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1.
Cardiovasc Res ; 116(1): 149-157, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350550

RESUMO

AIMS: To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments. METHODS AND RESULTS: National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), ß-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4-8.5) vs. 6.7 (6.5-6.9)] and NSTEMI [6.8 (6.4-7.2) vs. 4.9 (4.7-5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5-3.3) vs. 2.3 (2.2-2.5)] and [21.4 (20.0-22.8) vs. 18.3 (17.6-19.0)], but was similar for STEMI [0.7 (0.4-1.0) vs. 0.9 (0.7-1.0)] and [8.4 (6.7-10.1) vs. 8.3 (7.5-9.1)]. CONCLUSION: Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.

2.
Sci Rep ; 9(1): 18911, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31827124

RESUMO

Lack of efficacy in the intended disease indication is the major cause of clinical phase drug development failure. Explanations could include the poor external validity of pre-clinical (cell, tissue, and animal) models of human disease and the high false discovery rate (FDR) in preclinical science. FDR is related to the proportion of true relationships available for discovery (γ), and the type 1 (false-positive) and type 2 (false negative) error rates of the experiments designed to uncover them. We estimated the FDR in preclinical science, its effect on drug development success rates, and improvements expected from use of human genomics rather than preclinical studies as the primary source of evidence for drug target identification. Calculations were based on a sample space defined by all human diseases - the 'disease-ome' - represented as columns; and all protein coding genes - 'the protein-coding genome'- represented as rows, producing a matrix of unique gene- (or protein-) disease pairings. We parameterised the space based on 10,000 diseases, 20,000 protein-coding genes, 100 causal genes per disease and 4000 genes encoding druggable targets, examining the effect of varying the parameters and a range of underlying assumptions, on the inferences drawn. We estimated γ, defined mathematical relationships between preclinical FDR and drug development success rates, and estimated improvements in success rates based on human genomics (rather than orthodox preclinical studies). Around one in every 200 protein-disease pairings was estimated to be causal (γ = 0.005) giving an FDR in preclinical research of 92.6%, which likely makes a major contribution to the reported drug development failure rate of 96%. Observed success rate was only slightly greater than expected for a random pick from the sample space. Values for γ back-calculated from reported preclinical and clinical drug development success rates were also close to the a priori estimates. Substituting genome wide (or druggable genome wide) association studies for preclinical studies as the major information source for drug target identification was estimated to reverse the probability of late stage failure because of the more stringent type 1 error rate employed and the ability to interrogate every potential druggable target in the same experiment. Genetic studies conducted at much larger scale, with greater resolution of disease end-points, e.g. by connecting genomics and electronic health record data within healthcare systems has the potential to produce radical improvement in drug development success rate.

3.
Cardiovasc Diabetol ; 18(1): 168, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31815634

RESUMO

BACKGROUND: The use of metformin after acute myocardial infarction (AMI) has been associated with reduced mortality in people with type 2 diabetes mellitus (T2DM). However, it is not known if it is acutely cardioprotective in patients taking metformin at the time of AMI. We compared patient outcomes according to metformin status at the time of admission for fatal and non-fatal AMI in a large cohort of patients in England. METHODS: This study used linked data from primary care, hospital admissions and death registry from 4.7 million inhabitants in England, as part of the CALIBER resource. The primary endpoint was a composite of acute myocardial infarction requiring hospitalisation, stroke and cardiovascular death. The secondary endpoints were heart failure (HF) hospitalisation and all-cause mortality. RESULTS: 4,030 patients with T2DM and incident AMI recorded between January 1998 and October 2010 were included. At AMI admission, 63.9% of patients were receiving metformin and 36.1% another oral hypoglycaemic drug. Median follow-up was 343 (IQR: 1-1436) days. Adjusted analyses showed an increased hazard of the composite endpoint in metformin users compared to non-users (HR 1.09 [1.01-1.19]), but not of the secondary endpoints. The higher risk of the composite endpoint in metformin users was only observed in people taking metformin at AMI admission, whereas metformin use post-AMI was associated with a reduction in risk of all-cause mortality (0.76 [0.62-0.93], P = 0.009). CONCLUSIONS: Our study suggests that metformin use at the time of first AMI is associated with increased risk of cardiovascular disease and death in patients with T2DM, while its use post-AMI might be beneficial. Further investigation in well-designed randomised controlled trials is indicated, especially in view of emerging evidence of cardioprotection from sodium-glucose co-transporter-2 (SGLT2) inhibitors.

