Epigenetics, heritability and longitudinal analysis

Background Longitudinal data and repeated measurements in epigenome-wide association studies (EWAS) provide a rich resource for understanding epigenetics. We summarize 7 analytical approaches to the GAW20 data sets that addressed challenges and potential applications of phenotypic and epigenetic data. All contributions used the GAW20 real data set and employed either linear mixed effect (LME) models or marginal models through generalized estimating equations (GEE). These contributions were subdivided into 3 categories: (a) quality control (QC) methods for DNA methylation data; (b) heritability estimates pretreatment and posttreatment with fenofibrate; and (c) impact of drug response pretreatment and posttreatment with fenofibrate on DNA methylation and blood lipids. Results Two contributions addressed QC and identified large statistical differences with pretreatment and posttreatment DNA methylation, possibly a result of batch effects. Two contributions compared epigenome-wide heritability estimates pretreatment and posttreatment, with one employing a Bayesian LME and the other using a variance-component LME. Density curves comparing these studies indicated these heritability estimates were similar. Another contribution used a variance-component LME to depict the proportion of heritability resulting from a genetic and shared environment. By including environmental exposures as random effects, the authors found heritability estimates became more stable but not significantly different. Two contributions investigated treatment response. One estimated drug-associated methylation effects on triglyceride levels as the response, and identified 11 significant cytosine-phosphate-guanine (CpG) sites with or without adjusting for high-density lipoprotein. The second contribution performed weighted gene coexpression network analysis and identified 6 significant modules of at least 30 CpG sites, including 3 modules with topological differences pretreatment and posttreatment. Conclusions Four conclusions from this GAW20 working group are: (a) QC measures are an important consideration for EWAS studies that are investigating multiple time points or repeated measurements; (b) application of heritability estimates between time points for individual CpG sites is a useful QC measure for DNA methylation studies; (c) drug intervention demonstrated strong epigenome-wide DNA methylation patterns across the 2 time points; and (d) new statistical methods are required to account for the environmental contributions of DNA methylation across time. These contributions demonstrate numerous opportunities exist for the analysis of longitudinal data in future epigenetic studies

Adherence to a healthy and potentially sustainable Nordic diet is associated with child development in The Norwegian Mother, Father and Child Cohort Study (MoBa)

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Individual consent in cluster randomised trials for non-pharmaceutical interventions: going beyond the Ottawa statement

This paper discusses the issue of overriding the right of individual consent to participation in cluster randomised trials (CRTs). We focus on CRTs testing the efficacy of non-pharmaceutical interventions. As an example, we consider school closures during the COVID-19 pandemic. In Norway, a CRT was promoted as necessary for providing the best evidence to inform pandemic management policy. However, the proposal was rejected by the Norwegian Research Ethics Committee since it would violate the requirement for individual informed consent. This sparked debate about whether ethics stand in the way of evidence-based health policy, since the Norwegian Research Ethics law’s strict requirements for individual consent make it practically impossible to carry out CRTs of public health interventions. We argue that, in the case of the school closure trial, the suggested CRT would not have eliminated an epistemic gap and thus would not have justified the violation of consent rights. First, we focus on the methodological challenges to estimating quantifiable effects of school closures in the specific case of an airborne infectious disease. Second, in line with Evidential Pluralism, we highlight the value of alternative lines of evidence for informing school closure policy in a pandemic. In general, we propose that a trial requiring the waiver of participants’ consent rights must be highly likely to eliminate an epistemic gap. We elaborate on the practical aspects of this criterion and discuss the potential advantages of adding it to the Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials

Geographical variation in cardiovascular disease mortality in Norway: The role of life course socioeconomic position and parental health

