A Wolf in Sheep's Clothing: Reuse of Routinely Obtained Laboratory Data in Research.

Electronic health records (EHRs) contain valuable data for reuse in science, quality evaluations, and clinical decision support. Because routinely obtained laboratory data are abundantly present, often numeric, generated by certified laboratories, and stored in a structured way, one may assume that they are immediately fit for (re)use in research. However, behind each test result lies an extensive context of choices and considerations, made by both humans and machines, that introduces hidden patterns in the data. If they are unaware, researchers reusing routine laboratory data may eventually draw incorrect conclusions. In this paper, after discussing health care system characteristics on both the macro and micro level, we introduce the reader to hidden aspects of generating structured routine laboratory data in 4 steps (ordering, preanalysis, analysis, and postanalysis) and explain how each of these steps may interfere with the reuse of routine laboratory data. As researchers reusing these data, we underline the importance of domain knowledge of the health care professional, laboratory specialist, data manager, and patient to turn routine laboratory data into meaningful data sets to help obtain relevant insights that create value for clinical care.

A pan-inflammatory microRNA-cluster is associated with orbital non-Hodgkin lymphoma and idiopathic orbital inflammation.

Non-Hodgkin orbital lymphoma (NHOL) and idiopathic orbital inflammation (IOI) are common orbital conditions with largely unknown pathophysiology that can be difficult to diagnose. In this study we aim to identify serum miRNAs associated with NHOL and IOI. We performed OpenArray® miRNA profiling in 33 patients and controls. Differentially expressed miRNAs were technically validated across technology platforms and replicated in an additional cohort of 32 patients and controls. We identified and independently validated a serum miRNA profile of NHOL that was remarkably similar to IOI and characterized by an increased expression of a cluster of eight miRNAs. Pathway enrichment analysis indicated that the miRNA-cluster is associated with immune-mediated pathways, which we supported by demonstrating the elevated expression of this cluster in serum of patients with other inflammatory conditions. The cluster contained miR-148a, a key driver of B-cell tolerance, and miR-365 that correlated with serum IgG and IgM concentrations. In addition, miR-29a and miR-223 were associated with blood lymphocyte and neutrophil populations, respectively. NHOL and IOI are characterized by an abnormal serum miRNA-cluster associated with immune pathway activation and linked to B cell and neutrophil dysfunction.

Intra-Operative Hypotension is a Risk Factor for Post-operative Silent Brain Ischaemia in Patients With Pre-operative Hypertension Undergoing Carotid Endarterectomy.

OBJECTIVE: Intra-operative haemodynamic instability during carotid endarterectomy (CEA) has been associated with an increased risk of procedural stroke. Diffusion weighted imaging (DWI) lesions have been proposed as a surrogate marker for peri-operative silent cerebral ischaemia. This study aimed to investigate the relationship between peri-operative blood pressure (BP) and presence of post-operative DWI lesions in patients undergoing CEA. METHODS: A retrospective analysis was performed based on patients with symptomatic CEA included in the MRI substudy of the International Carotid Stenting Study. Relative intra-operative hypotension was defined as a decrease of intra-operative systolic BP ≥ 20% compared with pre-operative ('baseline') BP, absolute hypotension was defined as a drop in systolic BP < 80  mmHg. The primary endpoint was the presence of any new DWI lesions on post-operative MRI (DWI positive). The occurrence and duration of intra-operative hypotension was compared between DWI positive and DWI negative patients as was the magnitude of the difference between pre- and intra-operative BP. RESULTS: Fifty-five patients with symptomatic CEA were included, of whom eight were DWI positive. DWI positive patients had a significantly higher baseline systolic (186 ± 31 vs. 158 ± 27 mmHg, p = .011) and diastolic BP (95 ± 15 vs. 84 ± 13 mmHg, p = .046) compared with DWI negative patients. Other pre-operative characteristics did not differ. Relative intra-operative hypotension compared with baseline occurred in 53/55 patients (median duration 34 min; range 0-174). Duration of hypotension did not differ significantly between the groups (p = .088). Mean systolic intra-operative BP compared with baseline revealed a larger drop in BP (-37 ± 29 mmHg) in DWI positive compared with DWI negative patients (-14 ± 26 mmHg, p = .024). Absolute intra-operative systolic BP values did not differ between the groups. CONCLUSION: In this exploratory study, high pre-operative BP and a larger drop of intra-operative BP were associated with peri-procedural cerebral ischaemia as documented with DWI. These results call for confirmation in an adequately sized prospective study, as they suggest important consequences for peri-operative haemodynamic management in carotid revascularisation.