4.
BMJ ; 367: l6055, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748235

RESUMO

OBJECTIVE: To determine the relation between age and troponin level and its prognostic implication. DESIGN: Retrospective cohort study. SETTING: Five cardiovascular centres in the UK National Institute for Health Research Health Informatics Collaborative (UK-NIHR HIC). PARTICIPANTS: 257 948 consecutive patients undergoing troponin testing for any clinical reason between 2010 and 2017. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: 257 948 patients had troponin measured during the study period. Analyses on troponin were performed using the peak troponin level, which was the highest troponin level measured during the patient's hospital stay. Troponin levels were standardised as a multiple of each laboratory's 99th centile of the upper limit of normal (ULN). During a median follow-up of 1198 days (interquartile range 514-1866 days), 55 850 (21.7%) deaths occurred. A positive troponin result (that is, higher than the upper limit of normal) signified a 3.2 higher mortality hazard (95% confidence interval 3.1 to 3.2) over three years. Mortality varied noticeably with age, with a hazard ratio of 10.6 (8.5 to 13.3) in 18-29 year olds and 1.5 (1.4 to 1.6) in those older than 90. A positive troponin result was associated with an approximately 15 percentage points higher absolute three year mortality across all age groups. The excess mortality with a positive troponin result was heavily concentrated in the first few weeks. Results were analysed using multivariable adjusted restricted cubic spline Cox regression. A direct relation was seen between troponin level and mortality in patients without acute coronary syndrome (ACS, n=120 049), whereas an inverted U shaped relation was found in patients with ACS (n=14 468), with a paradoxical decline in mortality at peak troponin levels >70×ULN. In the group with ACS, the inverted U shaped relation persisted after multivariable adjustment in those who were managed invasively; however, a direct positive relation was found between troponin level and mortality in patients managed non-invasively. CONCLUSIONS: A positive troponin result was associated with a clinically important increased mortality, regardless of age, even if the level was only slightly above normal. The excess mortality with a raised troponin was heavily concentrated in the first few weeks. STUDY REGISTRATION: ClinicalTrials.gov NCT03507309.


Assuntos
Envelhecimento/sangue , Doenças Cardiovasculares , Troponina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Estudos de Coortes , Tratamento Conservador/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Reino Unido/epidemiologia
5.
J Biomed Semantics ; 10(Suppl 1): 20, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31711543

RESUMO

BACKGROUND: Free text in electronic health records (EHR) may contain additional phenotypic information beyond structured (coded) information. For major health events - heart attack and death - there is a lack of studies evaluating the extent to which free text in the primary care record might add information. Our objectives were to describe the contribution of free text in primary care to the recording of information about myocardial infarction (MI), including subtype, left ventricular function, laboratory results and symptoms; and recording of cause of death. We used the CALIBER EHR research platform which contains primary care data from the Clinical Practice Research Datalink (CPRD) linked to hospital admission data, the MINAP registry of acute coronary syndromes and the death registry. In CALIBER we randomly selected 2000 patients with MI and 1800 deaths. We implemented a rule-based natural language engine, the Freetext Matching Algorithm, on site at CPRD to analyse free text in the primary care record without raw data being released to researchers. We analysed text recorded within 90 days before or 90 days after the MI, and on or after the date of death. RESULTS: We extracted 10,927 diagnoses, 3658 test results, 3313 statements of negation, and 850 suspected diagnoses from the myocardial infarction patients. Inclusion of free text increased the recorded proportion of patients with chest pain in the week prior to MI from 19 to 27%, and differentiated between MI subtypes in a quarter more patients than structured data alone. Cause of death was incompletely recorded in primary care; in 36% the cause was in coded data and in 21% it was in free text. Only 47% of patients had exactly the same cause of death in primary care and the death registry, but this did not differ between coded and free text causes of death. CONCLUSIONS: Among patients who suffer MI or die, unstructured free text in primary care records contains much information that is potentially useful for research such as symptoms, investigation results and specific diagnoses. Access to large scale unstructured data in electronic health records (millions of patients) might yield important insights.

