RECAP-KG: Mining Knowledge Graphs from Raw Primary Care Physician Notes for Remote COVID-19 Assessment in Primary Care.

Building Clinical Decision Support Systems, whether from regression models or machine learning requires clinical data either in standard terminology or as text for Natural Language Processing (NLP). Unfortunately, many clinical notes are written quickly during the consultation and contain many abbreviations, typographical errors, and a lack of grammar and punctuation Processing these highly unstructured clinical notes is an open challenge for NLP that we address in this paper. We present RECAP-KG - a knowledge graph construction frame workfrom primary care clinical notes. Our framework extracts structured knowledge graphs from the clinical record by utilising the SNOMED-CT ontology both the entire finding hierarchy and a COVID-relevant curated subset. We apply our framework to consultation notes in the UK COVID-19 Clinical Assessment Service (CCAS) dataset and provide a quantitative evaluation of our framework demonstrating that our approach has better accuracy than traditional NLP methods when answering questions about patients.

Remote COVID-19 Assessment in Primary Care (RECAP) risk prediction tool: derivation and real-world validation studies.

BACKGROUND: Accurate assessment of COVID-19 severity in the community is essential for patient care and requires COVID-19-specific risk prediction scores adequately validated in a community setting. Following a qualitative phase to identify signs, symptoms, and risk factors, we aimed to develop and validate two COVID-19-specific risk prediction scores. Remote COVID-19 Assessment in Primary Care-General Practice score (RECAP-GP; without peripheral oxygen saturation [SpO2]) and RECAP-oxygen saturation score (RECAP-O2; with SpO2). METHODS: RECAP was a prospective cohort study that used multivariable logistic regression. Data on signs and symptoms (predictors) of disease were collected from community-based patients with suspected COVID-19 via primary care electronic health records and linked with secondary data on hospital admission (outcome) within 28 days of symptom onset. Data sources for RECAP-GP were Oxford-Royal College of General Practitioners Research and Surveillance Centre (RCGP-RSC) primary care practices (development set), northwest London primary care practices (validation set), and the NHS COVID-19 Clinical Assessment Service (CCAS; validation set). The data source for RECAP-O2 was the Doctaly Assist platform (development set and validation set in subsequent sample). The two probabilistic risk prediction models were built by backwards elimination using the development sets and validated by application to the validation datasets. Estimated sample size per model, including the development and validation sets was 2880 people. FINDINGS: Data were available from 8311 individuals. Observations, such as SpO2, were mostly missing in the northwest London, RCGP-RSC, and CCAS data; however, SpO2 was available for 1364 (70·0%) of 1948 patients who used Doctaly. In the final predictive models, RECAP-GP (n=1863) included sex (male and female), age (years), degree of breathlessness (three point scale), temperature symptoms (two point scale), and presence of hypertension (yes or no); the area under the curve was 0·80 (95% CI 0·76-0·85) and on validation the negative predictive value of a low risk designation was 99% (95% CI 98·1-99·2; 1435 of 1453). RECAP-O2 included age (years), degree of breathlessness (two point scale), fatigue (two point scale), and SpO2 at rest (as a percentage); the area under the curve was 0·84 (0·78-0·90) and on validation the negative predictive value of low risk designation was 99% (95% CI 98·9-99·7; 1176 of 1183). INTERPRETATION: Both RECAP models are valid tools to assess COVID-19 patients in the community. RECAP-GP can be used initially, without need for observations, to identify patients who require monitoring. If the patient is monitored and SpO2 is available, RECAP-O2 is useful to assess the need for treatment escalation. FUNDING: Community Jameel and the Imperial College President's Excellence Fund, the Economic and Social Research Council, UK Research and Innovation, and Health Data Research UK.

Immediate oral versus immediate topical versus delayed oral antibiotics for children with acute otitis media with discharge: the REST three-arm non-inferiority electronic platform-supported RCT.

