Association of mental health with the risk of coronary artery disease in patients with diabetes: A mendelian randomization study

Background and aimsObservational studies have shown an association between mental health and coronary artery disease (CAD) in patients with diabetes. Nevertheless, whether these associations are causal is still unknown. In this two-sample Mendelian randomization (MR) study, we aimed to assess the causality between mental health and CAD in patients with diabetes.Methods and resultsSingle-nucleotide polymorphisms (SNPs) associated with: depression (807,553 individuals), anxiety (83,556 individuals) and neuroticism (329,821 individuals) were identified from the largest genome-wide association studies (GWAS). Summary-level data for CAD were extracted from the recently published GWAS of 15,666 diabetic patients (3968 CAD cases and 11,696 controls). The inverse-variance weighted (IVW) method was used for the main analysis. Sensitivity analyses included weighted median, maximum likelihood, and the MR-Egger method. Genetic liability to depression was significantly associated with a higher risk of CAD in patients with diabetes (odds ratio [OR], 1.286; 95%CI,1.018–1.621;p = 0.035). For anxiety and neuroticism, no causal association with CAD in patients with diabetes was observed. Consistent results were obtained in most sensitivity analyses.ConclusionsThis MR study provides genetic evidence that depression is a potential risk factor for CAD in patients with diabetes. However, anxiety and neuroticism were not causally associated with CAD in patients with diabetes. Mental health treatments should be enhanced to prevent CAD in patients with diabetes.     

Lipoprotein(a): An independent,genetic, and causal factor for cardiovascular disease and acute myocardial infarction

Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy.     

Improving the sensitivity of cluster‐based statistics for functional magnetic resonance imaging data

Because of the high dimensionality of neuroimaging data, identifying a statistical test that is both valid and maximally sensitive is an important challenge. Here, we present a combination of two approaches for functional magnetic resonance imaging (fMRI) data analysis that together result in substantial improvements of the sensitivity of cluster‐based statistics. The first approach is to create novel cluster definitions that optimize sensitivity to plausible effect patterns. The second is to adopt a new approach to combine test statistics with different sensitivity profiles, which we call the min(p) method. These innovations are made possible by using the randomization inference framework. In this article, we report on a set of simulations and analyses of real task fMRI data that demonstrate (a) that the proposed methods control the false‐alarm rate, (b) that the sensitivity profiles of cluster‐based test statistics vary depending on the cluster defining thresholds and cluster definitions, and (c) that the min(p) method for combining these test statistics results in a drastic increase of sensitivity (up to fivefold), compared to existing fMRI analysis methods. This increase in sensitivity is not at the expense of the spatial specificity of the inference.     

Associations of immunological proteins/traits with schizophrenia,major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study

BackgroundSchizophrenia, bipolar disorder and depression are associated with inflammation. However, it is unclear whether associations of immunological proteins/traits with these disorders are likely to be causal, or could be explained by reverse causality/residual confounding.MethodsWe used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality, specificity and direction of association of 20 immunological proteins/traits (pro-inflammatory cytokines: interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-12, IL-16, IL-17, IL-18; anti-inflammatory cytokines: IL-1 receptor antagonist (RA), IL-10, IL-13; chemokines: IL-8, monocyte chemo-attractant protein-1 (MCP-1); lymphoid growth-factors: soluble (s) IL-2Rα, IL-4, IL-7, IL-9; myeloid growth-factor: IL-5; acute phase protein: C-Reactive Protein (CRP); immune cells: neutrophils, lymphocytes; neurotrophic factor: brain derived neurotrophic factor (BDNF)) with schizophrenia, major depression and bipolar disorder.ResultsGenetically-predicted IL-6 was associated with increased risk of schizophrenia in univariable MR (OR = 1.24; 95% C.I., 1.05–1.47) and with major depression in MVMR (OR = 1.08; 95% C.I., 1.03–1.12). These results survived Bonferroni-correction. Genetically-predicted sIL-2Rα (OR = 1.07; 95% C.I., 1.01–1.12) and IL-9 (OR = 1.06; 95% C.I., 1.01–1.11) were associated with increased schizophrenia risk. Genetically-predicted BDNF (OR = 0.97; 95% C.I., 0.94–1.00) and MCP-1 (OR = 0.96; 95% C.I., 0.91–0.99) were associated with reduced schizophrenia risk. However, these findings did not survive correction for multiple testing. The CRP-schizophrenia association attenuated completely after taking into account IL-6 and sIL-2Rα in MVMR (OR = 1.02; 95% C.I., 0.81–1.28). No significant associations were observed for bipolar disorder. Evidence from bidirectional MR did not support reverse causality.ConclusionsWe report evidence in support of potential causal associations of several immunological proteins/traits with schizophrenia, and of IL-6 with depression. Some of the findings did not survive correction for multiple testing and so replication in larger samples is required. Experimental studies are also required to further examine causality, mechanisms, and treatment potential for these immunological proteins/pathways for schizophrenia and depression.     

