Imperial College London

Professor Toby Prevost

Faculty of MedicineSchool of Public Health

Visiting Professor
 
 
 
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a.prevost

 
 
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57Stadium HouseWhite City Campus

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Summary

 

Publications

Publication Type
Year
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229 results found

Antcliffe D, Mi Y, Santhakumaran S, Burnham K, Prevost AT, Ward J, Marshall T, Bradley C, Al-Beidh F, Hutton P, McKechnie S, Davenport E, Hinds C, O'Kane C, McAuley D, Shankar-Hari M, Gordon A, Knight Jet al., 2024, Patient stratification using plasma cytokines and their regulators in sepsis: relationship to outcomes, treatment effect and leukocyte transcriptomic sub-phenotypes, Thorax, ISSN: 0040-6376

Journal article

Cope AP, Jasenecova M, Vasconcelos JC, Filer A, Raza K, Qureshi S, D'Agostino MA, McInnes IB, Isaacs JD, Pratt AG, Fisher BA, Buckley CD, Emery P, Ho P, Buch MH, Ciurtin C, van Schaardenburg D, Huizinga T, Toes R, Georgiou E, Kelly J, Murphy C, Prevost AT, APIPPRA study investigatorset al., 2024, Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial., Lancet, Vol: 403, Pages: 838-849

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for

Journal article

Gurudas S, Vasconcelos JC, Prevost AT, Raman R, Rajalakshmi R, Ramasamy K, Mohan V, Rani PK, Das T, Conroy D, Tapp RJ, Sivaprasad S, SMART-India Study Collaboratorset al., 2024, National prevalence of vision impairment and blindness and associated risk factors in adults aged 40 years and older with known or undiagnosed diabetes: results from the SMART-India cross-sectional study., Lancet Glob Health

BACKGROUND: National estimates of the prevalence of vision impairment and blindness in people with diabetes are required to inform resource allocation. People with diabetes are more susceptible to conditions such as diabetic retinopathy that can impair vision; however, these are often missed in national studies. This study aims to determine the prevalence and risk factors of vision impairment and blindness in people with diabetes in India. METHODS: Data from the SMART-India study, a cross-sectional survey with national coverage of 42 147 Indian adults aged 40 years and older, collected using a complex sampling design, were used to obtain nationally representative estimates for the prevalence of vision impairment and blindness in people with diabetes in India. Vulnerable adults (primarily those who did not have capacity to provide consent); pregnant and breastfeeding women; anyone deemed too ill to be screened; those who did not provide consent; and people with type 1 diabetes, gestational diabetes, or secondary diabetes were excluded from the study. Vision impairment was defined as presenting visual acuity of 0·4 logMAR or higher and blindness as presenting a visual acuity of 1·0 logMAR or higher in the better-seeing eye. Demographic, anthropometric, and laboratory data along with geographic distribution were analysed in all participants with available data. Non-mydriatic retinal images were used to grade diabetic retinopathy, and risk factors were also assessed. FINDINGS: A total of 7910 people with diabetes were included in the analysis, of whom 5689 had known diabetes and 2221 were undiagnosed. 4387 (55·5%) of 7909 participants with available sex data were female and 3522 (44·5%) participants were male. The estimated national prevalence of vision impairment was 21·1% (95% CI 15·7-27·7) and blindness 2·4% (1·7-3·4). A higher prevalence of any vision impairment (29·2% vs 19·6

Journal article

Surr C, Marsden L, Griffiths A, Cox S, Fossey J, Martin A, Prevost AT, Walshe C, Walwyn Ret al., 2024, Researchers' experiences of the design and conduct challenges associated with parallel-group cluster-randomised trials and views on a novel open-cohort design., PLoS One, Vol: 19

BACKGROUND: Two accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An 'open-cohort' design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs. AIM: To document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs,b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs,c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs. METHODS: Qualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding. RESULTS: Two central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings. CONCLUSIONS: Open-cohort CRT designs hold promis

Journal article

Rockall AG, Li X, Johnson N, Lavdas I, Santhakumaran S, Prevost AT, Punwani S, Goh V, Barwick TD, Bharwani N, Sandhu A, Sidhu H, Plumb A, Burn J, Fagan A, Wengert GJ, Koh D-M, Reczko K, Dou Q, Warwick J, Liu X, Messiou C, Tunariu N, Boavida P, Soneji N, Johnston EW, Kelly-Morland C, De Paepe KN, Sokhi H, Wallitt K, Lakhani A, Russell J, Salib M, Vinnicombe S, Haq A, Aboagye EO, Taylor S, Glocker Bet al., 2023, Development and evaluation of machine learning in whole-body magnetic resonance imaging for detecting metastases in patients with lung or colon cancer: a diagnostic test accuracy study, Investigative Radiology, Vol: 58, Pages: 823-831, ISSN: 0020-9996