BACKGROUND: Acute otitis media is a painful infection of the middle ear that is commonly seen in children. In some children, the eardrum spontaneously bursts, discharging visible pus (otorrhoea) into the outer ear. OBJECTIVE: To compare the clinical effectiveness of immediate topical antibiotics or delayed oral antibiotics with the clinical effectiveness of immediate oral antibiotics in reducing symptom duration in children presenting to primary care with acute otitis media with discharge and the economic impact of the alternative strategies. DESIGN: This was a pragmatic, three-arm, individually randomised (stratified by age < 2 vs. ≥ 2 years), non-inferiority, open-label trial, with economic and qualitative evaluations, supported by a health-record-integrated electronic trial platform [TRANSFoRm (Translational Research and Patient Safety in Europe)] with an internal pilot. SETTING: A total of 44 English general practices. PARTICIPANTS: Children aged ≥ 12 months and < 16 years whose parents (or carers) were seeking medical care for unilateral otorrhoea (ear discharge) following recent-onset (≤ 7 days) acute otitis media. INTERVENTIONS: (1) Immediate ciprofloxacin (0.3%) solution, four drops given three times daily for 7 days, or (2) delayed 'dose-by-age' amoxicillin suspension given three times daily (clarithromycin twice daily if the child was penicillin allergic) for 7 days, with structured delaying advice. All parents were given standardised information regarding symptom management (paracetamol/ibuprofen/fluids) and advice to complete the course. COMPARATOR: Immediate 'dose-by-age' oral amoxicillin given three times daily (or clarithromycin given twice daily) for 7 days. Parents received standardised symptom management advice along with advice to complete the course. MAIN OUTCOME MEASURE: Time from randomisation to the first day on which all symptoms (pain, fever, being unwell, sleep disturbance, otorrhoea and episodes of distress/crying) were rated 'no' or 'very slight' problem (without need for analgesia). METHODS: Participants were recruited from routine primary care appointments. The planned sample size was 399 children. Follow-up used parent-completed validated symptom diaries. RESULTS: Delays in software deployment and configuration led to small recruitment numbers and trial closure at the end of the internal pilot. Twenty-two children (median age 5 years; 62% boys) were randomised: five, seven and 10 to immediate oral, delayed oral and immediate topical antibiotics, respectively. All children received prescriptions as randomised. Seven (32%) children fully adhered to the treatment as allocated. Symptom duration data were available for 17 (77%) children. The median (interquartile range) number of days until symptom resolution in the immediate oral, delayed oral and immediate topical antibiotic arms was 6 (4-9), 4 (3-7) and 4 (3-6), respectively. Comparative analyses were not conducted because of small numbers. There were no serious adverse events and six reports of new or worsening symptoms. Qualitative clinician interviews showed that the trial question was important. When the platform functioned as intended, it was liked. However, staff reported malfunctioning software for long periods, resulting in missed recruitment opportunities. Troubleshooting the software placed significant burdens on staff. LIMITATIONS: The over-riding weakness was the failure to recruit enough children. CONCLUSIONS: We were unable to answer the main research question because of a failure to reach the required sample size. Our experience of running an electronic platform-supported trial in primary care has highlighted challenges from which we have drawn recommendations for the National Institute for Health Research (NIHR) and the research community. These should be considered before such a platform is used again. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12873692 and EudraCT 2017-003635-10. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 67. See the NIHR Journals Library website for further project information.

Ear infections are common in childhood. Some are complicated by a burst eardrum, followed by discharge from the ear. The usual treatment for this is a short course of antibiotics taken by mouth. However, alternative treatment using antibiotic drops, or a 'wait and see' policy before starting antibiotics, would result in less antibiotic use and reduce the subsequent risk of antibiotic resistance, which is bad for both patients and the environment. This study set out to see if these alternative treatments were as effective as the usual treatment for children with ear discharge. Although ear infections are common, only one in six children develops ear discharge, so only a few children might be available to take part at each general practice. We planned to use an electronic recruitment system to help us to gather enough patients. The system [called the 'TRANSFoRm' (Translational Research and Patient Safety in Europe) platform] was designed to remind busy general practitioners and nurses about the study and take them through the recruitment process step by step, as well as to support trial processes. Although the TRANSFoRm platform had been developed and tested, it had not been used in general practices before. We were surprised to find that there were many technical problems in setting up the TRANSFoRm platform in general practices, and staff were too busy and/or did not have the skills to overcome the technical issues. As a result, recruiting patients was slow and the study was halted before we had enough children to answer the main research question. In total, we managed to get 44 general practices and 22 children, but this was not enough. We still think that this kind of research and electronic trial platforms are important. We have noted many system and technical issues that need to be solved to enable funders and researchers to use this recruitment approach in the future.

The role of the state in financing and regulating primary care in Europe: a taxonomy.