6.
BMC Med ; 17(1): 206, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31744503

RESUMO

BACKGROUND: Clinical guidelines and public health authorities lack recommendations on scalable approaches to defining and monitoring the occurrence and severity of bleeding in populations prescribed antithrombotic therapy. METHODS: We examined linked primary care, hospital admission and death registry electronic health records (CALIBER 1998-2010, England) of patients with newly diagnosed atrial fibrillation, acute myocardial infarction, unstable angina or stable angina with the aim to develop algorithms for bleeding events. Using the developed bleeding phenotypes, Kaplan-Meier plots were used to estimate the incidence of bleeding events and we used Cox regression models to assess the prognosis for all-cause mortality, atherothrombotic events and further bleeding. RESULTS: We present electronic health record phenotyping algorithms for bleeding based on bleeding diagnosis in primary or hospital care, symptoms, transfusion, surgical procedures and haemoglobin values. In validation of the phenotype, we estimated a positive predictive value of 0.88 (95% CI 0.64, 0.99) for hospitalised bleeding. Amongst 128,815 patients, 27,259 (21.2%) had at least 1 bleeding event, with 5-year risks of bleeding of 29.1%, 21.9%, 25.3% and 23.4% following diagnoses of atrial fibrillation, acute myocardial infarction, unstable angina and stable angina, respectively. Rates of hospitalised bleeding per 1000 patients more than doubled from 1.02 (95% CI 0.83, 1.22) in January 1998 to 2.68 (95% CI 2.49, 2.88) in December 2009 coinciding with the increased rates of antiplatelet and vitamin K antagonist prescribing. Patients with hospitalised bleeding and primary care bleeding, with or without markers of severity, were at increased risk of all-cause mortality and atherothrombotic events compared to those with no bleeding. For example, the hazard ratio for all-cause mortality was 1.98 (95% CI 1.86, 2.11) for primary care bleeding with markers of severity and 1.99 (95% CI 1.92, 2.05) for hospitalised bleeding without markers of severity, compared to patients with no bleeding. CONCLUSIONS: Electronic health record bleeding phenotyping algorithms offer a scalable approach to monitoring bleeding in the population. Incidence of bleeding has doubled in incidence since 1998, affects one in four cardiovascular disease patients, and is associated with poor prognosis. Efforts are required to tackle this iatrogenic epidemic.

