Obstetrical mode of delivery and behavioural outcomes in childhood and adolescence: findings from the Millennium Cohort Study

Purpose To examine the association between mode of delivery (in particular caesarean section) and behavioural outcomes in offspring at six time-points between age 3 and 17 years. Methods Similar to previous work examining the association between mode of delivery and behavioural outcomes in offspring at age 7, we used maternal-reported data from the Millennium Cohort Study. Data on mode of delivery were collected when children were 9 months and categorised as spontaneous vaginal delivery, assisted vaginal delivery, induced vaginal delivery, emergency caesarean section, planned caesarean section and caesarean section after induction of labor. Data on behavioural outcomes were collected at ages 3, 5, 7, 11, 14 and 17 years using the Strengths and Difficulties Questionnaire (SDQ). Crude and adjusted logistic regression examined mode of delivery–behavioural difficulties relationship, using validated SDQ cut-off points (total SDQ ≥ 17, emotional ≥ 5, conduct ≥ 4, hyperactivity ≥ 7, peer problems ≥ 4 and prosocial behaviour ≤ 4). Multilevel models with linear splines examined the association between mode of delivery and repeated measures of SDQ. Results There were 18,213 singleton mother–child pairs included at baseline, 13,600 at age 3; 13,831 at age 5; 12,687 at age 7; 11,055 at age 11; 10,745 at age 14 and 8839 at age 17. Adjusted logistic regression suggested few associations between mode of delivery and behavioural outcomes at ages 3, 5, 11, 14 and 17 years using validated SDQ cut-off points. After correction for multiple testing, only the protective association between planned caesarean section-Conduct difficulties at age 5 years (OR 0.63, 95% CI 0.46, 0.85) and positive association between caesarean section after induction-Emotional difficulties at age 11 years (OR 1.57, 95% CI 1.19, 2.07) remained statistically significant. Multilevel modelling suggested mean SDQ scores were similar in each mode of delivery group at each time point. Conclusions Results of this study indicate that mode of delivery is unlikely to have a major impact on behavioural outcomes.

Case-control study of adverse childhood experiences and multiple sclerosis risk and clinical outcomes

Background Adverse childhood experiences (ACEs) are linked to numerous health conditions but understudied in multiple sclerosis (MS). This study’s objective was to test for the association between ACEs and MS risk and several clinical outcomes. Methods We used a sample of adult, non-Hispanic MS cases (n = 1422) and controls (n = 1185) from Northern California. Eighteen ACEs were assessed including parent divorce, parent death, and abuse. Outcomes included MS risk, age of MS onset, Multiple Sclerosis Severity Scale score, and use of a walking aid. Logistic and linear regression estimated odds ratios (ORs) (and beta coefficients) and 95% confidence intervals (CIs) for ACEs operationalized as any/none, counts, individual events, and latent factors/patterns. Results Overall, more MS cases experienced ≥1 ACE compared to controls (54.5% and 53.8%, respectively). After adjusting for sex, birthyear, and race, this small difference was attenuated (OR = 1.01, 95% CI: 0.87, 1.18). There were no trends of increasing or decreasing odds of MS across ACE count categories. Consistent associations between individual ACEs between ages 0–10 and 11–20 years and MS risk were not detected. Factor analysis identified five latent ACE factors, but their associations with MS risk were approximately null. Age of MS onset and other clinical outcomes were not associated with ACEs after multiple testing correction. Conclusion Despite rich data and multiple approaches to operationalizing ACEs, no consistent and statistically significant effects were observed between ACEs with MS. This highlights the challenges of studying sensitive, retrospective events among adults that occurred decades before data collection.

Multiple secondary outcome analyses: precise interpretation is important

Analysis of multiple secondary outcomes in a clinical trial leads to an increased probability of at least one false significant result among all secondary outcomes studied. In this paper, we question the notion that that if no multiplicity adjustment has been applied to multiple secondary outcome analyses in a clinical trial, then they must necessarily be regarded as exploratory. Instead, we argue that if individual secondary outcome results are interpreted carefully and precisely, there is no need to downgrade our interpretation to exploratory. This is because the probability of a false significant result for each comparison, the per-comparison wise error rate, does not increase with multiple testing. Strong effects on secondary outcomes should always be taken seriously and must not be dismissed purely on the basis of multiplicity concerns.

Baseline clinical features of COVID-19 patients, delay of hospital admission and clinical outcome: A complex relationship