Traditional health systems typologies were based on health system financing type, such as the well-known OECD typology. However, the number of dimensions captured in classifications increased to reflect health systems complexity. This study aims to develop a taxonomy of primary care (PC) systems based on the actors involved (state, societal and private) and mechanisms used in governance, financing and regulation, which conceptually represents the degree of decentralisation of functions. We use nonlinear canonical correlations analysis and agglomerative hierarchical clustering on data obtained from the European Observatory on Health Systems and Policy and informants from 24 WHO European Region countries. We obtain four clusters: 1) Bosnia Herzegovina, Czech Republic, Germany, Slovakia and Switzerland: corporatist and/or fragmented PC system, with state involvement in PC supply regulation, without gatekeeping; 2) Greece, Ireland, Israel, Malta, Sweden, and Ukraine: public and (re)centralised PC financing and regulation with private involvement, without gatekeeping; 3) Finland, Norway, Spain and United Kingdom: public financing and devolved regulation and organisation of PC, with gatekeeping; and 4) Bulgaria, Croatia, France, North Macedonia, Poland, Romania, Serbia, Slovenia and Turkey: public and deconcentrated with professional involvement in supply regulation, and gatekeeping. This taxonomy can serve as a framework for performance comparisons and a means to analyse the effect that different actors and levels of devolution or fragmentation of PC delivery may have in health outcomes.

What items should be included in an early warning score for remote assessment of suspected COVID-19? qualitative and Delphi study.

BACKGROUND: To develop items for an early warning score (RECAP: REmote COVID-19 Assessment in Primary Care) for patients with suspected COVID-19 who need escalation to next level of care. METHODS: The study was based in UK primary healthcare. The mixed-methods design included rapid review, Delphi panel, interviews, focus groups and software development. Participants were 112 primary care clinicians and 50 patients recovered from COVID-19, recruited through social media, patient groups and snowballing. Using rapid literature review, we identified signs and symptoms which are commoner in severe COVID-19. Building a preliminary set of items from these, we ran four rounds of an online Delphi panel with 72 clinicians, the last incorporating fictional vignettes, collating data on R software. We refined the items iteratively in response to quantitative and qualitative feedback. Items in the penultimate round were checked against narrative interviews with 50 COVID-19 patients. We required, for each item, at least 80% clinician agreement on relevance, wording and cut-off values, and that the item addressed issues and concerns raised by patients. In focus groups, 40 clinicians suggested further refinements and discussed workability of the instrument in relation to local resources and care pathways. This informed design of an electronic template for primary care systems. RESULTS: The prevalidation RECAP-V0 comprises a red flag alert box and 10 assessment items: pulse, shortness of breath or respiratory rate, trajectory of breathlessness, pulse oximeter reading (with brief exercise test if appropriate) or symptoms suggestive of hypoxia, temperature or fever symptoms, duration of symptoms, muscle aches, new confusion, shielded list and known risk factors for poor outcome. It is not yet known how sensitive or specific it is. CONCLUSIONS: Items on RECAP-V0 align strongly with published evidence, clinical judgement and patient experience. The validation phase of this study is ongoing. TRIAL REGISTRATION NUMBER: NCT04435041.

Risk assessment and antibiotic prescribing decisions in children presenting to UK primary care with cough: a vignette study.

OBJECTIVES: The validated 'STARWAVe' (Short illness duration, Temperature, Age, Recession, Wheeze, Asthma, Vomiting) clinical prediction rule (CPR) uses seven variables to guide risk assessment and antimicrobial stewardship in children presenting with cough. We aimed to compare general practitioners' (GPs) risk assessments and prescribing decisions to those of STARWAVe and assess the influence of the CPR's clinical variables. SETTING: Primary care. PARTICIPANTS: 252 GPs, currently practising in the UK. DESIGN: GPs were randomly assigned to view four (of a possible eight) clinical vignettes online. Each vignette depicted a child presenting with cough, who was described in terms of the seven STARWAVe variables. Systematically, we manipulated patient age (20 months vs 5 years), illness duration (3 vs 6 days), vomiting (present vs absent) and wheeze (present vs absent), holding the remaining STARWAVe variables constant. OUTCOME MEASURES: Per vignette, GPs assessed risk of hospitalisation and indicated whether they would prescribe antibiotics or not. RESULTS: GPs overestimated risk of hospitalisation in 9% of vignette presentations (88/1008) and underestimated it in 46% (459/1008). Despite underestimating risk, they overprescribed: 78% of prescriptions were unnecessary relative to GPs' own risk assessments (121/156), while 83% were unnecessary relative to STARWAVe risk assessments (130/156). All four of the manipulated variables influenced risk assessments, but only three influenced prescribing decisions: a shorter illness duration reduced prescribing odds (OR 0.14, 95% CI 0.08 to 0.27, p<0.001), while vomiting and wheeze increased them (ORvomit 2.17, 95% CI 1.32 to 3.57, p=0.002; ORwheeze 8.98, 95% CI 4.99 to 16.15, p<0.001). CONCLUSIONS: Relative to STARWAVe, GPs underestimated risk of hospitalisation, overprescribed and appeared to misinterpret illness duration (prescribing for longer rather than shorter illnesses). It is important to ascertain discrepancies between CPRs and current clinical practice. This has implications for the integration of CPRs into the electronic health record and the provision of intelligible explanations to decision-makers.