OBJECTIVES: Whole-body magnetic resonance imaging (WB-MRI) has been demonstrated to be efficient and cost-effective for cancer staging. The study aim was to develop a machine learning (ML) algorithm to improve radiologists' sensitivity and specificity for metastasis detection and reduce reading times. MATERIALS AND METHODS: A retrospective analysis of 438 prospectively collected WB-MRI scans from multicenter Streamline studies (February 2013-September 2016) was undertaken. Disease sites were manually labeled using Streamline reference standard. Whole-body MRI scans were randomly allocated to training and testing sets. A model for malignant lesion detection was developed based on convolutional neural networks and a 2-stage training strategy. The final algorithm generated lesion probability heat maps. Using a concurrent reader paradigm, 25 radiologists (18 experienced, 7 inexperienced in WB-/MRI) were randomly allocated WB-MRI scans with or without ML support to detect malignant lesions over 2 or 3 reading rounds. Reads were undertaken in the setting of a diagnostic radiology reading room between November 2019 and March 2020. Reading times were recorded by a scribe. Prespecified analysis included sensitivity, specificity, interobserver agreement, and reading time of radiology readers to detect metastases with or without ML support. Reader performance for detection of the primary tumor was also evaluated. RESULTS: Four hundred thirty-three evaluable WB-MRI scans were allocated to algorithm training (245) or radiology testing (50 patients with metastases, from primary 117 colon [n = 117] or lung [n = 71] cancer). Among a total 562 reads by experienced radiologists over 2 reading rounds, per-patient specificity was 86.2% (ML) and 87.7% (non-ML) (-1.5% difference; 95% confidence interval [CI], -6.4%, 3.5%; P = 0.39). Sensitivity was 66.0% (ML) and 70.0% (non-ML) (-4.0% difference; 95% CI, -13.5%, 5.5%; P = 0.344). Among 161 reads by inexperienced readers, per-patient spec

Journal article

Doe G, Taylor SJC, Topalovic M, Russell R, Evans RA, Maes J, Van Orshovon K, Sunjaya A, Scott D, Prevost AT, El-Emir E, Harvey J, Hopkinson NS, Kon SS, Patel S, Jarrold I, Spain N, Man WD-C, Hutchinson Aet al., 2023, Spirometry services in England post-pandemic and the potential role of AI support software: a qualitative study of challenges and opportunities, BRITISH JOURNAL OF GENERAL PRACTICE, ISSN: 0960-1643

Journal article

Hagag AM, Kaye R, Hoang V, Riedl S, Anders P, Stuart B, Traber G, Appenzeller-Herzog C, Schmidt-Erfurth U, Bogunovic H, Scholl HP, Prevost T, Fritsche L, Rueckert D, Sivaprasad S, Lotery AJet al., 2023, Systematic review of prognostic factors associated with progression to late age-related macular degeneration: Pinnacle study report 2., Surv Ophthalmol

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.

Journal article

Rajalakshmi RC, Vasconcelos J, Prevost AT, Sivaprasad S, Deepa M, Raman R, Ramasamy K, Anjana RM, Conroy D, Das T, Hanif W, Mohan Vet al., 2023, Burden of undiagnosed and suboptimally controlled diabetes in selected regions of India: Results from the SMART India population-level diabetes screening study, DIABETIC MEDICINE, Vol: 40, ISSN: 0742-3071

Journal article

Naughton F, Hope A, Siegele-Brown C, Grant K, Barton G, Notley C, Mascolo C, Coleman T, Shepstone L, Sutton S, Prevost AT, Crane D, Greaves F, High Jet al., 2023, An Automated, Online Feasibility Randomized Controlled Trial of a Just-In-Time Adaptive Intervention for Smoking Cessation (Quit Sense), NICOTINE & TOBACCO RESEARCH, Vol: 25, Pages: 1319-1329, ISSN: 1462-2203

Journal article

Cope A, Jasenecova M, Vasconcelos J, Filer A, Raza K, Qureshi S, D’agostino MA, Mcinnes I, Isaacs J, Pratt A, Fisher B, Buckley CD, Emery P, Ho P, Buch MH, Ciurtin C, Huizinga T, Van Schaardenburg D, Murphy C, Prevost Tet al., 2023, OP0130 ABATACEPT IN INDIVIDUALS AT RISK OF DEVELOPING RHEUMATOID ARTHRITIS: RESULTS FROM THE ARTHRITIS PREVENTION IN THE PRE-CLINICAL PHASE OF RA WITH ABATACEPT (APIPPRA) TRIAL, EULAR 2023 European Congress of Rheumatology, 31 May - 3 June. Milan, Italy, Publisher: BMJ Publishing Group Ltd and European League Against Rheumatism