7.
Lancet Digit Health ; 1(2): e63-e77, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31650125

RESUMO

Background: To effectively prevent, detect, and treat health conditions that affect people during their lifecourse, health-care professionals and researchers need to know which sections of the population are susceptible to which health conditions and at which ages. Hence, we aimed to map the course of human health by identifying the 50 most common health conditions in each decade of life and estimating the median age at first diagnosis. Methods: We developed phenotyping algorithms and codelists for physical and mental health conditions that involve intensive use of health-care resources. Individuals older than 1 year were included in the study if their primary-care and hospital-admission records met research standards set by the Clinical Practice Research Datalink and they had been registered in a general practice in England contributing up-to-standard data for at least 1 year during the study period. We used linked records of individuals from the CALIBER platform to calculate the sex-standardised cumulative incidence for these conditions by 10-year age groups between April 1, 2010, and March 31, 2015. We also derived the median age at diagnosis and prevalence estimates stratified by age, sex, and ethnicity (black, white, south Asian) over the study period from the primary-care and secondary-care records of patients. Findings: We developed case definitions for 308 disease phenotypes. We used records of 2 784 138 patients for the calculation of cumulative incidence and of 3 872 451 patients for the calculation of period prevalence and median age at diagnosis of these conditions. Conditions that first gained prominence at key stages of life were: atopic conditions and infections that led to hospital admission in children (<10 years); acne and menstrual disorders in the teenage years (10-19 years); mental health conditions, obesity, and migraine in individuals aged 20-29 years; soft-tissue disorders and gastro-oesophageal reflux disease in individuals aged 30-39 years; dyslipidaemia, hypertension, and erectile dysfunction in individuals aged 40-59 years; cancer, osteoarthritis, benign prostatic hyperplasia, cataract, diverticular disease, type 2 diabetes, and deafness in individuals aged 60-79 years; and atrial fibrillation, dementia, acute and chronic kidney disease, heart failure, ischaemic heart disease, anaemia, and osteoporosis in individuals aged 80 years or older. Black or south-Asian individuals were diagnosed earlier than white individuals for 258 (84%) of the 308 conditions. Bone fractures and atopic conditions were recorded earlier in male individuals, whereas female individuals were diagnosed at younger ages with nutritional anaemias, tubulointerstitial nephritis, and urinary disorders. Interpretation: We have produced the first chronological map of human health with cumulative-incidence and period-prevalence estimates for multiple morbidities in parallel from birth to advanced age. This can guide clinicians, policy makers, and researchers on how to formulate differential diagnoses, allocate resources, and target research priorities on the basis of the knowledge of who gets which diseases when. We have published our phenotyping algorithms on the CALIBER open-access Portal which will facilitate future research by providing a curated list of reusable case definitions. Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council, Arthritis Research UK, British Heart Foundation, Cancer Research UK, Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Department of Health and Social Care (England), Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), Economic and Social Research Council, Engineering and Physical Sciences Research Council, National Institute for Social Care and Health Research, and The Alan Turing Institute.

8.
BMJ Open ; 9(9): e032165, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31492797

RESUMO

INTRODUCTION: For non-ST-segment elevation acute coronary syndrome (NSTEACS) there is a gap between the use of class I guideline recommended therapies and clinical practice. The Global Registry of Acute Coronary Events (GRACE) risk score is recommended in international guidelines for the risk stratification of NSTEACS, but its impact on adherence to guideline-indicated treatments and reducing adverse clinical outcomes is unknown. The objective of the UK GRACE Risk Score Intervention Study (UKGRIS) trial is to assess the effectiveness of the GRACE risk score tool and associated treatment recommendations on the use of guideline-indicated care and clinical outcomes. METHODS AND ANALYSIS: The UKGRIS, a parallel-group cluster randomised registry-based controlled trial, will allocate hospitals in a 1:1 ratio to manage NSTEACS by standard care or according to the GRACE risk score and associated international guidelines. UKGRIS will recruit a minimum of 3000 patients from at least 30 English National Health Service hospitals and collect healthcare data from national electronic health records. The co-primary endpoints are the use of guideline-indicated therapies, and the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospitalisation or cardiovascular readmission at 12 months. Secondary endpoints include duration of inpatient hospital stay over 12 months, EQ-5D-5L responses and utilities, unscheduled revascularisation and the components of the composite endpoint over 12 months follow-up. ETHICS AND DISSEMINATION: The study has ethical approval (North East - Tyne & Wear South Research Ethics Committee reference: 14/NE/1180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the funder's open access policy. TRIAL REGISTRATION NUMBER: ISRCTN29731761; Pre-results.