Reticulated Platelets as Predictor of Myocardial Injury and 30 Day Mortality After Non-cardiac Surgery.

OBJECTIVE: A pre-operative marker for identification of patients at risk of peri-operative adverse events and 30 day mortality might be the percentage of young, reticulated platelets (pRP). This study aimed to determine the predictive value of pre-operative pRP on post-operative myocardial injury (PMI) and 30 day mortality, in patients aged ≥ 60 years undergoing moderate to high risk non-cardiac surgery. METHODS: The incidence of PMI (troponin I > 0.06 µg/L) and 30 day mortality was compared for patients with normal and high pRP (≥2.82%) obtained from The Utrecht Patient Orientated Database. The predictive pRP value was assessed using logistic regression. A prediction model for PMI or 30 day mortality with known risk factors was compared with a model including increased pRP using the area under the receiving operator characteristics curve (AUROC). RESULTS: In total, 26.5% (607/2289) patients showed pre-operative increased pRP. Increased pRP was associated with more PMI and 30 day mortality compared with normal pRP (36.1% vs. 28.3%, p < .001 and 8.6% vs. 3.6%, p < .001). The median pRP was higher in patients suffering PMI and 30 day mortality compared with not (2.21 [IQR: 1.57-3.11] vs. 2.07 [IQR: 1.52-1.78], p = .002, and 2.63 [IQR: 1.76-4.15] vs. 2.09 [IQR: 1.52-3.98], p < .001). pRP was independently related to PMI (OR: 1.28 [95% CI: 1.04-1.59], p = .02) and 30 day mortality (OR: 2.35 [95% CI: 1.56-3.55], p < .001). Adding increased pRP to the predictive model of PMI or 30 day mortality did not increase the AUROC 0.71 vs. 0.72, and 0.80 vs. 0.81. CONCLUSION: In patients undergoing major non-cardiac surgery, increased pre-operative pRP is related to 30 day mortality and PMI.

A single preoperative blood test predicts postoperative sepsis and pneumonia after coronary bypass or open aneurysm surgery.

BACKGROUND: Major surgery comes with a high risk for postoperative inflammatory complications. Preoperative risk scores predict mortality risk but fail to identify patients at risk for complications following cardiovascular surgery. We therefore assessed the value of preoperative red cell distribution width (RDW) as a predictor for pneumonia and sepsis after cardiovascular surgery and studied the relation of RDW with hematopoietic tissue activity. METHODS: RDW is an easily accessible, yet seldomly used parameter from routine haematology measurements. RDW was extracted from the Utrecht Patient Orientated Database (UPOD) for preoperative measurements in patients undergoing open abdominal aortic anuerysm repair (AAA)(N = 136) or coronary artery bypass grafting (CABG)(N = 2193). The cohorts were stratified in tertiles to assess effects over the different groups. Generalized Linear Models were used to determine associations between RDW and postoperative inflammatory complications. Hematopoietic tissue activity was scored using fluor-18-(18F)-deoxyglucose positron emission tomography and associated with RDW using linear regression models. RESULTS: In total, 43(31.6%) and 73 patients (3.3%) suffered from inflammatory complications after AAA-repair or CABG, respectively; the majority being pneumonia in both cohorts. Postoperative inflammatory outcome incidence increased from 19.6% in the lowest to 48.9% in the highest RDW tertile with a corresponding risk ratio (RR) of 2.35 ([95%CI:1.08-5.14] P = 0.032) in AAA patients. In the CABG cohort, the incidence of postoperative inflammatory outcomes increased from 1.8% to 5.3% with an adjusted RR of 1.95 ([95%CI:1.02-3.75] P = 0.044) for the highest RDW tertile compared with the lowest RDW tertile. FDG-PET scans showed associations of RDW with tissue activity in the spleen (B = 0.517 [P = 0.001]) and the lumbar bone marrow (B = 0.480 [P = 0.004]). CONCLUSION: Elevated RDW associates with increased risk for postoperative inflammatory complications and hematopoietic tissue activity. RDW likely reflects chronic low-grade inflammation and should be considered to identify patients at risk for postoperative inflammatory complications following cardiovascular surgery.