The impact of governance in primary health care delivery: a systems thinking approach with a European panel.

BACKGROUND: Enhancing primary health care (PHC) is considered a policy priority for health systems strengthening due to PHC's ability to provide accessible and continuous care and manage multimorbidity. Research in PHC often focuses on the effects of specific interventions (e.g. physicians' contracts) in health care outcomes. This informs narrowly designed policies that disregard the interactions between the health functions (e.g. financing and regulation) and actors involved (i.e. public, professional, private), and their impact in care delivery and outcomes. The purpose of this study is to analyse the interactions between PHC functions and their impact in PHC delivery, particularly in providers' behaviour and practice organisation. METHODS: Following a systems thinking approach with data obtained through a three-round European Delphi process, we developed a framework that captures (1) the interactions between PHC functions by analysing correlations between PHC characteristics of participating countries, (2) how actors involved shaped these interactions by identifying the actor and level of devolution (or fragmentation) in the analysis, and (3) their potential effect on care delivery by exploring panellists' opinions. RESULTS: A total of 59 panellists from 24 countries participated in the first round and 76% of the initial panellists (22 countries) completed the last round. Findings show correlations between governance, financing and regulation based on their degree of decentralisation. This is supported by panellists, who agreed that the actors involved in health system governance determine the type of PHC financing (e.g. ownership or payment mechanisms) and regulation (e.g. competences or gatekeeping), and this may impact care delivery and outcomes. Governance in our framework is an overarching function whose impact in PHC delivery is mediated through the degree of decentralisation (both delegation and devolution) of PHC financing and regulation. CONCLUSIONS: The application of this approach in policy implementation assessment intends to uncover limitations due to poor accountability and commitment to shared objectives. Its application in the design of health strategies helps foresee (and prevent) undesired or unexpected effects of narrow interventions. This approach will assist in the development of the realistic and long-term policies required for health systems strengthening.

The Diagnosis of Urinary Tract infection in Young children (DUTY): a diagnostic prospective observational study to derive and validate a clinical algorithm for the diagnosis of urinary tract infection in children presenting to primary care with an acute illness.

