2019 06 17;9(6):e025788. Epub 2019 Jun 17.

Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Introduction: Currently, all people with diabetes (PWD) aged 12 years and over in the UK are invited for screening for diabetic retinopathy (DR) annually. Resources are not increasing despite a 5% increase in the numbers of PWD nationwide each year. We describe the rationale, design and methodology for a randomised controlled trial (RCT) evaluating the safety, acceptability and cost-effectiveness of personalised variable-interval risk-based screening for DR. This is the first randomised trial of personalised screening for DR and the largest ophthalmic RCT in the UK.

Methods And Analysis: PWD attending seven screening clinics in the Liverpool Diabetic Eye Screening Programme were recruited into a single site RCT with a 1:1 allocation to individualised risk-based variable-interval or annual screening intervals. A risk calculation engine developed for the trial estimates the probability that an individual will develop referable disease (screen positive DR) within the next 6, 12 or 24 months using demographic, retinopathy and systemic risk factor data from primary care and screening programme records. Dynamic, secure, real-time data connections have been developed. The primary outcome is attendance for follow-up screening. We will test for equivalence in attendance rates between the two arms. Secondary outcomes are rates and severity of DR, visual outcomes, cost-effectiveness and health-related quality of life. The required sample size was 4460 PWD. Recruitment is complete, and the trial is in follow-up.

Ethics And Dissemination: Ethical approval was obtained from National Research Ethics Service Committee North West - Preston, reference 14/NW/0034. Results will be presented at international meetings and published in peer-reviewed journals. This pragmatic RCT will inform screening policy in the UK and elsewhere.

Trial Registration Number: ISRCTN87561257; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2018-025788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588999PMC
June 2019

High incidence and prevalence of visual problems after acute stroke: An epidemiology study with implications for service delivery.

PLoS One 2019 6;14(3):e0213035. Epub 2019 Mar 6.

Vision and Stroke Patient and Public Group (VISable), University of Liverpool, Liverpool, United Kingdom.

Background: Visual problems are an under-reported sequela following stroke. The aim of this study is to report annual incidence and point prevalence of visual problems in an acute adult stroke population and to explore feasibility of early timing of visual assessment.

Methods And Findings: Multi-centre acute stroke unit, prospective, epidemiology study (1st July 2014 to 30th June 2015). Orthoptists reviewed all patients with assessment of visual acuity, visual fields, ocular alignment, ocular motility, visual inattention and visual perception. 1033 patients underwent visual screening at a median of 3 days (IQR 2) and full visual assessment at a median of 4 days (IQR 7) after the incident stroke: 52% men, 48% women, mean age 73 years and 87% ischaemic strokes. Excluding pre-existent eye problems, the incidence of new onset visual sequelae was 48% for all stroke admissions and 60% in stroke survivors. Three quarters 752/1033 (73%) had visual problems (point prevalence): 56% with impaired central vision, 40% eye movement abnormalities, 28% visual field loss, 27% visual inattention, 5% visual perceptual disorders. 281/1033 (27%) had normal eye exams.

Conclusions: Incidence and point prevalence of visual problems in acute stroke is alarmingly high, affecting over half the survivors. For most, visual screening and full visual assessment was achieved within about 5 days of stroke onset. Crucial information can thus be provided on visual status and its functional significance to the stroke team, patients and carers, enabling early intervention.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402759PMC
December 2019

Personalized risk-based screening for diabetic retinopathy: A multivariate approach versus the use of stratification rules.

Diabetes Obes Metab 2019 03 30;21(3):560-568. Epub 2018 Oct 30.

Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.

Aims: To evaluate our proposed multivariate approach to identify patients who will develop sight-threatening diabetic retinopathy (STDR) within a 1-year screen interval, and explore the impact of simple stratification rules on prediction.

Materials And Methods: A 7-year dataset (2009-2016) from people with diabetes (PWD) was analysed using a novel multivariate longitudinal discriminant approach. Level of diabetic retinopathy, assessed from routine digital screening photographs of both eyes, was jointly modelled using clinical data collected over time. Simple stratification rules based on retinopathy level were also applied and compared with the multivariate discriminant approach.

Results: Data from 13 103 PWD (49 520 screening episodes) were analysed. The multivariate approach accurately predicted whether patients developed STDR or not within 1 year from the time of prediction in 84.0% of patients (95% confidence interval [CI] 80.4-89.7), compared with 56.7% (95% CI 55.5-58.0) and 79.7% (95% CI 78.8-80.6) achieved by the two stratification rules. While the stratification rules detected up to 95.2% (95% CI 92.2-97.6) of the STDR cases (sensitivity) only 55.6% (95% CI 54.5-56.7) of patients who did not develop STDR were correctly identified (specificity), compared with 85.4% (95% CI 80.4-89.7%) and 84.0% (95% CI 80.7-87.6%), respectively, achieved by the multivariate risk model.