The impact of serum potassium-influencing antihypertensive drugs on the risk of out-of-hospital cardiac arrest: A case-control study.

AIMS: Sudden cardiac arrest (SCA) is a complex multifactorial event and most commonly caused by ventricular tachycardia/ fibrillation (VT/ VF). Some antihypertensive drugs could induce hypokalaemia or hyperkalaemia, which may increase susceptibility to VT/VF and SCA. OBJECTIVE: To assess the association between different classes of antihypertensive drugs classified according to their potential impact on serum potassium levels and the occurrence of out-of-hospital cardiac arrest (OHCA) based on VT/VF. METHODS: A case-control study was performed among current users of antihypertensive drugs. Cases were OHCA victims with electrocardiogram documented VT/VF drawn from the AmsteRdam REsuscitation STudies (ARREST) registry, and controls were non-OHCA individuals from the PHARMO database. Antihypertensive drugs were classified into: (i) antihypertensives with neutral effect on serum potassium levels; (ii) hypokalaemia-inducing antihypertensives; (iii) hyperkalaemia-inducing antihypertensives; (iv) combination of antihypertensives with hypo- and hyperkalaemic effects. RESULTS: We included 1345 cases and 4145 controls. The risk of OHCA was significantly increased among users of hypokalaemia-inducing antihypertensives [adjusted odds ratio (OR) 1.39; 95% confidence interval (CI) 1.10-1.76] and among users of a combination of antihypertensives with hypo- and hyperkalaemic effects (adjusted OR 1.42; 95%CI 1.17-1.72) vs. users of antihypertensives with neutral effect. There was no difference in OHCA risk between users of hyperkalaemia-inducing antihypertensives vs. users of antihypertensive drugs with neutral effect (adjusted OR 1.15; 95%CI 0.95-1.40). CONCLUSION: The risk of OHCA is significantly increased in patients who were current users of hypokalaemia-inducing antihypertensives and patients using a combination of antihypertensives with hypo- and hyperkalaemic effects.

The IMI PROTECT project: purpose, organizational structure, and procedures.

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally.

Multi-centre, multi-database studies with common protocols: lessons learnt from the IMI PROTECT project.

PURPOSE: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases. METHODS: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases. RESULTS: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10 years and different types of cancer. CONCLUSIONS: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

Risk of acute liver injury associated with use of antibiotics. Comparative cohort and nested case-control studies using two primary care databases in Europe.

PURPOSE: To assess the impact of varying study designs, exposure and outcome definitions on the risk of acute liver injury (ALI) associated with antibiotic use. METHODS: The source population comprised of patients registered in two primary care databases, in the UK and in Spain. We identified a cohort consisting of new users of antibiotics during the study period (2004-2009) and non-users during the study period or in the previous year. Cases with ALI were identified within this cohort and classified as definite or probable, based on recorded medical information. The relative risk (RR) of ALI associated with antibiotic use was computed using Poisson regression. For the nested case-control analyses, up to five controls were matched to each case by age, sex, date and practice (in CPRD) and odds ratios (OR) were computed with conditional logistic regression. RESULTS: The age, sex and year adjusted RRs of definite ALI in the current antibiotic use periods was 10.04 (95% CI: 6.97-14.47) in CPRD and 5.76 (95% CI: 3.46-9.59) in BIFAP. In the case-control analyses adjusting for life-style, comorbidities and use of medications, the OR of ALI for current users of antibiotics was and 5.7 (95% CI: 3.46-9.36) in CPRD and 2.6 (95% CI: 1.26-5.37) in BIFAP. CONCLUSION: Guided by a common protocol, both cohort and case-control study designs found an increased risk of ALI associated with the use of antibiotics in both databases, independent of the exposure and case definitions used. However, the magnitude of the risk was higher in CPRD compared to BIFAP.

Case-only designs for studying the association of antidepressants and hip or femur fracture.