BACKGROUND: It is not clear which young children presenting acutely unwell to primary care should be investigated for urinary tract infection (UTI) and whether or not dipstick testing should be used to inform antibiotic treatment. OBJECTIVES: To develop algorithms to accurately identify pre-school children in whom urine should be obtained; assess whether or not dipstick urinalysis provides additional diagnostic information; and model algorithm cost-effectiveness. DESIGN: Multicentre, prospective diagnostic cohort study. SETTING AND PARTICIPANTS: Children < 5 years old presenting to primary care with an acute illness and/or new urinary symptoms. METHODS: One hundred and seven clinical characteristics (index tests) were recorded from the child's past medical history, symptoms, physical examination signs and urine dipstick test. Prior to dipstick results clinician opinion of UTI likelihood ('clinical diagnosis') and urine sampling and treatment intentions ('clinical judgement') were recorded. All index tests were measured blind to the reference standard, defined as a pure or predominant uropathogen cultured at ≥ 10(5) colony-forming units (CFU)/ml in a single research laboratory. Urine was collected by clean catch (preferred) or nappy pad. Index tests were sequentially evaluated in two groups, stratified by urine collection method: parent-reported symptoms with clinician-reported signs, and urine dipstick results. Diagnostic accuracy was quantified using area under receiver operating characteristic curve (AUROC) with 95% confidence interval (CI) and bootstrap-validated AUROC, and compared with the 'clinician diagnosis' AUROC. Decision-analytic models were used to identify optimal urine sampling strategy compared with 'clinical judgement'. RESULTS: A total of 7163 children were recruited, of whom 50% were female and 49% were < 2 years old. Culture results were available for 5017 (70%); 2740 children provided clean-catch samples, 94% of whom were ≥ 2 years old, with 2.2% meeting the UTI definition. Among these, 'clinical diagnosis' correctly identified 46.6% of positive cultures, with 94.7% specificity and an AUROC of 0.77 (95% CI 0.71 to 0.83). Four symptoms, three signs and three dipstick results were independently associated with UTI with an AUROC (95% CI; bootstrap-validated AUROC) of 0.89 (0.85 to 0.95; validated 0.88) for symptoms and signs, increasing to 0.93 (0.90 to 0.97; validated 0.90) with dipstick results. Nappy pad samples were provided from the other 2277 children, of whom 82% were < 2 years old and 1.3% met the UTI definition. 'Clinical diagnosis' correctly identified 13.3% positive cultures, with 98.5% specificity and an AUROC of 0.63 (95% CI 0.53 to 0.72). Four symptoms and two dipstick results were independently associated with UTI, with an AUROC of 0.81 (0.72 to 0.90; validated 0.78) for symptoms, increasing to 0.87 (0.80 to 0.94; validated 0.82) with the dipstick findings. A high specificity threshold for the clean-catch model was more accurate and less costly than, and as effective as, clinical judgement. The additional diagnostic utility of dipstick testing was offset by its costs. The cost-effectiveness of the nappy pad model was not clear-cut. CONCLUSIONS: Clinicians should prioritise the use of clean-catch sampling as symptoms and signs can cost-effectively improve the identification of UTI in young children where clean catch is possible. Dipstick testing can improve targeting of antibiotic treatment, but at a higher cost than waiting for a laboratory result. Future research is needed to distinguish pathogens from contaminants, assess the impact of the clean-catch algorithm on patient outcomes, and the cost-effectiveness of presumptive versus dipstick versus laboratory-guided antibiotic treatment. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The value of structured data elements from electronic health records for identifying subjects for primary care clinical trials.

BACKGROUND: An increasing number of clinical trials are conducted in primary care settings. Making better use of existing data in the electronic health records to identify eligible subjects can improve efficiency of such studies. Our study aims to quantify the proportion of eligibility criteria that can be addressed with data in electronic health records and to compare the content of eligibility criteria in primary care with previous work. METHODS: Eligibility criteria were extracted from primary care studies downloaded from the UK Clinical Research Network Study Portfolio. Criteria were broken into elemental statements. Two expert independent raters classified each statement based on whether or not structured data items in the electronic health record can be used to determine if the statement was true for a specific patient. Disagreements in classification were discussed until 100 % agreement was reached. Statements were also classified based on content and the percentages of each category were compared to two similar studies reported in the literature. RESULTS: Eligibility criteria were retrieved from 228 studies and decomposed into 2619 criteria elemental statements. 74 % of the criteria elemental statements were considered likely associated with structured data in an electronic health record. 79 % of the studies had at least 60 % of their criteria statements addressable with structured data likely to be present in an electronic health record. Based on clinical content, most frequent categories were: "disease, symptom, and sign", "therapy or surgery", and "medication" (36 %, 13 %, and 10 % of total criteria statements respectively). We also identified new criteria categories related to provider and caregiver attributes (2.6 % and 1 % of total criteria statements respectively). CONCLUSIONS: Electronic health records readily contain much of the data needed to assess patients' eligibility for clinical trials enrollment. Eligibility criteria content categories identified by our study can be incorporated as data elements in electronic health records to facilitate their integration with clinical trial management systems.

A cluster randomised controlled trial evaluating the effectiveness of eHealth-supported patient recruitment in primary care research: the TRANSFoRm study protocol.