9.
Europace ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31408153

RESUMO

AIMS: To evaluate population-based electronic health record (EHR) definitions of atrial fibrillation (AF) and valvular heart disease (VHD) subtypes, time trends in prevalence and prognosis. METHODS AND RESULTS: A total of 76 019 individuals with AF were identified in England in 1998-2010 in the CALIBER resource, linking primary and secondary care EHR. An algorithm was created, implemented, and refined to identify 18 VHD subtypes using 406 diagnosis, procedure, and prescription codes. Cox models were used to investigate associations with a composite endpoint of incident stroke (ischaemic, haemorrhagic, and unspecified), systemic embolism (SSE), and all-cause mortality. Among individuals with AF, the prevalence of AF with concomitant VHD increased from 11.4% (527/4613) in 1998 to 17.6% (7014/39 868) in 2010 and also in individuals aged over 65 years. Those with mechanical valves, mitral stenosis (MS), or aortic stenosis had highest risk of clinical events compared to AF patients with no VHD, in relative [hazard ratio (95% confidence interval): 1.13 (1.02-1.24), 1.20 (1.05-1.36), and 1.27 (1.19-1.37), respectively] and absolute (excess risk: 2.04, 4.20, and 6.37 per 100 person-years, respectively) terms. Of the 95.2% of individuals with indication for warfarin (men and women with CHA2DS2-VASc ≥1 and ≥2, respectively), only 21.8% had a prescription 90 days prior to the study. CONCLUSION: Prevalence of VHD among individuals with AF increased from 1998 to 2010. Atrial fibrillation associated with aortic stenosis, MS, or mechanical valves (compared to AF without VHD) was associated with an excess absolute risk of stroke, SSE, and mortality, but anticoagulation was underused in the pre-direct oral anticoagulant (DOAC) era, highlighting need for urgent clarity regarding DOACs in AF and concomitant VHD.

10.
BMJ Open ; 9(8): e026677, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31446403

RESUMO

OBJECTIVES: Despite the publication of hundreds of trials on gout and hyperuricemia, management of these conditions remains suboptimal. We aimed to assess the quality and consistency of guidance documents for gout and hyperuricemia. DESIGN: Systematic review and quality assessment using the appraisal of guidelines for research and evaluation (AGREE) II methodology. DATA SOURCES: PubMed and EMBASE (27 October 2016), two Chinese academic databases, eight guideline databases, and Google and Google scholar (July 2017). ELIGIBILITY CRITERIA: We included the latest version of international and national/regional clinical practice guidelines and consensus statements for diagnosis and/or treatment of hyperuricemia and gout, published in English or Chinese. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently screened searched items and extracted data. Four reviewers independently scored documents using AGREE II. Recommendations from all documents were tabulated and visualised in a coloured grid. RESULTS: Twenty-four guidance documents (16 clinical practice guidelines and 8 consensus statements) published between 2003 and 2017 were included. Included documents performed well in the domains of scope and purpose (median 85.4%, range 66.7%-100.0%) and clarity of presentation (median 79.2%, range 48.6%-98.6%), but unsatisfactory in applicability (median 10.9%, range 0.0%-66.7%) and editorial independence (median 28.1%, range 0.0%-83.3%). The 2017 British Society of Rheumatology guideline received the highest scores. Recommendations were concordant on the target serum uric acid level for long-term control, on some indications for urate-lowering therapy (ULT), and on the first-line drugs for ULT and for acute attack. Substantially inconsistent recommendations were provided for many items, especially for the timing of initiation of ULT and for treatment for asymptomatic hyperuricemia. CONCLUSIONS: Methodological quality needs improvement in guidance documents on gout and hyperuricemia. Evidence for certain clinical questions is lacking, despite numerous trials in this field. Promoting standard guidance development methods and synthesising high-quality clinical evidence are potential approaches to reduce recommendation inconsistencies. PROSPERO REGISTRATION NUMBER: CRD42016046104.

