Mendelian randomization (MR) is an epidemiological technique that uses genetic variants to distinguish correlation from causation in observational data. The reliability of a MR investigation depends ...on the validity of the genetic variants as instrumental variables (IVs). We develop the contamination mixture method, a method for MR with two modalities. First, it identifies groups of genetic variants with similar causal estimates, which may represent distinct mechanisms by which the risk factor influences the outcome. Second, it performs MR robustly and efficiently in the presence of invalid IVs. Compared to other robust methods, it has the lowest mean squared error across a range of realistic scenarios. The method identifies 11 variants associated with increased high-density lipoprotein-cholesterol, decreased triglyceride levels, and decreased coronary heart disease risk that have the same directions of associations with various blood cell traits, suggesting a shared mechanism linking lipids and coronary heart disease risk mediated via platelet aggregation.
Cortisol's immunosuppressive, obesogenic, and hyperglycaemic effects suggest that it may play a role in cancer development. However, whether cortisol increases cancer risk is not known. We ...investigated the potential causal association between plasma cortisol and risk of overall and common site-specific cancers using Mendelian randomisation.
Three genetic variants associated with morning plasma cortisol levels at the genome-wide significance level (P < 5 × 10
) in the Cortisol Network consortium were used as genetic instruments. Summary-level genome-wide association study data for the cancer outcomes were obtained from large-scale cancer consortia, the UK Biobank, and the FinnGen consortium. Two-sample Mendelian randomisation analyses were performed using the fixed-effects inverse-variance weighted method. Estimates across data sources were combined using meta-analysis.
A standard deviation increase in genetically predicted plasma cortisol was associated with increased risk of endometrial cancer (odds ratio 1.50, 95% confidence interval 1.13-1.99; P = 0.005). There was no significant association between genetically predicted plasma cortisol and risk of other common site-specific cancers, including breast, ovarian, prostate, colorectal, lung, or malignant skin cancer, or overall cancer.
These results indicate that elevated plasma cortisol levels may increase the risk of endometrial cancer but not other cancers. The mechanism by which this occurs remains to be investigated.
Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization ...analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10
; IFNAR2, P = 9.8 × 10
and IL-10RB, P = 2.3 × 10
) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.
Abstract
Context
Atrial fibrillation (AF), cardiac arrhythmias, and related risk factors are common in patients with Cushing’s syndrome, or clinical chronic hypercortisolism. While hypercortisolism ...may be associated with AF, this association has not yet been ascertained causally.
Objective
To determine whether plasma cortisol is causally associated with AF using a 2-sample Mendelian randomization (MR) design.
Methods
Three genetic variants in the SERPINA1/SERPINA6 locus and functionally associated with plasma cortisol were identified in the CORtisol NETwork consortium (12 597 participants). Summary-level genome-wide association study (GWAS) data for the associations between the cortisol-associated variants and AF were obtained from a GWAS meta-analysis of 6 studies (60 620 AF cases and 970 216 noncases) and the FinnGen consortium (17 325 AF cases and 97 214 noncases). The fixed-effects inverse-variance weighted approach accounting for genetic correlations between variants was used for analysis. Multivariable MR analyses were conducted to assess potential mediating effects of systolic blood pressure (SBP) and waist circumference (WC). Summary-level GWAS data for SBP and WC were obtained respectively from the International Consortium of Blood Pressure (757 601 participants) and the Genetic Investigation of ANthropometric Traits consortium (232 101 participants).
Results
One standard deviation increase in genetically predicted plasma cortisol was associated with greater risk of AF (odds ratio OR 1.20, 95% CI 1.06-1.35). The association attenuated when adjusting for genetically predicted SBP and WC (OR 0.99, 95% CI 0.72-1.38).
Conclusion
Evidence derived from the MR study suggests a positive association between plasma cortisol and risk of AF, likely mediated through SBP and WC.
Abstract
Background
Accurate monitoring of population health is essential to ensure proper recovery after earthquakes. We aimed to summarize the findings and features of post-earthquake ...epidemiological studies conducted in high-income countries and to prompt the development of future surveillance plans.
Methods
Medline, Scopus and six sources of grey literature were systematically searched. Inclusion criteria were: observational study conducted in high-income countries with at least one comparison group of unexposed participants, and measurement of health outcomes at least 1 month after the earthquake.
Results
A total of 52 articles were included, assessing the effects of 13 earthquakes that occurred in eight countries. Most studies: had a time-series (33%) or cross-sectional (29%) design; included temporal comparison groups (63%); used routine data (58%); and focused on patient subgroups rather than the whole population (65%). Individuals exposed to earthquakes had: 2% higher all-cause mortality rates 95% confidence interval (CI), 1% to 3%; 36% (95% CI, 19% to 57%) and 37% (95% CI, 29% to 46%) greater mortality rates from myocardial infarction and stroke, respectively; and 0.16 higher mean percent points of glycated haemoglobin (95% CI, 0.07% to 0.25% points). There was no evidence of earthquake effects for blood pressure, body mass index or lipid biomarkers.
Conclusions
A more regular and coordinated use of large and routinely collected datasets would benefit post-earthquake epidemiological surveillance. Whenever possible, a cohort design with geographical and temporal comparison groups should be used, and both communicable and non-communicable diseases should be assessed. Post-earthquake epidemiological surveillance should also capture the impact of seismic events on the access to and use of health care services.