BACKGROUND: Opportunistic recruitment is a highly laborious and time-consuming process that is currently performed manually, increasing the workload of already busy practitioners and resulting in many studies failing to achieve their recruitment targets. The Translational Medicine and Patient Safety in Europe (TRANSFoRm) platform enables automated recruitment, data collection and follow-up of patients, potentially improving the efficiency, time and costs of clinical research. This study aims to assess the effectiveness of TRANSFoRm in improving patient recruitment and follow-up in primary care trials. METHODS/DESIGN: This multi-centre, parallel-arm cluster randomised controlled trial will compare TRANSFoRm-supported with standard opportunistic recruitment. Participants will be general practitioners and patients with gastro-oesophageal reflux disease from 40 primary care centres in five European countries. Randomisation will take place at the care centre level. The intervention arm will use the TRANSFoRm tools for recruitment, baseline data collection and follow-up. The control arm will use web-based case report forms and paper self-completed questionnaires. The primary outcome will be the proportion of eligible patients successfully recruited at the end of the 16-week recruitment period. Secondary outcomes will include the proportion of recruited patients with complete baseline and follow-up data and the proportion of participants withdrawn or lost to follow-up. The study will also include an economic evaluation and measures of technology acceptance and user experience. DISCUSSION: The study should shed light on the use of eHealth to improve the effectiveness of recruitment and follow-up in primary care research and provide an evidence base for future eHealth-supported recruitment initiatives. Reporting of results is expected in October 2015. TRIAL REGISTRATION: EudraCT: 2014-001314-25.

A standardised graphic method for describing data privacy frameworks in primary care research using a flexible zone model.

PURPOSE: To develop a model describing core concepts and principles of data flow, data privacy and confidentiality, in a simple and flexible way, using concise process descriptions and a diagrammatic notation applied to research workflow processes. The model should help to generate robust data privacy frameworks for research done with patient data. METHODS: Based on an exploration of EU legal requirements for data protection and privacy, data access policies, and existing privacy frameworks of research projects, basic concepts and common processes were extracted, described and incorporated into a model with a formal graphical representation and a standardised notation. The Unified Modelling Language (UML) notation was enriched by workflow and own symbols to enable the representation of extended data flow requirements, data privacy and data security requirements, privacy enhancing techniques (PET) and to allow privacy threat analysis for research scenarios. RESULTS: Our model is built upon the concept of three privacy zones (Care Zone, Non-care Zone and Research Zone) containing databases, data transformation operators, such as data linkers and privacy filters. Using these model components, a risk gradient for moving data from a zone of high risk for patient identification to a zone of low risk can be described. The model was applied to the analysis of data flows in several general clinical research use cases and two research scenarios from the TRANSFoRm project (e.g., finding patients for clinical research and linkage of databases). The model was validated by representing research done with the NIVEL Primary Care Database in the Netherlands. CONCLUSIONS: The model allows analysis of data privacy and confidentiality issues for research with patient data in a structured way and provides a framework to specify a privacy compliant data flow, to communicate privacy requirements and to identify weak points for an adequate implementation of data privacy.

The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials.