Introduction Delay between symptom onset and access to care is essential to prevent clinical worsening for different infectious diseases. For COVID-19, this delay might be associated with the clinical prognosis, but also with the different characteristics of patients. The objective was to describe characteristics and symptoms of community-acquired (CA) COVID-19 patients at hospital admission according to the delay between symptom onset and hospital admission, and to identify determinants associated with delay of admission. Methods The present work was based on prospective NOSO-COR cohort data, and restricted to patients with laboratory confirmed CA SARS-CoV-2 infection admitted to Lyon hospitals between February 8 and June 30, 2020. Long delay of hospital admission was defined as ≥6 days between symptom onset and hospital admission. Determinants of the delay between symptom onset and hospital admission were identified by univariate and multiple logistic regression analysis. Results Data from 827 patients were analysed. Patients with a long delay between symptom onset and hospital admission were younger (p<0.01), had higher body mass index (p<0.01), and were more frequently admitted to intensive care unit (p<0.01). Their plasma levels of C-reactive protein were also significantly higher (p<0.01). The crude in-hospital fatality rate was lower in this group (13.3% versus 27.6%), p<0.01. Multiple analysis with correction for multiple testing showed that age ≥75 years was associated with a short delay between symptom onset and hospital admission (≤5 days) (aOR: 0.47 95% CI (0.34–0.66)) and CRP>100 mg/L at admission was associated with a long delay (aOR: 1.84 95% CI (1.32–2.55)). Discussion Delay between symptom onset and hospital admission is a major issue regarding prognosis of COVID-19 but can be related to multiple factors such as individual characteristics, organization of care and severe pathogenic processes. Age seems to play a key role in the delay of access to care and the disease prognosis.

Plasma and ovarian metabolomics responses to chronic stress in female mice

Background: Chronic stress may affect metabolism of amino acids, lipids, and other small molecule metabolites, but these alterations may differ depending on tissue evaluated. We examined metabolomic changes in plasma and ovarian tissue samples from female mice due to chronic stress exposure. Methods: At 12 weeks old, healthy, female, C57 black mice were randomly assigned to three weeks of chronic stress using daily restraint (2 hours/day; n=9) or normal care (n=10). Metabolomic profiling was conducted on plasma and ovarian tissues. Using the Wilcoxon Rank Test, Metabolite Set Enrichment Analysis, and Differential Network Analysis we identified metabolomic alterations occurring in response to restraint stress. All p-values were corrected for multiple testing using the false discovery rate approach. Results: In plasma, individual lysophosphatidylcholines (positively) and the metabolite classes carnitines (positively), diacylglycerols and triacylglycerols (inversely) were associated with restraint stress (adjusted-p's<0.2). In contrast, diacylglycerols and triacylglycerols were increased while carnitines were decreased in ovarian tissue from stressed mice (adjusted-p's<0.2). However, several metabolites (cholesteryl esters, phosphatidylcholines/ phosphatidylethanolamines plasmalogens and multiple amino acids) were consistently inversely associated with restraint stress in plasma and ovarian tissue (adjusted-p's<0.2). Conclusion: We identified differences in multiple lipid and amino acid metabolites in plasma and ovarian tissue of female mice after exposure to chronic stress. Some affected metabolites (primarily triacylglycerols and diacylglycerols) exhibited opposite associations with chronic stress in plasma (a marker of systemic influences) versus in ovarian tissue (representing local changes), suggesting research to understand the biological impact of chronic stress needs to consider both systemic and tissue-specific alterations.

Novel lipidomic signature associated with metabolic risk in women with and without polycystic ovary syndrome

Background Dyslipidaemia is a feature of polycystic ovary syndrome (PCOS) and may augment metabolic dysfunction in this population. Objective Using comprehensive lipidomic profiling and gold-standard metabolic measures, we examined whether distinct lipid biomarkers were associated with metabolic risk in women with and without PCOS. Methods Using pre-existing data and bio-banked samples from 76 women (n=42 with PCOS), we profiled &gt;700 lipid species by mass spectrometry. Lipids were compared between women with and without PCOS and correlated with direct measures of adiposity (dual X-ray absorptiometry and computed tomography) and insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), as well as fasting insulin, HbA1c, and hormonal parameters (luteinizing and follicle stimulating hormones; total and free testosterone; sex hormone-binding globulin [SHBG]; and free androgen index [FAI]). Multivariable linear regression was used with correction for multiple testing. Results Despite finding no differences by PCOS status, lysophosphatidylinositol (LPI) species esterified with an 18:0 fatty acid were the strongest lipid species associated with all the metabolic risk factors measured in women with and without PCOS. Across the cohort, higher concentrations of LPI(18:0) and lower concentrations of lipids containing docosahexaenoic acid (DHA, 22:6) n-3 polyunsaturated fatty acids (PUFA) were associated with higher adiposity, insulin resistance, fasting insulin, HbA1c and FAI, and lower SHBG. Conclusions Our data indicate that a distinct lipidomic signature comprising high LPI(18:0) and low DHA-containing lipids are associated with key metabolic risk factors that cluster in PCOS, independent of PCOS status. Prospective studies are needed to corroborate these findings in larger cohorts of women with varying PCOS phenotypes.