Conference paper

Sutton J, Menten MJ, Riedl S, Bogunovic H, Leingang O, Anders P, Hagag AM, Waldstein S, Wilson A, Cree AJ, Traber G, Fritsche LG, Scholl H, Rueckert D, Schmidt-Erfurth U, Sivaprasad S, Prevost T, Lotery Aet al., 2023, Developing and validating a multivariable prediction model which predicts progression of intermediate to late age-related macular degeneration-the PINNACLE trial protocol, Eye, Vol: 37, Pages: 1275-1283, ISSN: 0950-222X

AimsAge-related macular degeneration (AMD) is characterised by a progressive loss of central vision. Intermediate AMD is a risk factor for progression to advanced stages categorised as geographic atrophy (GA) and neovascular AMD. However, rates of progression to advanced stages vary between individuals. Recent advances in imaging and computing technologies have enabled deep phenotyping of intermediate AMD. The aim of this project is to utilise machine learning (ML) and advanced statistical modelling as an innovative approach to discover novel features and accurately quantify markers of pathological retinal ageing that can individualise progression to advanced AMD.MethodsThe PINNACLE study consists of both retrospective and prospective parts. In the retrospective part, more than 400,000 optical coherent tomography (OCT) images collected from four University Teaching Hospitals and the UK Biobank Population Study are being pooled, centrally stored and pre-processed. With this large dataset featuring eyes with AMD at various stages and healthy controls, we aim to identify imaging biomarkers for disease progression for intermediate AMD via supervised and unsupervised ML. The prospective study part will firstly characterise the progression of intermediate AMD in patients followed between one and three years; secondly, it will validate the utility of biomarkers identified in the retrospective cohort as predictors of progression towards late AMD. Patients aged 55–90 years old with intermediate AMD in at least one eye will be recruited across multiple sites in UK, Austria and Switzerland for visual function tests, multimodal retinal imaging and genotyping. Imaging will be repeated every four months to identify early focal signs of deterioration on spectral-domain optical coherence tomography (OCT) by human graders. A focal event triggers more frequent follow-up with visual function and imaging tests. The primary outcome is the sensitivity and specificity of the OCT ima

Journal article

Bayly J, Ahmedzai HH, Blandini MG, Bressi B, Caraceni AT, Carvalho Vasconcelos J, Costi S, Fugazzaro S, Guberti M, Guldin M-B, Hauken M, Higginson I, Laird BJA, Ling J, Normand C, Nottelmann L, Oldervoll L, Payne C, Prevost AT, Stene GB, Vanzulli E, Veber E, Economos G, Maddocks Met al., 2023, Integrated Short-term Palliative Rehabilitation to improve quality of life and equitable care access in incurable cancer (INSPIRE): a multinational European research project., Palliat Care Soc Pract, Vol: 17

BACKGROUND: Disability related to incurable cancer affects over a million Europeans each year and people with cancer rank loss of function among the most common unmet supportive care needs. OBJECTIVES: To test the clinical and cost-effectiveness of an integrated short-term palliative rehabilitation intervention, to optimise function and quality of life in people affected by incurable cancer. DESIGN: This is a multinational, parallel group, randomised, controlled, assessor blind, superiority trial. METHODS: The INSPIRE consortium brings together leaders in palliative care, oncology and rehabilitation from partner organisations across Europe, with complementary expertise in health service research, trials of complex interventions, mixed-method evaluations, statistics and economics. Partnership with leading European civil society organisations ensures citizen engagement and dissemination at the highest level. We will conduct a multinational randomised controlled trial across five European countries, recruiting participants to assess the effectiveness of palliative rehabilitation for people with incurable cancer on the primary outcome - quality of life - and secondary outcomes including disability, symptom burden and goal attainment. To support trial conduct and enhance analysis of trial data, we will also conduct: comparative analysis of current integration of rehabilitation across oncology and palliative care services; mixed-method evaluations of equity and inclusivity, processes and implementation for the intervention, at patient, health service and health system levels. Finally, we will conduct an evidence synthesis, incorporating INSPIRE findings, and a Delphi consensus to develop an international framework for palliative rehabilitation practice and policy, incorporating indicators, core interventions, outcomes and integration methods. SCIENTIFIC CONTRIBUTION: If positive, the trial could produce a scalable and equitable intervention to improve function and quality