11.
BMJ Open ; 9(8): e027577, 2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31446406

RESUMO

OBJECTIVE: To assess global health (GH) training in all postgraduate medical education in the UK. DESIGN: Mixed methodology: scoping review and curricular content analysis using two GH competency frameworks. SETTING AND PARTICIPANTS: A scoping review (until December 2017) was used to develop a framework of GH competencies for doctors. National postgraduate medical training curricula were analysed against this and a prior framework for GH competencies. The number of core competencies addressed and/or appearing in each programme was recorded. OUTCOMES: The scoping review identified eight relevant publications. A 16-competency framework was developed and, with a prior 5-competency framework, used to analyse each of 71 postgraduate medical curricula. Curricula were examined by a team of researchers and relevant learning outcomes were coded as one of the 5 or 16 core competencies. The number of core competencies in each programme was recorded. RESULTS: Using the 5-competency and 16-competency frameworks, 23 and 20, respectively, out of 71 programmes contained no global health competencies, most notably the Foundation Programme (equivalent to internship), a compulsory programme for UK medical graduates. Of a possible 16 competencies, the mean number across all 71 programmes was 1.73 (95% CI 1.42 to 2.04) and the highest number were in paediatrics and infectious diseases, each with five competencies. Of the 16 core competencies, global burden of disease and socioeconomic determinants of health were the two most cited with 47 and 35 citations, respectively. 8/16 competencies were not cited in any curriculum. CONCLUSIONS: Equity of care and the challenges of practising in an increasingly globalised world necessitate GH competencies for all doctors. Across the whole of postgraduate training, the majority of UK doctors are receiving minimal or no training in GH. Our GH competency framework can be used to map and plan integration across postgraduate programmes.

12.
Stud Health Technol Inform ; 262: 220-223, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31349307

RESUMO

Electronic health records (EHR) are increasingly being used for observational research at scale. In the UK, we have established the CALIBER research resource which utilizes national primary and hospital EHR data sources and enables researchers to create and validate longitudinal disease phenotypes at scale. In this work, we will describe the core components of the resource and provide results from three exemplar research studies on high-resolution epidemiology, disease risk prediction and subtype discovery which demonstrate both the opportunities and challenges of using EHR for research.


Assuntos
Registros Eletrônicos de Saúde , Fenótipo , Medicina de Precisão , Humanos , Armazenamento e Recuperação da Informação , Reino Unido
13.
J Am Med Inform Assoc ; 26(12): 1545-1559, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31329239

RESUMO

OBJECTIVE: Electronic health records (EHRs) are a rich source of information on human diseases, but the information is variably structured, fragmented, curated using different coding systems, and collected for purposes other than medical research. We describe an approach for developing, validating, and sharing reproducible phenotypes from national structured EHR in the United Kingdom with applications for translational research. MATERIALS AND METHODS: We implemented a rule-based phenotyping framework, with up to 6 approaches of validation. We applied our framework to a sample of 15 million individuals in a national EHR data source (population-based primary care, all ages) linked to hospitalization and death records in England. Data comprised continuous measurements (for example, blood pressure; medication information; coded diagnoses, symptoms, procedures, and referrals), recorded using 5 controlled clinical terminologies: (1) read (primary care, subset of SNOMED-CT [Systematized Nomenclature of Medicine Clinical Terms]), (2) International Classification of Diseases-Ninth Revision and Tenth Revision (secondary care diagnoses and cause of mortality), (3) Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures, Fourth Revision (hospital surgical procedures), and (4) DM+D prescription codes. RESULTS: Using the CALIBER phenotyping framework, we created algorithms for 51 diseases, syndromes, biomarkers, and lifestyle risk factors and provide up to 6 validation approaches. The EHR phenotypes are curated in the open-access CALIBER Portal (https://www.caliberresearch.org/portal) and have been used by 40 national and international research groups in 60 peer-reviewed publications. CONCLUSIONS: We describe a UK EHR phenomics approach within the CALIBER EHR data platform with initial evidence of validity and use, as an important step toward international use of UK EHR data for health research.