Capturing SNP Association across the NK Receptor and HLA Gene Regions in Multiple Sclerosis by Targeted Penalised Regression Models

Conventional genome-wide association studies (GWASs) of complex traits, such as Multiple Sclerosis (MS), are reliant on per-SNP p-values and are therefore heavily burdened by multiple testing correction. Thus, in order to detect more subtle alterations, ever increasing sample sizes are required, while ignoring potentially valuable information that is readily available in existing datasets. To overcome this, we used penalised regression incorporating elastic net with a stability selection method by iterative subsampling to detect the potential interaction of loci with MS risk. Through re-analysis of the ANZgene dataset (1617 cases and 1988 controls) and an IMSGC dataset as a replication cohort (1313 cases and 1458 controls), we identified new association signals for MS predisposition, including SNPs above and below conventional significance thresholds while targeting two natural killer receptor loci and the well-established HLA loci. For example, rs2844482 (98.1% iterations), otherwise ignored by conventional statistics (p = 0.673) in the same dataset, was independently strongly associated with MS in another GWAS that required more than 40 times the number of cases (~45 K). Further comparison of our hits to those present in a large-scale meta-analysis, confirmed that the majority of SNPs identified by the elastic net model reached conventional statistical GWAS thresholds (p < 5 × 10−8) in this much larger dataset. Moreover, we found that gene variants involved in oxidative stress, in addition to innate immunity, were associated with MS. Overall, this study highlights the benefit of using more advanced statistical methods to (re-)analyse subtle genetic variation among loci that have a biological basis for their contribution to disease risk.

Mycobacterium chelonae Infection Identified by Metagenomic Next-Generation Sequencing as the Probable Cause of Acute Contained Rupture of a Biological Composite Graft—A Case Report

We present the case of a 72-year-old female patient with acute contained rupture of a biological composite graft, 21 months after replacement of the aortic valve and the ascending aorta due to an aortic dissection. Auramine-rhodamine staining of intraoperative biopsies showed acid-fast bacilli, but classical culture and molecular methods failed to identify any organism. Metagenomic analysis indicated infection with Mycobacterium chelonae, which was confirmed by target-specific qPCR. The complexity of the sample required a customized bioinformatics pipeline, including cleaning steps to remove sequences of human, bovine ad pig origin. Our study underlines the importance of multiple testing to increase the likelihood of pathogen identification in highly complex samples.

Cardiac Magnetic Resonance Radiomics Reveal Differential Impact of Sex, Age, and Vascular Risk Factors on Cardiac Structure and Myocardial Tissue

Background: Cardiovascular magnetic resonance (CMR) radiomics analysis provides multiple quantifiers of ventricular shape and myocardial texture, which may be used for detailed cardiovascular phenotyping.Objectives: We studied variation in CMR radiomics phenotypes by age and sex in healthy UK Biobank participants. Then, we examined independent associations of classical vascular risk factors (VRFs: smoking, diabetes, hypertension, high cholesterol) with CMR radiomics features, considering potential sex and age differential relationships.Design: Image acquisition was with 1.5 Tesla scanners (MAGNETOM Aera, Siemens). Three regions of interest were segmented from short axis stack images using an automated pipeline: right ventricle, left ventricle, myocardium. We extracted 237 radiomics features from each study using Pyradiomics. In a healthy subset of participants (n = 14,902) without cardiovascular disease or VRFs, we estimated independent associations of age and sex with each radiomics feature using linear regression models adjusted for body size. We then created a sample comprising individuals with at least one VRF matched to an equal number of healthy participants (n = 27,400). We linearly modelled each radiomics feature against age, sex, body size, and all the VRFs. Bonferroni adjustment for multiple testing was applied to all p-values. To aid interpretation, we organised the results into six feature clusters.Results: Amongst the healthy subset, men had larger ventricles with dimmer and less texturally complex myocardium than women. Increasing age was associated with smaller ventricles and greater variation in myocardial intensities. Broadly, all the VRFs were associated with dimmer, less varied signal intensities, greater uniformity of local intensity levels, and greater relative presence of low signal intensity areas within the myocardium. Diabetes and high cholesterol were also associated with smaller ventricular size, this association was of greater magnitude in men than women. The pattern of alteration of radiomics features with the VRFs was broadly consistent in men and women. However, the associations between intensity based radiomics features with both diabetes and hypertension were more prominent in women than men.Conclusions: We demonstrate novel independent associations of sex, age, and major VRFs with CMR radiomics phenotypes. Further studies into the nature and clinical significance of these phenotypes are needed.

FaDA: A web application for regular laboratory data analyses

Web-based data analysis and visualization tools are mostly designed for specific purposes, such as the analysis of data from whole transcriptome RNA sequencing or single-cell RNA sequencing. However, generic tools designed for the analysis of common laboratory data for noncomputational scientists are also needed. The importance of such web-based tools is emphasized by the continuing increases in the sample capacity of conventional laboratory tools such as quantitative PCR, flow cytometry or ELISA instruments. We present a web-based application FaDA, developed with the R Shiny package that provides users with the ability to perform statistical group comparisons, including parametric and nonparametric tests, with multiple testing corrections suitable for most standard wet-laboratory analyses. FaDA provides data visualizations such as heatmaps, principal component analysis (PCA) plots, correlograms and receiver operating curves (ROCs). Calculations are performed through the R language. The FaDA application provides a free and intuitive interface that allows biologists without bioinformatic skill to easily and quickly perform common laboratory data analyses. The application is freely accessible at https://shiny-bird.univ-nantes.fr/app/Fada.