Journal article

Raman R, Vasconcelos JC, Rajalakshmi R, Prevost AT, Ramasamy K, Mohan V, Mohan D, Rani PK, Conroy D, Das T, Sivaprasad S, SMART India Study Collaboratorset al., 2022, Prevalence of diabetic retinopathy in India stratified by known and undiagnosed diabetes, urban-rural locations, and socioeconomic indices: results from the SMART India population-based cross-sectional screening study., Lancet Glob Health, Vol: 10, Pages: e1764-e1773

BACKGROUND: National and subnational estimates of the prevalence of diabetic retinopathy and vision-threatening diabetic retinopathy (VTDR) are needed to inform the stepwise implementation of systematic retinal screening for people with diabetes in India to decrease the rate of blindness. We aimed to assess these national and subnational estimates and to stratify the prevalence of diabetic retinopathy and VTDR on the basis of people with known versus undiagnosed diabetes, urban versus rural residence, and epidemiological transition level (ETL) and Socio-demographic Index (SDI) categories of states. METHODS: We did a multicentre cross-sectional screening study for diabetic retinopathy using a complex cluster sampling design in people aged 40 years or older in ten Indian states and one union territory between Dec 20, 2018, and March 20, 2020. We did non-mydriatic retinal screening and assessed risk factor burden for people with diabetes. We estimated nationally weighted prevalence of diabetic retinopathy and VTDR for individuals with known and undiagnosed diabetes by urban versus rural residence, and by state categorisation by ETL and SDI. We also assessed adjusted risk factors. FINDINGS: From 42 146 participants screened, 7910 (18·8%) were identified to have diabetes. Of these, 6133 (77·5%; 4350 with known diabetes and 1783 with undiagnosed diabetes) had gradable retinal images. 3411 (56%) participants were women and 2722 (44%) were men, and the median age was 56 years (IQR 49-65). The estimated national prevalence was 12·5% (95% CI 11·0-14·2) for diabetic retinopathy and 4·0% (3·4-4·8) for VTDR, with no significant differences between urban and rural residence for diabetic retinopathy. Compared with individuals with undiagnosed diabetes, we observed a higher prevalence of diabetic retinopathy (15·5% [13·4-17·8] vs 8·0% [6·3-10·1]) and VTDR (5·3% [4·5-6&mid

Journal article

Pugh J, Anjum A, Petropoulou K, Thom G, Mccombie L, Tashkova M, Alaraj-Alshehhi S, Babalis D, Prechtl C, Lean MJ, Prevost AT, Vasconcelos JC, Preston T, Morrison D, Frost Get al., 2022, Increase in colonic PRopionate as a method of prEVENTing weight gain in adults aged 20-40 years (iPREVENT): A multi-centre, double-blind, randomised, parallel-group study to investigate the efficacy of inulin-propionate ester versus inulin (control) in the prevention of weight gain over 12 months, F1000Research, Vol: 11, Pages: 1-14, ISSN: 2046-1402

Introduction: Overweight and obesity affects over 70% of the UK population and is a major risk factor for the development of co-morbidities, including type 2 diabetes and cardiovascular disease. There now exists a considerable evidence base for the management of obesity. However, this is not the case for the prevention of obesity. Preventing weight gain in periods of life where there is an elevated risk of fat mass expansion could be beneficial to preventing associated diseases in later life. This protocol investigates the impact of novel food ingredient inulin propionate ester (IPE) in the prevention of weight gain. This trial aims to investigate the primary hypothesis that IPE has a superior effect on preventing body weight gain, compared with inulin, in young (<40 years old) adults over 12 months, whilst also investigating several complementary mechanisms that may explain the prevention of weight gain and improved long-term energy balance from consuming IPE. Methods: In this multi-centre, double-blind, randomised, parallel-group study, eligible participants will be randomly assigned to consume 10g IPE or 10g inulin (control) daily for 12 months. Study visits will be conducted at baseline, two-month, six-month and 12-month time points. The primary outcome is weight gain from baseline to 12 months. Secondary outcomes will examine changes in metabolic and cardiovascular health biomarkers, body composition and appetite. A mechanistic sub-group will explore causal mechanisms around energy balance, body composition, appetite regulation and the gut microbiota. Based on the power calculation, the sample size required is 270 participants or 135 per study group.Ethics and dissemination: The trial protocol and participant-facing documents have been reviewed and approved, by the London Hampstead Ethics Committee (REC Reference 19/LO/0095, 29th January 2019). Upon completion, the trial results will be published in peer-reviewed journals and presented at scientific confer