Background:
Chronic lung allograft dysfunction (CLAD), a complication affecting the survival of lung transplanted patients, includes two clinical phenotypes: bronchiolitis obliterans syndrome (BOS) ...and restrictive allograft syndrome (RAS). Everolimus is used in CLAD because of its antiproliferative mechanism. In lung transplant patients treated with everolimus, the clinical course of renal and lung function has not yet been assessed systematically in CLAD, BOS and RAS patients for more than 6 months.
Methods:
We retrospectively evaluated the 12-month follow-up of renal and lung function of lung-transplanted patients switched to everolimus and evaluated the reduction in immunosuppressant dosage (ISD) and mortality. Subgroups were based on indication for everolimus treatment: CLAD and non-CLAD patients, BOS and RAS among CLAD patients.
Results:
We included 26 patients, 17 with CLAD (10 BOS, seven RAS). After 1 year from the everolimus switch, we observed renal function improvement (serum creatinine −17%, estimated glomerular filtration rate +24%) and stable pulmonary function forced expiratory volume in the first second (FEV1) −0.5%, forced vital capacity (FVC) +0.05%. RAS patients had progressive functional loss, whereas BOS patients had FEV1 improvement and FVC stability. All-cause mortality was higher in the CLAD versus non-CLAD group (41% versus 11%), without differences between BOS and RAS patients (p > 0.05). All patients had significant and persistent ISD reduction.
Conclusion:
Lung transplant patients treated with everolimus had improvements in renal function and reduced ISD. We observed sustained improvements in lung function for CLAD related to BOS subgroup results, whereas RAS confirmed the 1-year worsening functional trend. Data seem to suggest one more piece of the puzzle in CLAD phenotyping.
Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of ...genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.
ObjectiveSecure data environments (SDE) ensure safe access to large population-level sensitive data. However, computational capacity is limited in these environments, which leads to challenges in the ...analysis of large population data within the constraints of a complex cloud architecture leveraging multiple software ecosystems. Here we present an efficient pipeline to conduct phenome-wide analyses using electronic health records (EHR) in the NHS England SDE.
MethodsWe accessed deidentified linked EHR from NHS SDE for around 50 million people in England. The exposure is SARS-CoV-2 infection, with outcomes being a phenome-wide atlas of all diseases recorded in EHR data. For computational efficiency, we created three cohorts tables using PySpark within the Databricks environment and a sampling algorithm with inverse probability weights which adds a flag to the dataset to mark the inclusion of a row in the sample of a specific outcome. We will conduct survival analysis using Cox models in RStudio on the samples while adjusting for potential confounders in the main datasets and 15 subgroups.
ResultsSampling with inverse probability weighting produced datasets that are statistically equivalent to the original population data. In terms of computational efficiency, the time needed to sample and read the data for modeling one outcome is 2.3 min compared to ~45 min when trying to read the entire dataset, which could fail due to the 4GB memory limits of in Rstudio within the SDE. This is particularly important in our study since we will be running at least 13,296 models for main and subgroup analysis in the three cohorts. By adding a flag to each data row to indicate its inclusion in a sample, the sampling strategy significantly reduced the storage space required for the outcome table of each sample.
ConclusionPreparing datasets in Databricks and applying sampling can increase the efficiency of big data analysis pipelines within SDE, save storage space, and help in avoiding memory overload caused by using complete datasets for statistical analysis.
Fabrizio Faggiano and colleagues discuss how a central, transparent, and evidence-based approval process is needed for behavioral prevention interventions in Europe and propose a way forward. Please ...see later in the article for the Editors' Summary.
Compliance with validated guidelines is crucial to guide management of patients hospitalized with community-acquired pneumonia (CAP). Data describing real-life management and treatment of CAP are ...limited. We aimed to evaluate the compliance with guidelines over time, and to assess its impact on all-cause mortality and clinical outcomes. We retrospectively compared two cohorts of patients admitted to the hospital, throughout 2005, just after the implementation of a local clinical pathway based on CAP international guidelines, and 7 years later over 2012. We included all patients with a diagnosis of pneumonia and/or related complications. 564 patients were included. The Pneumonia Severity Index calculation was better documented in 2012 (25.23 %) compared to 2005 (17.70 %;
p
= 0.032), but compliance with guideline empirical antibiotic therapy was lower in 2012 (56.70 %) than in 2005 (68.75 %;
p
= 0.004). Performance of guideline recommended urinary antigen tests was higher in 2012, and associated with 57.3 % lower odds of in-hospital mortality (95 % CI 15.0–78.5 %) and with 65.9 % lower odds of 30-day mortality (95 % CI 31.5–83.0 %). Compliance with empirical antibiotic therapy was associated with 2.9 days lower mean length of hospital stay (95 % CI −4.2 to −1.6 days) and with 2.0 days lower mean duration of antibiotic therapy (95 % CI −3.3 to −0.7 days). Compliance with guidelines changed over time, with some effects on mortality and with an apparent reduction in the length of hospital stay and the duration of antibiotic therapy. Specific clinical training and hospital control policies could achieve greater compliance with guidelines, and thus reduce a burden on hospital services.
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