BACKGROUND: Pragmatic trials compare the effects of different decisions in usual clinical practice. OBJECTIVES: To develop and evaluate methods to implement simple pragmatic trials using routinely collected electronic health records (EHRs) and recruiting patients at the point of care; to identify the barriers and facilitators for general practitioners (GPs) and patients and the experiences of trial participants. DESIGN: Two exemplar randomised trials (Retropro and eLung) with qualitative evaluations. SETTING: Four hundred and fifty-nine English and Scottish general practices contributing EHRs to a research database, of which 17 participated in the trials. PARTICIPANTS: Retropro aimed to recruit 300 patients with hypercholesterolaemia and high cardiovascular risk and eLung aimed to recruit 150 patients with a chronic obstructive pulmonary disease exacerbation. INTERVENTIONS: Retropro randomised between simvastatin and atorvastatin and eLung between immediate antibiotics and deferred or non-use. eLung recruited during an unscheduled consultation using EHR flagging. MAIN OUTCOME MEASURE: Successful trial completion with implementation of information technology (IT) system for flagging and data processing and documentation of operational and scientific experiences. DATA SOURCES: EHR research database. RESULTS: The governance approval process took over 3 years. A total of 58.8% of the practices (n = 270) expressed interest in participating. The number of interested practices dropped substantially with each stage of the governance process. In Retropro, 6.5% of the practices (n = 30) were eventually approved and 3.7% (n = 17) recruited patients; in eLung, these numbers were 6.8% (n = 31) and 1.3% (n = 6) respectively. Retropro successfully completed recruitment (301 patients) whereas eLung recruited 31 patients. Retropro recruited 20.6% of all statin starters in recruiting practices and 1.1% in the EHR database; the comparable numbers for eLung were 32.3% and 0.9% respectively. The IT system allowed for complex eligibility criteria with central on and off control of recruitment and flagging at a practice. Good Clinical Practice guidelines, governance and consent procedures were found to have substantially affected the intended simple nature of the trials. One qualitative study of 13 clinicians found that clinicians were generally positive about the principle of computerised trial recruitment (flagging during consultation). However, trials which did not include patients with acute illness were favoured. The second qualitative process evaluation interviewed 27 GPs about their actual experiences, including declining, recruiting and non-recruiting GPs. Opportunistic patient recruitment during a routine GP consultation was found to be the most controversial element. The actual experiences of recruiting patients during unscheduled consultation were generally more positive than the hypothetical views of GPs. Several of the recruiting GPs reported the process took 5 minutes and was straightforward and feasible on most occasions. Almost all GPs expressed their strong support for the use of EHRs for trials. Ten eLung participants were interviewed, all of whom considered it acceptable to be recruited during a consultation and to use EHRs for trials. CONCLUSIONS: EHR point-of-care trials are feasible, although the recruitment of clinicians is a major challenge owing to the complexity of trial approvals. These trials will provide substantial evidence on clinical effectiveness only if trial interventions and participating clinicians and patients are typical of usual clinical care and trials are simple to initiate and conduct. Recommendations for research include the development of evidence and implementation of risk proportionality in trial governance and conduct. TRIAL REGISTRATION: Current Controlled Trials ISRCTN33113202 and ISRCTN72035428. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and the Wellcome Trust and will be published in full in Health Technology Assessment; Vol. 18, No. 43. See the NIHR Journals Library website for further project information.

The diagnosis of urinary tract infections in young children (DUTY): protocol for a diagnostic and prospective observational study to derive and validate a clinical algorithm for the diagnosis of UTI in children presenting to primary care with an acute illness.

BACKGROUND: Urinary tract infection (UTI) is common in children, and may cause serious illness and recurrent symptoms. However, obtaining a urine sample from young children in primary care is challenging and not feasible for large numbers. Evidence regarding the predictive value of symptoms, signs and urinalysis for UTI in young children is urgently needed to help primary care clinicians better identify children who should be investigated for UTI. This paper describes the protocol for the Diagnosis of Urinary Tract infection in Young children (DUTY) study. The overall study aim is to derive and validate a cost-effective clinical algorithm for the diagnosis of UTI in children presenting to primary care acutely unwell. METHODS/DESIGN: DUTY is a multicentre, diagnostic and prospective observational study aiming to recruit at least 7,000 children aged before their fifth birthday, being assessed in primary care for any acute, non-traumatic, illness of ≤ 28 days duration. Urine samples will be obtained from eligible consented children, and data collected on medical history and presenting symptoms and signs. Urine samples will be dipstick tested in general practice and sent for microbiological analysis. All children with culture positive urines and a random sample of children with urine culture results in other, non-positive categories will be followed up to record symptom duration and healthcare resource use. A diagnostic algorithm will be constructed and validated and an economic evaluation conducted.The primary outcome will be a validated diagnostic algorithm using a reference standard of a pure/predominant growth of at least >103, but usually >105 CFU/mL of one, but no more than two uropathogens.We will use logistic regression to identify the clinical predictors (i.e. demographic, medical history, presenting signs and symptoms and urine dipstick analysis results) most strongly associated with a positive urine culture result. We will then use economic evaluation to compare the cost effectiveness of the candidate prediction rules. DISCUSSION: This study will provide novel, clinically important information on the diagnostic features of childhood UTI and the cost effectiveness of a validated prediction rule, to help primary care clinicians improve the efficiency of their diagnostic strategy for UTI in young children.

Trials within trials? Researcher, funder and ethical perspectives on the practicality and acceptability of nesting trials of recruitment methods in existing primary care trials.