Journal article

Farne H, Glanville N, Johnson N, Kebadze T, Aniscenko J, Regis E, Zhu J, Trujillo-Torralbo M-B, Kon OM, Mallia P, Prevost A, Edwards M, Johnston S, Singanayagam A, Jackson Det al., 2022, Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomized controlled trial, Thorax, Vol: 77, Pages: 950-959, ISSN: 0040-6376

Background and aimsThe CRTH2 antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesized that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomized to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 three weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post-infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant- and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0-14 (difference 3.0 (95% CI -29.0 to 17.0), P=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo- but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events, or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.

Journal article

Nugawela MD, Gurudas S, Prevost AT, Mathur R, Robson J, Sathish T, Rafferty JM, Rajalakshmi R, Anjana RM, Jebarani S, Mohan V, Owens DR, Sivaprasad Set al., 2022, Development and validation of predictive risk models for sight threatening diabetic retinopathy in patients with type 2 diabetes to be applied as triage tools in resource limited settings, ECLINICALMEDICINE, Vol: 51

Journal article

Ibrahim F, Tom BDM, Scott DL, Prevost ATet al., 2022, Characterization of missing data patterns and mechanisms in longitudinal composite outcome trial in rheumatoid arthritis, THERAPEUTIC ADVANCES IN MUSCULOSKELETAL DISEASE, Vol: 14, ISSN: 1759-720X

Journal article

Gulliford MC, Prevost AT, Clegg A, Rezel-Potts Eet al., 2022, Mortality of Care Home Residents and Community-Dwelling Controls During the COVID-19 Pandemic in 2020: Matched Cohort Study, JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION, Vol: 23, Pages: 923-+, ISSN: 1525-8610

Journal article

Gurudas S, Frudd K, Maheshwari JJ, Revathy YR, Sivaprasad S, Ramanathan SM, Pooleeswaran V, Prevost AT, Karatsai E, Halim S, Chandra S, Nderitu P, Conroy D, Krishnakumar S, Parameswaran S, Dharmalingam K, Ramasamy K, Raman R, Jones C, Eleftheriadis H, Greenwood J, Turowski Pet al., 2022, Multicenter Evaluation of Diagnostic Circulating Biomarkers to Detect Sight-Threatening Diabetic Retinopathy, JAMA OPHTHALMOLOGY, Vol: 140, Pages: 587-597, ISSN: 2168-6165

Journal article

Lee MJ, Collins S, Babalis D, Johnson N, Falaschetti E, Prevost AT, Ashraf A, Jacob M, Cole T, Hurley L, Pace M, Ogbe A, Khan M, Zacharopoulou P, Brown H, Sutherland E, Box H, Fox J, Deeks S, Horowitz J, Nussenzweig MC, Caskey M, Frater J, Fidler Set al., 2022, The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial, Trials, Vol: 23, ISSN: 1745-6215

Background:Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control.Methods:RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures.Discussion:The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tes

Journal article

Day E, Eldred-Evans D, Prevost AT, Hashim U A, Fiorentino Fet al., 2022, Adjusting for verification bias in diagnostic accuracy measures when comparing multiple screening 2 tests - an application to the IP1-PROSTAGRAM study, BMC Medical Research Methodology, Vol: 22, ISSN: 1471-2288

Introduction Novel screening tests used to detect a target condition are compared against either a reference standard or other existing screening methods. However, as it is not always possible to apply the reference standard on the whole population under study, verification bias is introduced. Statistical methods exist to adjust estimates to account for this bias. We extend common methods to adjust for verification bias when multiple tests are compared to a reference standard using data from a prospective double blind screening study for prostate cancer. Methods Begg and Greenes method and multiple imputation are extended to include the results of multiple screening tests which determine condition verification status. These two methods are compared to the complete case analysis using the IP1-PROSTAGRAM study data. IP1-PROSTAGRAM used a paired84 cohort double-blind design to evaluate the use of imaging as alternative tests to screen for prostate85 cancer, compared to a blood test called prostate specific antigen (PSA). Participants with positive imaging (index) and/or PSA (control) underwent a prostate biopsy (reference). Results When comparing complete case results to Begg and Greenes and methods of multiple imputation there is a statistically significant increase in the specificity estimates for all screening tests. Sensitivity estimates remained similar across the methods, with completely overlapping 95% confidence intervals. Negative predictive value (NPV) estimates were higher when adjusting for verification bias, compared to complete case analysis, even though the 95% confidence intervals overlap. Positive predictive value (PPV) estimates were similar across all methods. Conclusion Statistical methods are required to adjust for verification bias in accuracy estimates of screening tests. Expanding Begg and Greenes method to include multiple screening tests can be computationally intensive, hence multiple imputation is recommended, especially as it can be modifie