Conclusions: Accurate prediction of progression to STDR in PWD can be achieved using a multivariate risk model whilst also maintaining desirable specificity. While simple stratification rules can achieve good levels of sensitivity, the present study indicates that their lower specificity (high false-positive rate) would therefore necessitate a greater frequency of eye examinations.
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http://dx.doi.org/10.1111/dom.13552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492102PMC
March 2019

Individualised variable-interval risk-based screening for sight-threatening diabetic retinopathy: the Liverpool Risk Calculation Engine.

Diabetologia 2017 Nov 24;60(11):2174-2182. Epub 2017 Aug 24.

Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, William Henry Duncan Building, 6, West Derby Street, Liverpool, L7 8TX, UK.

Aims/hypothesis: Individualised variable-interval risk-based screening offers better targeting and improved cost-effectiveness in screening for diabetic retinopathy. We developed a generalisable risk calculation engine (RCE) to assign personalised intervals linked to local population characteristics, and explored differences in assignment compared with current practice.

Methods: Data from 5 years of photographic screening and primary care for people with diabetes, screen negative at the first of > 1 episode, were combined in a purpose-built near-real-time warehouse. Covariates were selected from a dataset created using mixed qualitative/quantitative methods. Markov modelling predicted progression to screen-positive (referable diabetic retinopathy) against the local cohort history. Retinopathy grade informed baseline risk and multiple imputation dealt with missing data. Acceptable intervals (6, 12, 24 months) and risk threshold (2.5%) were established with patients and professional end users.

Results: Data were from 11,806 people with diabetes (46,525 episodes, 388 screen-positive). Covariates with sufficient predictive value were: duration of known disease, HbA, age, systolic BP and total cholesterol. Corrected AUC (95% CIs) were: 6 months 0.88 (0.83, 0.93), 12 months 0.90 (0.87, 0.93) and 24 months 0.91 (0.87, 0.94). Sensitivities/specificities for a 2.5% risk were: 6 months 0.61, 0.93, 12 months 0.67, 0.90 and 24 months 0.82, 0.81. Implementing individualised RCE-based intervals would reduce the proportion of people becoming screen-positive before the allocated screening date by > 50% and the number of episodes by 30%.

Conclusions/interpretation: The Liverpool RCE shows sufficient performance for a local introduction into practice before wider implementation, subject to external validation. This approach offers potential enhancements of screening in improved local applicability, targeting and cost-effectiveness.
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http://dx.doi.org/10.1007/s00125-017-4386-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448900PMC
November 2017

Cognition in school-age children exposed to levetiracetam, topiramate, or sodium valproate.

Neurology 2016 Nov 31;87(18):1943-1953. Epub 2016 Aug 31.

From the Institute of Human Development (R.L.B. J.C.-S.), Department of Clinical Psychology (P.T.), and Centre for Women's Mental Health (R.S.), University of Manchester; Royal Manchester Children's Hospital (R.L.B.), Manchester; Department of Clinical Psychology (R.C.), University of Lancaster; Departments of Biostatistics (C.P.C., M.G.-F.) and Molecular and Clinical Pharmacology (G.A.B.), University of Liverpool; Neuropsychology Trauma Pathway (C.R.), Merseycare NHS Trust, Liverpool; Manchester Centre for Genomic Medicine (J.C.-S.), St Mary's Hospital, Manchester; and Department of Neurology (B.I., J.I.M.), Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK.

Objective: To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning.

Methods: This was a cross-sectional observational study. Children exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses.

Results: In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (-10.6, 95% confidence interval [CI] -16.3 to -5.0, p < 0.001), verbal abilities (-11.2, 95% CI -16.8 to -5.5, p < 0.001), nonverbal abilities (-11.1, 95% CI -17.3 to -4.9, p < 0.001), and expressive language ability (-2.3, 95% CI -3.4 to -1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate.

Conclusions: Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.
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http://dx.doi.org/10.1212/WNL.0000000000003157DOI Listing
November 2016

Detection of Visual Field Loss in Pituitary Disease: Peripheral Kinetic Versus Central Static.

Neuroophthalmology 2015 Jun 13;39(3):116-124. Epub 2015 May 13.

Department of Orthoptics, Salford Royal NHS Foundation Trust Manchester UK.

Visual field assessment is an important clinical evaluation for eye disease and neurological injury. We evaluated Octopus semi-automated kinetic peripheral perimetry (SKP) and Humphrey static automated central perimetry for detection of neurological visual field loss in patients with pituitary disease. We carried out a prospective cross-sectional diagnostic accuracy study comparing Humphrey central 30-2 SITA threshold programme with a screening protocol for SKP on Octopus perimetry. Humphrey 24-2 data were extracted from 30-2 results. Results were independently graded for presence/absence of field defect plus severity of defect. Fifty patients (100 eyes) were recruited (25 males and 25 females), with mean age of 52.4 years (SD = 15.7). Order of perimeter assessment (Humphrey/Octopus first) and order of eye tested (right/left first) were randomised. The 30-2 programme detected visual field loss in 85%, the 24-2 programme in 80%, and the Octopus combined kinetic/static strategy in 100% of eyes. Peripheral visual field loss was missed by central threshold assessment. Qualitative comparison of type of visual field defect demonstrated a match between Humphrey and Octopus results in 58%, with a match for severity of defect in 50%. Tests duration was 9.34 minutes (SD = 2.02) for Humphrey 30-2 versus 10.79 minutes (SD = 4.06) for Octopus perimetry. Octopus semi-automated kinetic perimetry was found to be superior to central static testing for detection of pituitary disease-related visual field loss. Where reliant on Humphrey central static perimetry, the 30-2 programme is recommended over the 24-2 programme. Where kinetic perimetry is available, this is preferable to central static programmes for increased detection of peripheral visual field loss.
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http://dx.doi.org/10.3109/01658107.2014.990985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123138PMC
June 2015