BACKGROUND: Trials frequently encounter difficulties in recruitment, but evidence on effective recruitment methods in primary care is sparse. A robust test of recruitment methods involves comparing alternative methods using a randomized trial, 'nested' in an ongoing 'host' trial. There are potential scientific, logistical and ethical obstacles to such studies. METHODS: Telephone interviews were undertaken with four groups of stakeholders (funders, principal investigators, trial managers and ethics committee chairs) to explore their views on the practicality and acceptability of undertaking nested trials of recruitment methods. These semi-structured interviews were transcribed and analysed thematically. RESULTS: Twenty people were interviewed. Respondents were familiar with recruitment difficulties in primary care and recognised the case for 'nested' studies to build an evidence base on effective recruitment strategies. However, enthusiasm for this global aim was tempered by the challenges of implementation. Challenges for host studies included increasing complexity and management burden; compatibility between the host and nested study; and the impact of the nested study on trial design and relationships with collaborators. For nested recruitment studies, there were concerns that host study investigators might have strong preferences, limiting the nested study investigators' control over their research, and also concerns about sample size which might limit statistical power. Nested studies needed to be compatible with the main trial and should be planned from the outset. Good communication and adequate resources were seen as important. CONCLUSIONS: Although research on recruitment was welcomed in principle, the issue of which study had control of key decisions emerged as critical. To address this concern, it appeared important to align the interests of both host and nested studies and to reduce the burden of hosting a recruitment trial. These findings should prove useful in devising a programme of research involving nested studies of recruitment interventions.

Helicobacter pylori test and treat versus proton pump inhibitor in initial management of dyspepsia in primary care: multicentre randomised controlled trial (MRC-CUBE trial).

OBJECTIVE: To determine the cost effectiveness of Helicobacter pylori "test and treat" compared with empirical acid suppression in the initial management of patients with dyspepsia in primary care. DESIGN: Randomised controlled trial. SETTING: 80 general practices in the United Kingdom. PARTICIPANTS: 699 patients aged 18-65 who presented to their general practitioner with epigastric pain, heartburn, or both without "alarm symptoms" for malignancy. INTERVENTION: H pylori 13C urea breath test plus one week of eradication treatment if positive or proton pump inhibitor alone; subsequent management at general practitioner's discretion. MAIN OUTCOME MEASURES: Cost effectiveness in cost per quality adjusted life year (QALY) (EQ-5D) and effect on dyspeptic symptoms at one year measured with short form Leeds dyspepsia questionnaire. RESULTS: 343 patients were randomised to testing for H pylori, and 100 were positive. The successful eradication rate was 78%. 356 patients received proton pump inhibitor for 28 days. At 12 months no significant differences existed between the two groups in QALYs, costs, or dyspeptic symptoms. Minor reductions in costly resource use over the year in the test and treat group "paid back" the initial cost of the intervention. CONCLUSIONS: Test and treat and acid suppression are equally cost effective in the initial management of dyspepsia. Empirical acid suppression is an appropriate initial strategy. As costs are similar overall, general practitioners should discuss with patients at which point to consider H pylori testing. TRIAL REGISTRATION: Current Controlled Trials ISRCTN87644265.

A second-order simulation model of the cost-effectiveness of managing dyspepsia in the United States.

BACKGROUND: The "gold-standard'' evidence of effectiveness for a clinical practice guideline is the randomized controlled trial (RCT), although RCTs have a limited ability to explore potential management strategies for a chronic disease where these interact over time. Modeling can be used to fill this gap, and models have become increasingly complex, with both dynamic sampling and representation of second-order uncertainty to provide more precise estimates. However, both simulation modeling and probabilistic sensitivity analysis are rarely used together. The objective of this study was to explore uncertainty in controversial areas of the 2005 American Gastroenterology Association position statement on the management of dyspepsia. METHODS: Individual sampling model, incorporating a second-order probabilistic sensitivity analysis. POPULATION: US adult patients presenting in primary care with dyspepsia. Interventions compared: empirical acid suppression, test and treat for Helicobacter pylori, initial endoscopy, acid suppression then endoscopy, test and treat then proton pump inhibitor (PPI) then endoscopy. OUTCOMES: Cost-effectiveness, quality-adjusted life years, and costs in US dollars from a societal perspective, measured over a 5-year period. DATA SOURCES: mainly Cochrane meta-analyses. RESULTS: Endoscopy was dominated at all ages by other strategies. PPI therapy was the most cost-effective strategy in 30-year-olds with a low prevalence of H. pylori. In 60-year-olds, H. pylori test and treat was the most cost-effective option. CONCLUSIONS: Acid suppression alone was more cost-effective than either endoscopy or H. pylori test and treat in younger dyspepsia patients with a low prevalence of infection.