Journal article

Ramadoss V, Lazarus K, Prevost AT, Tan T, Meeran K, Choudhury Set al., 2021, Improving the interpretation of afternoon cortisol levels and SSTs to prevent misdiagnosis of Adrenal Insufficiency, Journal of the Endocrine Society, Vol: 5, Pages: 1-14, ISSN: 2472-1972

IntroductionAdrenal Insufficiency (AI), especially iatrogenic-AI, is a treatable cause of mortality. The difficulty in obtaining 9am cortisol levels means samples are taken at suboptimal times, including a substantial proportion in the afternoon. Low afternoon cortisol levels often provoke short Synacthen Tests (SSTs). It is important that this does not lead to patients misdiagnosed with AI, exposing them to the excess mortality and morbidity of inappropriate steroid replacement therapy.MethodsThis retrospective study collected 60,178 cortisol results. Medical records, including subsequent SSTs of initial cortisol results measured after midday were reviewed.ResultsROC analysis (AUC- 0.89) on 6531 suitable cortisol values showed that a limit of <201.5nmol/L achieved a sensitivity and specificity of 95.6% and 72.6%, whilst a limit of <234nmol/L had a sensitivity of 100% and a specificity of 59.5%. Out of 670 SSTs, 628 patients passed. Of these, 140 would have otherwise failed if only their 30-minute cortisol was assessed without the 60-minute value.A 30-minute and 60-minute SST cortisol cut-off of 366.5nmol/L and 418.5nmol/L respectively, can achieve a sensitivity of >95% on the Abbott analyser platform.ConclusionAn afternoon cortisol >234nmol/L excludes AI on Abbott analyser platforms. In patients who have an afternoon cortisol <234nmol/L, including both a 30-minute and a 60-minute SST cortisol values prevents unnecessary glucocorticoid replacement therapy in 22.3% of individuals in this study. The Abbott analyser SST cortisol cut-offs used to define AI should be 366.5nmol/L and 418.5nmol/L at 30- and 60-minutes respectively. All patients remained well subsequently with at least one year longitudinal follow up.

Journal article

Pennington B, Alshreef A, Flight L, Metry A, Poku E, Hykin P, Sivaprasad S, Prevost AT, Vasconcelos JC, Murphy C, Kelly J, Yang Y, Lotery A, Williams M, Brazier Jet al., 2021, Cost Effectiveness of Ranibizumab vs Aflibercept vs Bevacizumab for the Treatment of Macular Oedema Due to Central Retinal Vein Occlusion: The LEAVO Study (Apr, 10.1007/s40273-021-01026-5, 2021), PHARMACOECONOMICS, Vol: 39, Pages: 1099-1099, ISSN: 1170-7690

Journal article

Fiorentino F, 2021, Feasibility of Comparative Health Research Outcome of Novel Surgery in prostate cancer (IP4-CHRONOS): statistical analysis plan for the randomised feasibility phase of the CHRONOS study., Trials, Vol: 22, Pages: 1-12, ISSN: 1745-6215

BackgroundRandomised controlled trials (RCTs) for surgical interventions have often proven difficult with calls for innovative approaches. The Imperial Prostate (IP4) Comparative Health Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS) study aims to deliver level 1 evidence on outcomes following focal therapy which involves treating just the tumour rather than whole-gland surgery or radiotherapy. Our aim is to test the feasibility of two parallel RCTs within an overarching strategy that fits with existing patient and physician equipoise and maximises the chances of success and potential benefit to patients and healthcare services.Methods and designIP4-CHRONOS is a randomised, unblinded multi-centre study, including two parallel randomised controlled trials targeting the same patient population: IP4-CHRONOS-A and IP4-CHRONOS-B.IP4-CHRONOS-A is a 1:1 RCT and the other is a multi-arm, multi-stage (MAMS) RCT starting with three arms and a 1:1:1 randomisation. The two linked RCTs are discussed with patients at the time of consent and the choice of A or B is dependent on physician and patient equipoise. The primary outcome is the feasibility of recruitment, acceptance of randomisation and compliance to allocated arm.ResultsThis paper describes the statistical analysis plan (SAP) for the feasibility study within IP4-CHRONOS given its innovative approach. Version 1.0 of the SAP has been reviewed by the Trial Steering Committee (TSC), Chief Investigator (CI), Senior Statistician and Trial Statistician and signed off. The study is ongoing and recruiting. Recruitment is scheduled to finish later in 2021. The SAP documents approved methods and analyses that will be conducted. Since this is written in advance of the analysis, we avoid bias arising from prior knowledge of the study data and findings.DiscussionOur feasibility analysis will demonstrate if IP4-CHRONOS is feasible in terms of recruitment, randomisation and compliance, and whether to continue both A