PURPOSE: The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed. METHODS: Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases. AD exposure was classified into current, recent and past/non-use (reference). In the CCO, for each patient, a case moment (date of HF) and four prior control moments at -91, -182, -273 and -365 days were defined. In SCCS, incidence of HF was compared between exposure states. Conditional logistic regression was used in the CCO and Poisson regression in the SCCS to compute odds ratios and incidence rate ratios, respectively. In CCO, we adjusted for time-varying co-medication and in SCCS for age. RESULTS: Adjusted estimates for the effect of current AD exposure on HF were higher in the CCO (co-medication-adjusted odds ratio, THIN: 2.24, 95% confidence interval [CI]: 2.04-2.47; Mondriaan: 2.57, 95%CI [1.50, 4.43]) than in the SCCS (age-adjusted incidence rate ratio, THIN: 1.41, 95%CI [1.32, 1.49]; Mondriaan: 2.14, 95%CI [1.51, 3.03]). The latter were comparable with the traditional designs. CONCLUSION: Case-only designs confirmed the association between AD and HF. The CCO design violated assumptions in this study with regard to exchangeability and length of exposure, and transient effects on outcome. The SCCS seems to be an appropriate design for assessing AD-HF association.

Hip/femur fractures associated with the use of benzodiazepines (anxiolytics, hypnotics and related drugs): a methodological approach to assess consistencies across databases from the PROTECT-EU project.

BACKGROUND: Results from observational studies may be inconsistent because of variations in methodological and clinical factors that may be intrinsically related to the database (DB) where the study is performed. OBJECTIVES: The objectives of this paper were to evaluate the impact of applying a common study protocol to study benzodiazepines (BZDs) (anxiolytics, hypnotics, and related drugs) and the risk of hip/femur fracture (HFF) across three European primary care DBs and to investigate any resulting discrepancies. METHODS: To measure the risk of HFF among adult users of BZDs during 2001-2009, three cohort and nested case control (NCC) studies were performed in Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) (Spain), Clinical Practice Research Datalink (CPRD) (UK), and Mondriaan (The Netherlands). Four different models (A-D) with increasing levels of adjustment were analyzed. The risk according to duration and type of BZD was also explored. Adjusted hazard ratios (cohort), odds ratios (NCC), and their 95% confidence intervals were estimated. RESULTS: Adjusted hazard ratios (Model C) were 1.34 (1.23-1.47) in BIFAP, 1.66 (1.54-1.78) in CPRD, and 2.22 (1.55-3.29) in Mondriaan in cohort studies. Adjusted odds ratios (Model C) were 1.28 (1.16-1.42) in BIFAP, 1.60 (1.49-1.72) in CPRD, and 1.48 (0.89-2.48) in Mondriaan in NCC studies. A short-term effect was suggested in Mondriaan, but not in CPRD or BIFAP. All DBs showed an increased risk with the concomitant use of anxiolytic and hypnotic drugs. CONCLUSIONS: Applying similar study methods to different populations and DBs showed an increased risk of HFF in BZDs users but differed in the magnitude of the risk, which may be because of inherent differences between DBs.

Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.

PURPOSE: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs. METHODS: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture. A common protocol and statistical analysis plan was applied to harmonize study design and conduct between data sources. RESULTS: Current use of antidepressants was consistently associated with a 1.5 to 2.5-fold increased risk of hip/femur fractures in all data sources with both designs, with estimates for SSRIs generally higher than those for TCAs. In general, risk estimates in Mondriaan, the smallest data source, were higher compared to the other data sources. This difference may be partially explained by an interaction between SSRI and age in Mondriaan. Adjustment for GP-recorded lifestyle factors and matching on general practice had negligible impact on adjusted relative risk estimates. CONCLUSION: We found a consistent increased risk of hip/femur fracture with current use of antidepressants across different databases and different designs. Applying similar pharmacoepidemiological study methods resulted in similar risks for TCA use and some variation for SSRI use. Some of these differences may express real (or natural) variance in the exposure-outcome co-occurrences.

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PURPOSE: Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. METHODS: Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. RESULTS: Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. CONCLUSION: Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences.

Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.

Antiepileptic drug use in seven electronic health record databases in Europe: a methodologic comparison.

