Neutrophil Counts and Initial Presentation of 12 Cardiovascular Diseases: A CALIBER Cohort Study

BACKGROUND: Neutrophil counts are a ubiquitous measure of inflammation, but previous studies on their association with cardiovascular disease (CVD) were limited by small numbers of patients or a narrow range of endpoints. OBJECTIVES: This study investigated associations of clinically recorded neutrophil counts with initial presentation for a range of CVDs. METHODS: We used linked primary care, hospitalization, disease registry, and mortality data in England. We included people 30 years or older with complete blood counts performed in usual clinical care and no history of CVD. We used Cox models to estimate cause-specific hazard ratios (HRs) for 12 CVDs, adjusted for cardiovascular risk factors and acute conditions affecting neutrophil counts (such as infections and cancer). RESULTS: Among 775,231 individuals in the cohort, 154,179 had complete blood counts performed under acute conditions and 621,052 when they were stable. Over a median 3.8 years of follow-up, 55,004 individuals developed CVD. Adjusted HRs comparing neutrophil counts 6 to 7 versus 2 to 3 × 10(9)/l (both within the 'normal' range) showed strong associations with heart failure (HR: 2.04; 95% confidence interval [CI]: 1.82 to 2.29), peripheral arterial disease (HR: 1.95; 95% CI: 1.72 to 2.21), unheralded coronary death (HR: 1.78; 95% CI: 1.51 to 2.10), abdominal aortic aneurysm (HR: 1.72; 95% CI: 1.34 to 2.21), and nonfatal myocardial infarction (HR: 1.58; 95% CI: 1.42 to 1.76). These associations were linear, with greater risk even among individuals with neutrophil counts of 3 to 4 versus 2 to 3 × 10(9)/l. There was a weak association with ischemic stroke (HR: 1.36; 95% CI: 1.17 to 1.57), but no association with stable angina or intracerebral hemorrhage. CONCLUSIONS: Neutrophil counts were strongly associated with the incidence of some CVDs, but not others, even within the normal range, consistent with underlying disease mechanisms differing across CVDs. (White Blood Cell Counts and Onset of Cardiovascular Diseases: a CALIBER Study [CALIBER]; NCT02014610)

Low eosinophil and low lymphocyte counts and the incidence of 12 cardiovascular diseases: a CALIBER cohort study

BACKGROUND: Eosinophil and lymphocyte counts are commonly performed in clinical practice. Previous studies provide conflicting evidence of association with cardiovascular diseases. METHODS: We used linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER (CArdiovascular disease research using LInked Bespoke studies and Electronic health Records) programme). We included people aged 30 or older without cardiovascular disease at baseline, and used Cox models to estimate cause-specific HRs for the association of eosinophil or lymphocyte counts with the first occurrence of cardiovascular disease. RESULTS: The cohort comprised 775 231 individuals, of whom 55 004 presented with cardiovascular disease over median follow-up 3.8 years. Over the first 6 months, there was a strong association of low eosinophil counts (<0.05 compared with 0.15-0.25×10(9)/L) with heart failure (adjusted HR 2.05; 95% CI 1.72 to 2.43), unheralded coronary death (HR 1.94, 95% CI 1.40 to 2.69), ventricular arrhythmia/sudden cardiac death and subarachnoid haemorrhage, but not angina, non-fatal myocardial infarction, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, subarachnoid haemorrhage or abdominal aortic aneurysm. Low eosinophil count was inversely associated with peripheral arterial disease (HR 0.63, 95% CI 0.44 to 0.89). There were similar associations with low lymphocyte counts (<1.45 vs 1.85-2.15×10(9)/L); adjusted HR over the first 6 months for heart failure was 2.25 (95% CI 1.90 to 2.67). Associations beyond the first 6 months were weaker. CONCLUSIONS: Low eosinophil counts and low lymphocyte counts in the general population are associated with increased short-term incidence of heart failure and coronary death. TRIAL REGISTRATION NUMBER: NCT02014610; results

Data gaps in electronic health record (EHR) systems: An audit of problem list completeness during the COVID-19 pandemic

