Investigating the relationships between unfavourable habitual sleep and metabolomic traits:evidence from multi-cohort multivariable regression and Mendelian randomization analyses

BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.</p

The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip, supplementary table 3

Supplementary table 3: Summary statistics from an EWAS assessing the relationship between variance in DNA methylation value and DNA input level

Data from: Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

Background: The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is. Objectives: i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA. Methods: Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA. Results: The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans. Conclusions: This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits

Meta-EWAS results

Offspring methylation ~ Paternal BMI + Paternal age + Maternal age + Paternal smoking + Maternal smoking + Paternal SEP + Maternal parity + estimated cell proportions + 20 surrogate variables These files contains meta-analysis summary statistics for all Illumina 450k or EPIC probes for which at least one cohort supplied data. No filtering has taken place. For the paper describing this work, some probes (e.g. cross-hybridising probes, or probes on the sex chromosomes) were removed after meta-analysis, before any downstream analysis

Simulated multi-omic dataset including DNA methylation, proteins and metabolites

Dataset simulated for use in a short course in molecular epidemiology

Associations Between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birth Weight Identified by Investigating Methylation at Individual, Regional, and Genome Levels

Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels to test for associations with maternal stress and newborn birth weight. Maternal venous blood and newborn cord blood (n = 24 and 22, respectively) were assayed for methylation at ~450,000 CpG sites. Methylation was analyzed by examining CpG sites individually in an epigenome-wide association study (EWAS), as regional groups using variably methylated region (VMR) analysis in maternal blood only, and through the epigenome-wide measures genome-wide mean methylation (GMM), Horvath’s epigenetic clock, and mitotic age. These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birth weight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birth weight (p &lt; 1.95 × 10–7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birth weight in either maternal or cord blood, after Bonferroni multiple testing correction; however, the top-ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p = 1.95 × 10–7 and 8.3 × 10–6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p = 0.025) and was suggestively associated with sexual violence (p = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birth weight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues; specifically, a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we found associations only when CpG sites were analyzed in aggregate, either as VMRs or as a broad summary measure of GMM

ALSPAC peer reviewed publications 1989-2015

List of peer reviewed publications generated from the Avon Longitudinal Study of Parents and Children (ALSPAC) data from 1989 to the end of 2015

Speech disorders &amp; adolescent self-harm (McAllister et al., 2023)

Background: Adolescent self-harm is a major public health issue internationally. Various factors associated with adolescent self-harm have been identified, including being bullied and experiencing mental health problems. Stuttering and speech sound disorder are associated with both of these factors. It was hypothesized that both stuttering and speech sound disorder would be associated with self-harm. This is the first study to explore the relationship between communication disorders and adolescent self-harm. Method: Secondary analysis of a large, longitudinal, prospective, community sample, the Avon Longitudinal Study of Parents and Children, was carried out. Clinicians identified children who stuttered or exhibited speech sound disorder at the age of 8 years. When the cohort members were 16 years old, they were asked to complete a questionnaire about self-harm. Multinomial logistic regression was used to examine the associations between stuttering and speech sound disorder and the self-harm outcomes, adjusting for other relevant factors. Results: Of 3,824 participants with data for both speech status and self-harm, 94 (2.5%; 95% confidence interval [CI; 2.0, 3.0]) stuttered at 8 years of age and 127 (3.3%; 95% CI [2.8, 3.9]) displayed speech sound disorder. Speech sound disorder at the age of 8 years was associated with self-harm with suicidal intent in both unadjusted and adjusted models. Differences between the adjusted and unadjusted models were small, suggesting that speech sound disorder is largely an independent risk factor for self-harm with suicidal intent. Stuttering at the age of 8 years was not associated with adolescent self-harm, and there was no association between speech sound disorder and self-harm without suicidal intent. Conclusion: Compared with individuals without speech sound disorder, adolescents with speech sound disorder at the age of 8 years have twice the risk of reporting self-harm with suicidal intent, even when other important predictors are taken into account. Supplemental Material S1. Degree of “missingness” in variables. Supplemental Material S2. Associations between speech variables (Model 1) and self-harm with and without suicidal intent (N = 3,824). Supplemental Material S3. Associations between speech variables and demographic factors (Model 2) and self-harm with and without suicidal intent (N = 3,824). Supplemental Material S4. Associations between speech variables and personal factors (Model 3) and self-harm with and without suicidal intent (N = 3,824). Supplemental Material S5. Associations between speech variables and environmental factors (Model 4) and self-harm with and without suicidal intent (N = 3,824). Supplemental Material S6. Associations between speech variables and all factors (final model) and self-harm with and without suicidal intent (N = 3,824). McAllister, J., Skinner, J., Hayhow, R., Heron, J., &amp; Wren, Y. (2023). The association between atypical speech development and adolescent self-harm. Journal of Speech, Language, and Hearing Research. Advance online publication. https://doi.org/10.1044/2023_JSLHR-21-0065

Data from: An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

The age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (p&lt;5×10−05) derived from GWAS and 551 heritable traits from the UK Biobank study (N = 334,398). Findings can be investigated using a web application (http://mrcieu.mrsoftware.org/PRS_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility. To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.,5e05.txtPRS results using P&lt;5e05 threshold. These data are derived from the UK Biobank Resource as part of projects 8786 and 15825.5e08.txtPRS results using P&lt;5e08 threshold. These data are derived from the UK Biobank Resource as part of projects 8786 and 15825.

Additional file 1 of Assessing the effects of hyperparameters on knowledge graph embedding quality

Additional file 1: A .zip file containing all supplementary tables, in gzip compressed .csv format, that are referenced in this manuscript.Supplementary table 1 provides the possible values that each of the tested hyperparameters could take. Supplementary table 2 describes the 233 total jobs that were attempted to be run in LibKGE in terms of: dataset, KGE method, training method, and loss function. Supplementary table 3 provides the raw data used to generate Figure 2. Supplementary table 4 shows the results of an inverse-relation-leakage analysis that was run on the UMLS dataset. Supplementary tables 5.1, 5.2, and 5.3 are the raw symmetrical adjacency matrices used to visualise the network data in figures 3A, 3B, and 3C respectively.