An Easily Accessible Web-Based Minimization Random Allocation System for Clinical Trials

Background

Minimization as an adaptive allocation technique has been recommended in the literature for use in randomized clinical trials. However, it remains uncommonly used due in part to a lack of easily accessible implementation tools.

Objective

To provide clinical trialists with a robust, flexible, and readily accessible tool for implementing covariate-adaptive biased-coin randomization.

Methods

We developed a Web-based random allocation system, MinimRan, that applies Pocock–Simon (for trials with 2 or more arms) and 2-way (currently limited to 2-arm trials) minimization methods for trials using only categorical prognostic factors or the symmetric Kullback–Leibler divergence minimization method for trials (currently limited to 2-arm trials) using continuous prognostic factors with or without categorical factors, in covariate-adaptive biased-coin randomization.

Results

In this paper, we describe the system’s essential statistical and computer programming features and provide as an example the randomization results generated by it in a recently completed trial. The system can be used in single- and double-blind trials as well as single-center and multicenter trials.

Conclusions

We expect the system to facilitate the translation of the 3 validated random allocation methods into broad, efficient clinical research practice.     

Genetically Predicted Adiposity,Diabetes, and Lifestyle Factors in Relation to Diverticular Disease

Background & AimsAdiposity, type 2 diabetes, alcohol and coffee consumption, and smoking have been examined in relation to diverticular disease in observational studies. We conducted a Mendelian randomization study to assess the causality of these associations.MethodsIndependent genetic instruments associated with the studied exposures at genome-wide significance were obtained from published genome-wide association studies. Summary-level data for the exposure-associated single nucleotide polymorphisms with diverticular disease were available in the FinnGen consortium (10,978 cases and 149,001 noncases) and the UK Biobank study (12,662 cases and 348,532 noncases).ResultsHigher genetically predicted body mass index and genetic liability to type 2 diabetes and smoking initiation were associated with an increased risk of diverticular disease in meta-analyses of results from the two studies. The combined odds ratio of diverticular disease was 1.23 (95% confidence interval [CI], 1.14–1.33; P < .001) for a 1-standard deviation (~4.8 kg/m²) increase in body mass index, 1.04 (95% CI, 1.01–1.07; P = .007) for a 1-unit increase in log-transformed odds ratio of type 2 diabetes, and 1.21 (95% CI, 1.12–1.30; P < .001) for a 1-standard deviation increase in prevalence of smoking initiation. Coffee consumption was not associated with diverticular disease, whereas the association for alcohol consumption largely differed between the 2 studies.ConclusionsThis study strengthens the causal associations of higher body mass index, type 2 diabetes, and smoking with an increased risk of diverticular disease. Coffee consumption is not associated with diverticular disease. Whether alcohol consumption affects the risk of diverticular disease needs further investigation.     

Immunologic non-inferiority and safety of the investigational pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) 4-dose vial presentation compared to the licensed PHiD-CV 1-dose vial presentation in infants: A phase III randomized study

BackgroundTo support vaccination programs in developing countries, a 4-dose vial presentation of pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) was developed. This study assessed immunologic non-inferiority and safety of the investigational PHiD-CV 4-dose versus licensed 1-dose vial presentation in infants.MethodsIn this phase III, mono-center, observer-blind study in Bangladesh, 6–10-week-old infants were randomized 1:1 to receive PHiD-CV primary vaccination (at ages 6, 10, 18 weeks) and a booster dose (at age 9 months) with a 4-dose vial (with preservative, 4DV group) or 1-dose vial (preservative-free, 1DV group). DTPw-HBV/Hib was (co)-administered per study protocol and polio, measles and rubella vaccines as part of the national immunization program. Non-inferiority of PHiD-CV 4-dose versus 1-dose vial for each vaccine pneumococcal serotype (VT) and vaccine-related serotype 19A in terms of antibody geometric mean concentration (GMC) was assessed (criterion: upper limit of 2-sided 95% confidence interval of antibody GMC ratios [1DV/4DV] <2-fold). Immune responses were measured. Solicited, unsolicited and serious adverse events (AEs) were evaluated.ResultsOf 320 infants (160 per group) vaccinated during the primary vaccination phase, 297 received a booster. Non-inferiority was demonstrated for each VT and 19A. One month post-primary vaccination, for most VT, ≥97.9% of infants in each group had antibody concentrations ≥0.2 μg/mL; for 19A ≥ 80.1% reached this threshold. Pneumococcal antibody responses and opsonophagocytic activity for each VT and 19A were within similar ranges between groups after primary and booster vaccination, as were anti-protein D responses. Booster immune responses were observed in both groups. Reported AEs were within similar ranges for both presentations.ConclusionImmunologic non-inferiority of PHiD-CV 4-dose vial (with preservative) versus PHiD-CV 1-dose vial (preservative-free) was demonstrated. Immune responses and reactogenicity following primary/booster vaccination were within similar ranges for both presentations. PHiD-CV 4-dose vial would help improve access and coverage in resource-limited countries.Clinical Trial Registry: NCT02447432.