Journal article

Nugawela MD, Gurudas S, Prevost AT, Mathur R, Robson J, Hanif W, Majeed A, Sivaprasad Set al., 2021, Ethnic disparities in the development of sight-threatening diabetic retinopathy in a uk multi-ethnic population with diabetes: an observational cohort study, Journal of Personalized Medicine, Vol: 11, ISSN: 2075-4426

There is little data on ethnic differences in incidence of DR and sight threatening DR (STDR) in the United Kingdom. We aimed to determine ethnic differences in the development of DR and STDR and to identify risk factors of DR and STDR in people with incident or prevalent type II diabetes (T2DM). We used electronic primary care medical records of people registered with 134 general practices in East London during the period from January 2007–January 2017. There were 58,216 people with T2DM eligible to be included in the study. Among people with newly diagnosed T2DM, Indian, Pakistani and African ethnic groups showed an increased risk of DR with Africans having highest risk of STDR compared to White ethnic groups (HR: 1.36 95% CI 1.02–1.83). Among those with prevalent T2DM, Indian, Pakistani, Bangladeshi and Caribbean ethnic groups showed increased risk of DR and STDR with Indian having the highest risk of any DR (HR: 1.24 95% CI 1.16–1.32) and STDR (HR: 1.38 95% CI 1.17–1.63) compared with Whites after adjusting for all covariates considered. It is important to optimise prevention, screening and treatment options in these ethnic minority groups to avoid health inequalities in diabetes eye care.

Journal article

Shankar-Hari M, Santhakumaran S, Prevost AT, Ward JK, Marshall T, Bradley C, Calfee CS, Delucchi KL, Sinha P, Matthay MA, Hackett J, McDowell C, Laffey JG, Gordon A, OKane CM, McAuley DFet al., 2021, Defining phenotypes and treatment effect heterogeneity to inform acute respiratory distress syndrome and sepsis trials: secondary analyses of three RCTs, Efficacy and Mechanism Evaluation, Vol: 8, Pages: 1-104, ISSN: 2050-4365

BackgroundSepsis and acute respiratory distress syndrome are two heterogeneous acute illnesses with high risk of death and for which there are many ‘statistically negative’ randomised controlled trials. We hypothesised that negative randomised controlled trials occur because of between-participant differences in response to treatment, illness manifestation (phenotype) and risk of outcomes (heterogeneity).ObjectivesTo assess (1) heterogeneity of treatment effect, which tests whether or not treatment effect varies with a patient’s pre-randomisation risk of outcome; and (2) whether or not subphenotypes explain the treatment response differences in sepsis and acute respiratory distress syndrome demonstrated in randomised controlled trials.Study populationWe performed secondary analysis of two randomised controlled trials in patients with sepsis [i.e. the Vasopressin vs Noradrenaline as Initial Therapy in Septic Shock (VANISH) trial and the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial] and one acute respiratory distress syndrome multicentre randomised controlled trial [i.e. the Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial], conducted in the UK. The VANISH trial is a 2 × 2 factorial randomised controlled trial of vasopressin (Pressyn AR®; Ferring Pharmaceuticals, Saint-Prex, Switzerland) and hydrocortisone sodium phosphate (hereafter referred to as hydrocortisone) (EfcortesolTM; Amdipharm plc, St Helier, Jersey) compared with placebo. The LeoPARDS trial is a two-arm-parallel-group randomised controlled trial of levosimendan (Simdax®; Orion Pharma, Espoo, Finland) compared with placebo. The HARP-2 trial is a parallel-group randomised controlled trial of simvastatin compared with placebo.MethodsTo test for heterogeneity of the effect on 28-day mortality of vasopressin, hydrocortisone and levosimendan in

Journal article

Pennington B, Alshreef A, Flight L, Metry A, Poku E, Hykin P, Sivaprasad S, Prevost AT, Vasconcelos JC, Murphy C, Kelly J, Yang Y, Lotery A, Williams M, Brazier Jet al., 2021, Cost Effectiveness of Ranibizumab vs Aflibercept vs Bevacizumab for the Treatment of Macular Oedema Due to Central Retinal Vein Occlusion: The LEAVO Study, PHARMACOECONOMICS, Vol: 39, Pages: 913-927, ISSN: 1170-7690