14.
J Hepatol ; 71(3): 594-602, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31226389

RESUMO

BACKGROUND & AIMS: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. METHODS: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. RESULTS: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10-8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. CONCLUSION: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. LAY SUMMARY: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.

15.
Nat Commun ; 10(1): 2324, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113941

RESUMO

The original version of this Article contained an error in the spelling of the author Harry Hemingway, which was incorrectly given as Harry Hemmingway. This has been corrected in both the PDF and HTML versions of the Article.

16.
BMC Med Inform Decis Mak ; 19(1): 86, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999919

RESUMO

BACKGROUND: COPD is a highly heterogeneous disease composed of different phenotypes with different aetiological and prognostic profiles and current classification systems do not fully capture this heterogeneity. In this study we sought to discover, describe and validate COPD subtypes using cluster analysis on data derived from electronic health records. METHODS: We applied two unsupervised learning algorithms (k-means and hierarchical clustering) in 30,961 current and former smokers diagnosed with COPD, using linked national structured electronic health records in England available through the CALIBER resource. We used 15 clinical features, including risk factors and comorbidities and performed dimensionality reduction using multiple correspondence analysis. We compared the association between cluster membership and COPD exacerbations and respiratory and cardiovascular death with 10,736 deaths recorded over 146,466 person-years of follow-up. We also implemented and tested a process to assign unseen patients into clusters using a decision tree classifier. RESULTS: We identified and characterized five COPD patient clusters with distinct patient characteristics with respect to demographics, comorbidities, risk of death and exacerbations. The four subgroups were associated with 1) anxiety/depression; 2) severe airflow obstruction and frailty; 3) cardiovascular disease and diabetes and 4) obesity/atopy. A fifth cluster was associated with low prevalence of most comorbid conditions. CONCLUSIONS: COPD patients can be sub-classified into groups with differing risk factors, comorbidities, and prognosis, based on data included in their primary care records. The identified clusters confirm findings of previous clustering studies and draw attention to anxiety and depression as important drivers of the disease in young, female patients.


Assuntos
Registros Eletrônicos de Saúde , Atenção Primária à Saúde , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Doenças Cardiovasculares/epidemiologia , Análise por Conglomerados , Comorbidade , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prevalência , Prognóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Fatores de Risco
17.
BMJ Open ; 9(3): e025460, 2019 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-30928942

RESUMO

OBJECTIVE: To assess health informatics (HI) training in UK postgraduate medical education, across all specialties, against international standards in the context of UK digital health initiatives (eg, Health Data Research UK, National Health Service Digital Academy and Global Digital Exemplars). DESIGN: A mixed methods study of UK postgraduate clinician training curricula (71 specialties) against international HI standards: scoping review, curricular content analysis and expert consultation. SETTING AND PARTICIPANTS: A scoping literature review (PubMed until March 2017) informed development of a contemporary framework of HI competency domains for doctors. National training curricula for 71 postgraduate medical specialties were obtained from the UK General Medical Council and were analysed. Seven UK HI experts were consulted regarding findings. OUTCOMES: The International Medical Informatics Association (IMIA) Recommendations for Biomedical and Health Informatics Education were used to develop a framework of competency domains. The number (maximum 50) of HI competency domains included in each of the 71 UK postgraduate medical specialties was investigated. After expert review, a universal HI competency framework was proposed. RESULTS: A framework of 50 HI competency domains was developed using 21 curricula from a scoping review, curricular content analysis and expert consultation. All 71 UK postgraduate medical curricula documents were mapped across 29 of 50 framework domains; that is, 21 domains were unrepresented. Curricula mapped between 0 (child and adolescent psychiatry and core surgical training) and 16 (chemical pathology and paediatric and perinatal pathology) of the 50 domains (median=7). Expert consultation found that HI competencies should be universal and integrated with existing competencies for UK clinicians and were under-represented in current curricula. Additional universal HI competencies were identified, including information governance and security and secondary use of data. CONCLUSIONS: Postgraduate medical education in the UK neglects HI competencies set out by international standards. Key HI competencies need to be urgently integrated into training curricula to prepare doctors for work in increasingly digitised healthcare environments.