OBJECTIVE: The annual prevalence of antiepileptic drug (AED) prescribing reported in the literature differs considerably among European countries due to use of different type of data sources, time periods, population distribution, and methodologic differences. This study aimed to measure prevalence of AED prescribing across seven European routine health care databases in Spain, Denmark, The Netherlands, the United Kingdom, and Germany using a standardized methodology and to investigate sources of variation. METHODS: Analyses on the annual prevalence of AEDs were stratified by sex, age, and AED. Overall prevalences were standardized to the European 2008 reference population. RESULTS: Prevalence of any AED varied from 88 per 10,000 persons (The Netherlands) to 144 per 10,000 in Spain and Denmark in 2001. In all databases, prevalence increased linearly: from 6% in Denmark to 15% in Spain each year since 2001. This increase could be attributed entirely to an increase in "new," recently marketed AEDs while prevalence of AEDs that have been available since the mid-1990s, hardly changed. AED use increased with age for both female and male patients up to the ages of 80 to 89 years old and tended to be somewhat higher in female than in male patients between the ages of 40 and 70. No differences between databases in the number of AEDs used simultaneously by a patient were found. SIGNIFICANCE: We showed that during the study period of 2001-2009, AED prescribing increased in five European Union (EU) countries and that this increase was due entirely to the newer AEDs marketed since the 1990s. Using a standardized methodology, we showed consistent trends across databases and countries over time. Differences in age and sex distribution explained only part of the variation between countries. Therefore, remaining variation in AED use must originate from other differences in national health care systems.

Sources of heterogeneity in case-control studies on associations between statins, ACE-inhibitors, and proton pump inhibitors and risk of pneumonia.

The heterogeneity in case-control studies on the associations between community-acquired pneumonia (CAP) and ACE-inhibitors (ACEi), statins, and proton pump inhibitors (PPI) hampers translation to clinical practice. Our objective is to explore sources of this heterogeneity by applying a common protocol in different data settings. We conducted ten case-control studies using data from five different health care databases. Databases varied on type of patients (hospitalised vs. GP), level of case validity, and mode of exposure ascertainment (prescription or dispensing based). Identified CAP patients and controls were matched on age, gender, and calendar year. Conditional logistic regression was used to calculate odds ratios (OR) for the associations between the drugs of interest and CAP. Associations were adjusted by a common set of potential confounders. Data of 38,742 cases and 118,019 controls were studied. Comparable patterns of variation between case-control studies were observed for ACEi, statins and PPI use and pneumonia risk with adjusted ORs varying from 1.04 to 1.49, 0.82 to 1.50 and 1.16 to 2.71, respectively. Overall, higher ORs were found for hospitalised CAP patients matched to population controls versus GP CAP patients matched to population controls. Prevalence of drug exposure was higher in dispensing data versus prescription data. We show that case-control selection and methods of exposure ascertainment induce bias that cannot be adjusted for and to a considerable extent explain the heterogeneity in results obtained in case-control studies on statins, ACEi and PPIs and CAP. The common protocol approach helps to better understand sources of variation in observational studies.

Relationship of neutrophil-to-lymphocyte ratio, in addition to C-reactive protein, with cardiovascular events in patients with type 2 diabetes.

AIM: To quantify the relationship of neutrophil-to-lymphocyte ratio (NLR) with cardiovascular events and all-cause mortality in patients with type 2 diabetes (T2D), independent of C-reactive protein (CRP). METHODS: Patients with T2D from the UCC-SMART-cohort were studied using multivariable-adjusted Cox regression. The relationship of NLR and CRP with vascular events (cerebrovascular events, myocardial infarction and vascular death) and all-cause mortality was quantified. RESULTS: During 10,833 person-years, 232 vascular events and 302 deaths occurred in 1,239 patients with T2D. Risk of vascular events and all-cause mortality increased per standard deviation (SD) in NLR (hazard ratio (HR) 1.27; 95 % confidence interval (CI):1.11-1.46) and 1.15; 95 % CI:1.02-1.30) after adjustment for CRP. CRP was not associated with vascular events after adjustment for NLR, (HR per SD 1.03; 95 % CI: 0.90-1.19), but was associated with all-cause mortality (HR per SD 1.18; 95 % CI: 1.04-1.33). Notably, NLR was related to vascular events in patients with CRP < 2 mg/L (HR per unit 1.45; 95 % CI: 1.19-1.77). CONCLUSION: In patients with T2D, NLR is related to higher risk of CVD and all-cause mortality, independently from CRP. NLR is related to CVD even when CRP is low, indicating that NLR is a marker of CVD-risk in addition to CRP. Both NLR and CRP are independently related to all-cause mortality in T2D patients.

The role of vitamin D supplementation in the risk of developing pneumonia: three independent case-control studies.