OBJECTIVE: To evaluate the completeness of diagnosis recording in problem lists in a hospital electronic health record (EHR) system during the COVID-19 pandemic. DESIGN: Retrospective chart review with manual review of free text electronic case notes. SETTING: Major teaching hospital trust in London, one year after the launch of a comprehensive EHR system (Epic), during the first peak of the COVID-19 pandemic in the UK. PARTICIPANTS: 516 patients with suspected or confirmed COVID-19. MAIN OUTCOME MEASURES: Percentage of diagnoses already included in the structured problem list. RESULTS: Prior to review, these patients had a combined total of 2841 diagnoses recorded in their EHR problem lists. 1722 additional diagnoses were identified, increasing the mean number of recorded problems per patient from 5.51 to 8.84. The overall percentage of diagnoses originally included in the problem list was 62.3% (2841 / 4563, 95% confidence interval 60.8%, 63.7%). CONCLUSIONS: Diagnoses and other clinical information stored in a structured way in electronic health records is extremely useful for supporting clinical decisions, improving patient care and enabling better research. However, recording of medical diagnoses on the structured problem list for inpatients is incomplete, with almost 40% of important diagnoses mentioned only in the free text notes

Control of light transmission through opaque scattering media in space and time

We report the first experimental demonstration of combined spatial and temporal control of light trajectories through opaque media. This control is achieved by solely manipulating spatial degrees of freedom of the incident wavefront. As an application, we demonstrate that the present approach is capable to form bandwidth-limited ultrashort pulses from the otherwise randomly transmitted light with a controllable interaction time of the pulses with the medium. Our approach provides a new tool for fundamental studies of light propagation in complex media and has potential for applications for coherent control, sensing and imaging in nano- and biophotonics

Cardiac troponins and prediction of coronary artery disease risk

Cardiac troponins are released into the bloodstream as a result of myocardial injury and their detection in the blood is in routine clinical use for the diagnosis of myocardial infarction. A range of other cardiac and non-cardiac conditions may also cause a rise in troponin. A number of recent studies have found that high-sensitivity troponin is significantly associated with future coronary events in people without prior cardiovascular disease. Some studies have investigated its incremental benefit in risk prediction models, but have been too small to show a statistically significant improvement in the C statistic. Nevertheless, troponin measurements should be considered as a cardiovascular risk marker among healthy people as well as a diagnostic marker for myocardial infarction

Using electronic health records to investigate blood biomarkers and onset of cardiovascular diseases: example of differential white cell count

BACKGROUND: Electronic health records are invaluable for studying clinically recorded biomarkers and outcomes, but conversion of raw datasets to a research-ready format and replication of analyses can be challenging. The differential white cell count is a common blood test which may reflect inflammation and cardiovascular risk, but previous epidemiological studies have been small or in selected populations. AIM: To develop methods to assist in using electronic health record databases for research, and apply them to an exemplar study investigating differential white cell counts and onset of cardiovascular diseases. METHODS: The data source was CALIBER: linked electronic health records from primary care, hospitalisation, acute coronary syndrome registry and death registry. Software was developed to assist selection of relevant diagnostic codes, data manipulation, and multiple imputation of missing data. Individuals in CALIBER without prior cardiovascular disease were followed up for a range of specific initial cardiovascular presentations. Survival models were used to investigate the associations of type 2 diabetes and differential white cell counts with initial cardiovascular presentations. The association of total white cell count with mortality was investigated in CALIBER and replicated in the New Zealand PREDICT cohort. RESULTS: Add-on software packages for the R statistical system were developed and published in an open access repository. Type 2 diabetes was associated with higher risk of coronary disease and ischaemic stroke but lower risk of abdominal aortic aneurysm and subarachnoid haemorrhage. Among 775231 individuals with a record of differential leukocyte count followed up for median 3.8 years, 54980 experienced an initial presentation of cardiovascular disease. High neutrophil counts were strongly associated with heart failure and myocardial infarction, but not angina. Low eosinophil counts were associated with heart failure and unheralded coronary death. Total white cell count showed a ‘J’ shaped association with mortality in both CALIBER and PREDICT. CONCLUSIONS: White cell subtypes are differentially associated with specific initial cardiovascular presentations. A range of tools were developed to assist researchers using CALIBER and other electronic health record data sources

Data Resource Profile: Cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER)

The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼105 patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail [email protected]

White cell count in the normal range and short-term and long-term mortality: international comparisons of electronic health record cohorts in England and New Zealand