Journal article

Gurudas S, Nugawela M, Prevost AT, Sathish T, Mathur R, Rafferty JM, Blighe K, Rajalakshmi R, Mohan AR, Saravanan J, Majeed A, Mohan V, Owens DR, Robson J, Sivaprasad Set al., 2021, Development and validation of resource-driven risk prediction models for incident chronic kidney disease in type 2 diabetes, Scientific Reports, Vol: 11, Pages: 1-11, ISSN: 2045-2322

Prediction models for population-based screening need, for global usage, to be resource-driven, involving predictors that are affordably resourced. Here, we report the development and validation of three resource-driven risk models to identify people with type 2 diabetes (T2DM) at risk of stage 3 CKD defined by a decline in estimated glomerular filtration rate (eGFR) to below 60 mL/min/1.73m2. The observational study cohort used for model development consisted of data from a primary care dataset of 20,510 multi-ethnic individuals with T2DM from London, UK (2007–2018). Discrimination and calibration of the resulting prediction models developed using cox regression were assessed using the c-statistic and calibration slope, respectively. Models were internally validated using tenfold cross-validation and externally validated on 13,346 primary care individuals from Wales, UK. The simplest model was simplified into a risk score to enable implementation in community-based medicine. The derived full model included demographic, laboratory parameters, medication-use, cardiovascular disease history (CVD) and sight threatening retinopathy status (STDR). Two less resource-intense models were developed by excluding CVD and STDR in the second model and HbA1c and HDL in the third model. All three 5-year risk models had good internal discrimination and calibration (optimism adjusted C-statistics were each 0.85 and calibration slopes 0.999–1.002). In Wales, models achieved excellent discrimination(c-statistics ranged 0.82–0.83). Calibration slopes at 5-years suggested models over-predicted risks, however were successfully updated to accommodate reduced incidence of stage 3 CKD in Wales, which improved their alignment with the observed rates in Wales (E/O ratios near to 1). The risk score demonstrated similar model performance compared to direct evaluation of the cox model. These resource-driven risk prediction models may enable universal screening for Stage 3 CKD t

Journal article

Hykin P, Prevost AT, Sivaprasad S, Vasconcelos JC, Murphy C, Kelly J, Ramu J, Alshreef A, Flight L, Pennington R, Hounsome B, Lever E, Metry A, Poku E, Yang Y, Harding SP, Lotery A, Chakravarthy U, Brazier Jet al., 2021, Intravitreal ranibizumab versus aflibercept versus bevacizumab for macular oedema due to central retinal vein occlusion: the LEAVO non-inferiority three-arm RCT, HEALTH TECHNOLOGY ASSESSMENT, Vol: 25, Pages: 1-+, ISSN: 1366-5278

Journal article

Gulliford MC, Prevost AT, Clegg A, Rezel-Potts Eet al., 2021, Mortality of Care Home Residents and Community-Dwelling Controls During the COVID-19 Pandemic in 2020: Matched Cohort Study

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Objective</jats:title><jats:p>To estimate mortality of care home (CH) residents, and matched community-dwelling controls, during the Covid-19 pandemic from primary care electronic health records.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Matched cohort study</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>General practices contributing to the Clinical Practice Research Datalink Aurum Database in England.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>There were 83,627 CH residents contributing data in 2020, with 26,923 deaths; 80,730 (97%) were matched on age, gender and general practice with 300,445 community-dwelling adults.</jats:p></jats:sec><jats:sec><jats:title>Main outcome measures</jats:title><jats:p>All-cause mortality. Adjusted rate ratios (RR) by negative binomial regression were adjusted for age, gender, number of long-term conditions (LTCs), frailty category, region, calendar month or week, and clustering by general practice.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>During April 2020, the mortality rate of CH residents was 27.2 deaths per 1,000 patients per week, compared with 2.31 per 1,000 for controls, RR 11.1 (95% confidence interval 10.1 to 12.2). Compared with CH residents, LTCs and frailty were differentially associated with greater mortality in community-dwelling controls. During April 2020, mortality rates per 1,000 patients per week for persons with 9+ LTCs were: CH, 37.9; controls 17.7; RR 2.14 (1.18 to 3.89). In severe frailty, mortality rates were: CH, 29.6; controls 5.1; RR 6.17 (5.74 to 6.62).</jats:p></jats:sec><jats:sec><jats:title>Conclusions<

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