BACKGROUND: Vitamin D plays a role in host defence against infection. Vitamin D deficiency has been associated with an increased risk of respiratory tract infections in children and adults. This study aimed to examine whether vitamin D supplementation is associated with a lower pneumonia risk in adults. METHODS: Three independent case-control studies were performed including a total of 33 726 cases with pneumonia in different settings with respect to hospitalisation status and a total of 105 243 controls. Cases and controls were matched by year of birth, gender and index date. The major outcome measure was exposure to vitamin D supplementation at the time of pneumonia diagnosis. Conditional logistic regression was used to compute ORs for the association between vitamin D supplementation and occurrence of pneumonia. RESULTS: Vitamin D supplementation was not associated with a lower risk of pneumonia. In studies 1 and 2, adjustment for confounding resulted in non-significant ORs of 1.814 (95% CI 0.865 to 3.803) and 1.007 (95% CI 0.888 to 1.142), respectively. In study 3, after adjustment for confounding, the risk of pneumonia remained significantly higher among vitamin D users (OR 1.496, 95% CI 1.208 to 1.853). Additional analyses showed significant modification of the association through co-use of corticosteroids and drugs that affect bone mineralisation. For patients using these drugs, ORs below one were found combined with higher ORs for patients not using these drugs. CONCLUSIONS: This study showed no preventive association between vitamin D supplementation and the risk of pneumonia in adults.

Data mining to retrieve smoking status from electronic health records in general practice.

Aims: Optimize and assess the performance of an existing data mining algorithm for smoking status from hospital electronic health records (EHRs) in general practice EHRs. Methods and results: We optimized an existing algorithm in a training set containing all clinical notes from 498 individuals (75 712 contact moments) from the Julius General Practitioners' Network (JGPN). Each moment was classified as either 'current smoker', 'former smoker', 'never smoker', or 'no information'. As a reference, we manually reviewed EHRs. Algorithm performance was assessed in an independent test set (n = 494, 78 129 moments) using precision, recall, and F1-score. Test set algorithm performance for 'current smoker' was precision 79.7%, recall 78.3%, and F1-score 0.79. For former smoker, it was precision 73.8%, recall 64.0%, and F1-score 0.69. For never smoker, it was precision 92.0%, recall 74.9%, and F1-score 0.83. On a patient level, performance for ever smoker (current and former smoker combined) was precision 87.9%, recall 94.7%, and F1-score 0.91. For never smoker, it was 98.0, 82.0, and 0.89%, respectively. We found a more narrative writing style in general practice than in hospital EHRs. Conclusion: Data mining can successfully retrieve smoking status information from general practice clinical notes with a good performance for classifying ever and never smokers. Differences between general practice and hospital EHRs call for optimization of data mining algorithms when applied beyond a primary development setting.

Axial light loss of monocytes as a readily available prognostic biomarker in patients with suspected infection at the emergency department.

OBJECTIVES: To evaluate the prognostic value of the coefficient of variance of axial light loss of monocytes (cv-ALL of monocytes) for adverse clinical outcomes in patients suspected of infection in the emergency department (ED). METHODS: We performed an observational, retrospective monocenter study including all medical patients ≥18 years admitted to the ED between September 2016 and June 2019 with suspected infection. Adverse clinical outcomes included 30-day mortality and ICU/MCU admission <3 days after presentation. We determined the additional value of monocyte cv-ALL and compared to frequently used clinical prediction scores (SIRS, qSOFA, MEWS). Next, we developed a clinical model with routinely available parameters at the ED, including cv-ALL of monocytes. RESULTS: A total of 3526 of patients were included. The OR for cv-ALL of monocytes alone was 2.21 (1.98-2.47) for 30-day mortality and 2.07 (1.86-2.29) for ICU/MCU admission <3 days after ED presentation. When cv-ALL of monocytes was combined with a clinical score, the prognostic accuracy increased significantly for all tested scores (SIRS, qSOFA, MEWS). The maximum AUC for a model with routinely available parameters at the ED was 0.81 to predict 30-day mortality and 0.81 for ICU/MCU admission. CONCLUSIONS: Cv-ALL of monocytes is a readily available biomarker that is useful as prognostic marker to predict 30-day mortality. Furthermore, it can be used to improve routine prediction of adverse clinical outcomes at the ED. CLINICAL TRIAL REGISTRATION: Registered in the Dutch Trial Register (NTR) und number 6916.