Health state utility values for diabetic retinopathy: protocol for a systematic review and meta-analysis.

Syst Rev 2015 Feb 21;4:15. Epub 2015 Feb 21.

Division of Rehabilitation and Ageing, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.

Background: People with diabetic retinopathy tend to have lower levels of health-related quality of life than individuals with no retinopathy. Strategies for screening and treatment have been shown to be cost-effective. In order to reduce the bias in cost-effectiveness estimates, systematic reviews of health state utility values (HSUVs) are crucial for health technology assessment and the development of decision analytic models. A review and synthesis of HSUVs for the different stages of disease progression in diabetic retinopathy has not previously been conducted.

Methods/design: We will conduct a systematic review of the available literature that reports HSUVs for people with diabetic retinopathy, in correspondence with current stage of disease progression and/or visual acuity. We will search Medline, EMBASE, Web of Science, Cost-Effectiveness Analysis Registry, Centre for Reviews and Dissemination Database, and EconLit to identify relevant English-language articles. Data will subsequently be synthesized using linear mixed effects modeling meta-regression. Additionally, reported disease severity classifications will be mapped to a four-level grading scale for diabetic retinopathy.

Discussion: The systematic review and meta-analysis will provide important evidence for future model-based economic evaluations of technologies for diabetic retinopathy. The meta-regression will enable the estimation of utility values at different disease stages for patients with particular characteristics and will also highlight where the design of the study and HSUV instrument have influenced the reported utility values. We believe this protocol to be the first of its kind to be published.

Systematic Review Registration: PROSPERO CRD42014012891.
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http://dx.doi.org/10.1186/s13643-015-0006-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342097PMC
February 2015

IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.

Neurology 2015 Jan 24;84(4):382-90. Epub 2014 Dec 24.

From the Departments of Molecular and Clinical Pharmacology (G.A.B.), Biostatistics (C.P.C., M.G.-F.), and Clinical Psychology (R.S.), Institute of Infection and Global Health (M.J.C., A.G.), and Alder Hey Children's Hospital & Institute of Infection & Global Health (R.K.), University of Liverpool; Institute of Human Development (R.L.B., J.C.-S.), University of Manchester; Manchester Academic Health Sciences Centre (R.L.B., M.B., G.M., J.C.-S.), Central Manchester University Hospitals Foundation Trust, UK; Department of Neurology (M.J.C.), Georgia Regents University, Augusta; Department of Neurology & Pediatrics (D.W.L.), Emory University, Atlanta, GA; and Department of Neurology & Neurological Sciences (K.J.M.), Stanford University, CA.

Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs.

Methods: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models.

Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85.

Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.
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http://dx.doi.org/10.1212/WNL.0000000000001182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336006PMC
January 2015

The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs.

J Neurol Neurosurg Psychiatry 2013 Jun 31;84(6):637-43. Epub 2013 Jan 31.

Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until 6 years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (VPA) (6/50, 12.0%; aOR 6.05, 95%CI 1.65 to 24.53, p=0.007) and in those exposed to polytherapy with sodium VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005) compared with control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium VPA exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium VPA is a treatment option.
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http://dx.doi.org/10.1136/jnnp-2012-304270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115188PMC
June 2013

The effect of handedness on academic ability: a multivariate linear mixed model approach.

Laterality 2010 Jul 17;15(4):451-64. Epub 2009 Jun 17.

University of Liverpool, UK.

In recent years questions have arisen about whether there are any links between handedness and academic abilities as well as other factors. In this study we investigate the effects of gender, writing hand, relative hand skill, and UK region on mathematics and reading test scores by applying a multivariate linear mixed-effects model. A data sample based on 11,847 11-year-old pupils across the UK from the National Child Development Study was considered for the analysis. Our results show that pupils who write with one hand while having better skill with their other hand (i.e., inconsistent writing hand and superior hand) obtained lower test scores in both reading and mathematics than pupils with consistent writing hand and superior hand. Furthermore, we confirm previous findings that degree of relative hand skill has a significant effect on both reading and maths scores and that this association is not linear. We also found higher scores of reading in children from the south of England, and of mathematics in children from the south of England and Scotland, when compared to other UK regions.
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http://dx.doi.org/10.1080/13576500902976956DOI Listing
July 2010
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