OBJECTIVES: Electronic health records offer the opportunity to discover new clinical implications for established blood tests, but international comparisons have been lacking. We tested the association of total white cell count (WBC) with all-cause mortality in England and New Zealand. SETTING: Primary care practices in England (ClinicAl research using LInked Bespoke studies and Electronic health Records (CALIBER)) and New Zealand (PREDICT). DESIGN: Analysis of linked electronic health record data sets: CALIBER (primary care, hospitalisation, mortality and acute coronary syndrome registry) and PREDICT (cardiovascular risk assessments in primary care, hospitalisations, mortality, dispensed medication and laboratory results). PARTICIPANTS: People aged 30-75 years with no prior cardiovascular disease (CALIBER: N=686 475, 92.0% white; PREDICT: N=194 513, 53.5% European, 14.7% Pacific, 13.4% Maori), followed until death, transfer out of practice (in CALIBER) or study end. PRIMARY OUTCOME MEASURE: HRs for mortality were estimated using Cox models adjusted for age, sex, smoking, diabetes, systolic blood pressure, ethnicity and total:high-density lipoprotein (HDL) cholesterol ratio. RESULTS: We found 'J'-shaped associations between WBC and mortality; the second quintile was associated with lowest risk in both cohorts. High WBC within the reference range (8.65-10.05×10(9)/L) was associated with significantly increased mortality compared to the middle quintile (6.25-7.25×10(9)/L); adjusted HR 1.51 (95% CI 1.43 to 1.59) in CALIBER and 1.33 (95% CI 1.06 to 1.65) in PREDICT. WBC outside the reference range was associated with even greater mortality. The association was stronger over the first 6 months of follow-up, but similar across ethnic groups. CONCLUSIONS: Clinically recorded WBC within the range considered 'normal' is associated with mortality in ethnically different populations from two countries, particularly within the first 6 months. Large-scale international comparisons of electronic health record cohorts might yield new insights from widely performed clinical tests. TRIAL REGISTRATION NUMBER: NCT02014610

Net clinical benefit of warfarin in individuals with atrial fibrillation across stroke risk and across primary and secondary care

OBJECTIVE: To investigate net clinical benefit (NCB) of warfarin in individuals with atrial fibrillation (AF) across stroke risk and across primary and secondary care. METHODS: We conducted a linked electronic health record cohort study of 70 206 individuals with initial record of diagnosis of AF in primary (n=29 568) or secondary care (n=40 638) in England (1998-2010). We defined stroke risk according to the CHA2DS2-VASc score, and followed individuals over a median 2.2 years for 7005 ischaemic strokes (IS) and for 906 haemorrhagic strokes (HS). We calculated incidence rates (IRs) and 95% CIs per 100 person-years (PYs) (IR (95% CI)/100 PY) of IS and HS, with and without use of warfarin, and the NCB (ie, number of IS avoided) per 100 PYs of warfarin use (NCB (95% CI)/100 PY). RESULTS: Compared with individuals with initial record of diagnosis in secondary care, those in primary care had lower scores of IS risk (CHA2DS2-VASc≤2: 30.8% vs 20.6%), and lower overall incidence of IS (IR (95% CI)/100 PY: 2.3 (2.2 to 2.4) vs 4.3 (4.2 to 4.4), p value=0.00); however among individuals with CHA2DS2-VASc=0, 1 or 2 there were no differences in IS rate between those with initial record of diagnosis in primary care or secondary care (IR (95% CI)/100 PY: 0.2 (0.1 to 0.3) vs 0.3 (0.2 to 0.5), p value=0.16), (IR (95% CI)/100 PY: 0.6 (0.4 to 0.7) vs 0.7 (0.6 to 0.9), p value=0.08) and (IR (95% CI)/100 PY: 1.1 (1.00 to 1.3) vs 1.4 (1.2 to 1.6), p value=0.05), respectively. For CHA2DS2-VASc=0, 1 and 2, IRs of IS with versus without warfarin were (IR (95% CI)/100 PY: 0.4 (0.2 to 0.8) vs 0.2 (0.1 to 0.3), p value=0.16), (IR (95% CI)/100 PY: 0.4 (0.3 to 0.7) vs 0.7 (0.6 to 0.8), p value=0.03) and (IR (95% CI)/100 PY: 0.8 (0.7 to 1.0) vs 1.4 (1.3 to 1.6), p value=0.00), respectively. We found a significant positive NCB of warfarin from CHA2DS2-VASc≥2 in men (NCB (95% CI)/100 PY: 0.5 (0.1 to 0.9)) and from CHA2DS2-VASc≥3 in women (NCB (95% CI)/100 PY: 1.5 (1.1 to 1.9)). CONCLUSIONS: CHA2DS2-VASc accurately stratifies IS risk in individuals with AF across both primary and secondary care. However, the incidence rate of ischaemic stroke at CHA2DS2-VASc=1 are lower than previously reported, which may change the decision to start anticoagulation with warfarin in these individuals