18.
Nat Commun ; 10(1): 805, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30778056

RESUMO

We are increasingly accumulating molecular data about a cell. The challenge is how to integrate them within a unified conceptual and computational framework enabling new discoveries. Hence, we propose a novel, data-driven concept of an integrated cell, iCell. Also, we introduce a computational prototype of an iCell, which integrates three omics, tissue-specific molecular interaction network types. We construct iCells of four cancers and the corresponding tissue controls and identify the most rewired genes in cancer. Many of them are of unknown function and cannot be identified as different in cancer in any specific molecular network. We biologically validate that they have a role in cancer by knockdown experiments followed by cell viability assays. We find additional support through Kaplan-Meier survival curves of thousands of patients. Finally, we extend this analysis to uncover pan-cancer genes. Our methodology is universal and enables integrative comparisons of diverse omics data over cells and tissues.


Assuntos
Biologia Computacional/métodos , Neoplasias/genética , Neoplasias/metabolismo , Mapas de Interação de Proteínas , Células A549 , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes , Células HCT116 , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Masculino , Neoplasias/mortalidade , Reprodutibilidade dos Testes
19.
Wellcome Open Res ; 4: 4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30801036

RESUMO

Background: In 2017, 15.6% of the people living in England were born abroad, yet we have a limited understanding of their use of health services and subsequent health conditions. This linked population-based cohort study aims to describe the hospital-based healthcare and mortality outcomes of 1.5 million non-European Union (EU) migrants and refugees in England. Methods and analysis: We will link four data sources: first, non-EU migrant tuberculosis pre-entry screening data; second, refugee pre-entry health assessment data; third, national hospital episode statistics; and fourth, Office of National Statistics death records. Using this linked dataset, we will then generate a population-based cohort to examine hospital-based events and mortality outcomes in England between Jan 1, 2006, and Dec 31, 2017. We will compare outcomes across three groups in our analyses: 1) non-EU international migrants, 2) refugees, and 3) general population of England. Ethics and dissemination: We will obtain approval to use unconsented patient identifiable data from the Secretary of State for Health through the Confidentiality Advisory Group and the National Health Service Research Ethics Committee. After data linkage, we will destroy identifying data and undertake all analyses using the pseudonymised dataset. The results will provide policy makers and civil society with detailed information about the health needs of non-EU international migrants and refugees in England.

20.
Eur J Heart Fail ; 21(10): 1197-1206, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30618162

RESUMO

AIMS: Several risk factors for incident heart failure (HF) have been previously identified, however large electronic health records (EHR) datasets may provide the opportunity to examine the consistency of risk factors across different subgroups from the general population. METHODS AND RESULTS: We used linked EHR data from 2000 to 2010 as part of the UK-based CALIBER resource to select a cohort of 871 687 individuals 55 years or older and free of HF at baseline. The primary endpoint was the first record of HF from primary or secondary care. Cox proportional hazards analysis was used to estimate hazard ratios for associations between risk factors and incident HF, separately for men and women and by age category: 55-64, 65-74, and > 75 years. During 5.8 years of median follow-up, a total of 47 987 incident HF cases were recorded. Age, social deprivation, smoking, sedentary lifestyle, diabetes, atrial fibrillation, chronic obstructive pulmonary disease, body mass index, haemoglobin, total white blood cell count and creatinine were associated with HF. Smoking, atrial fibrillation and diabetes showed stronger associations with incident HF in women compared to men. CONCLUSION: We confirmed associations of several risk factors with HF in this large population-based cohort across age and sex subgroups. Mainly modifiable risk factors and comorbidities are strongly associated with incident HF, highlighting the importance of preventive strategies targeting such risk factors for HF.

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