Despite substantial geographical variation in cardiovascular (CVD) mortality within countries, little is known about whether this variation can be explained by individuals' life course socioeconomic position (SEP) or differences in family history of premature CVD deaths. Cox proportional hazards models were used to investigate the association between the county of residence at ages 50–59 and CVD death in Norwegians born between 1940 and 1959 and survived to at least age 60, using national data. Individual life course SEP and family history of premature CVD death reduced the geographical variation in CVD mortality across Norwegian counties, but some significant differences remained. Furthermore, CVD risk varied by residents' migration histories between two counties with distinct CVD and socioeconomic profiles.Geographical variation in cardiovascular disease mortality in Norway: The role of life course socioeconomic position and parental healthpublishedVersio

Candidate single nucleotide polymorphisms and thromboembolism in acute lymphoblastic leukemia - A NOPHO ALL2008 study

Introduction: Thromboembolism is a serious toxicity of acute lymphoblastic leukemia treatment, and contributes to substantial morbidity and mortality. Several single nucleotide polymorphisms have been associated with thromboembolism in the general population; however, their impact in patients with acute lymphoblastic leukemia, particularly in children, remains uncertain. Materials and methods: We collected constitutional DNA and prospectively registered thromboembolic events in 1252 patients, 1-45 years, with acute lymphoblastic leukemia included in the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol in the Nordic and Baltic countries (7/2008-7/2016). Based on previously published data and a priori power calculations, we selected four single nucleotide polymorphisms: F5 rs6025, F11 rs2036914, FGG rs2066865, and ABO rs8176719. Results: The 2.5 year cumulative incidence of thromboembolism was 7.1% (95% confidence interval (CI) 5.6-8.5). F11 rs2036914 was associated with thromboembolism (hazard ratio (HR) 1.52, 95%CI 1.11-2.07) and there was a borderline significant association for FGG rs2066865 (HR 1.37, 95%CI 0.99-1.91), but no association for ABO rs8176719 or F5 rs6025 in multiple cox regression. A genetic risk score based on F11 rs2036914 and FGG rs2066865 was associated with thromboembolism (HR 1.45 per risk allele, 95%CI 1.15-1.81), the association was strongest in adolescents 10.0-17.9 years (HR 1.64). Conclusion: If validated, a F11 rs2036914/FGG rs2066865 risk prediction model should be tested as a stratification tool for prevention of thromboembolism in patients with acute lymphoblastic leukemia.Peer reviewe

Fetal thoracic circumference in mid-pregnancy and infant lung function

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Background and Aim: Impaired lung function in early infancy is associated with later wheeze and asthma, while fetal thoracic circumference (TC) predicts severity of neonatal lung hypoplasia. Exploring fetal origins of lung function in infancy, we aimed to determine if fetal TC in mid‐pregnancy was associated with infant lung function. Methods: From the prospective Scandinavian general population‐based PreventADALL mother–child birth cohort, all 851 3‐month‐old infants with tidal flow‐volume measurements in the awake state and ultrasound fetal size measures at 18 (min–max 16–22) weeks gestational age were included. Associations between fetal TC and time to peak tidal expiratory flow to expiratory time (tPTEF/tE) were analyzed in linear regression models. To account for gestational age variation, we adjusted TC for simultaneously measured general fetal size, by head circumference (TC/HC), abdominal circumference (TC/AC), and femur length (TC/FL). Multivariable models were adjusted for maternal age, maternal asthma, pre‐pregnancy body mass index, parity, nicotine exposure in utero, and infant sex. Results: The infants (47.8% girls) were born at mean (SD) gestational age of 40.2 (1.30) weeks. The mean (SD) tPTEF/tE was 0.39 (0.08). The mean (SD) TC/HC was 0.75 (0.04), TC/AC 0.87 (0.04), and TC/FL 4.17 (0.26), respectively. Neither TC/HC nor TC/AC were associated with infant tPTEF/tE while a week inverse association was observed between TC/FL and tPTEF/tE (β ^ = −0.03, 95% confidence interval [−0.05, −0.007], p = 0.01). Conclusion: Mid‐pregnancy fetal TC adjusted for fetal head or abdominal size was not associated with tPTEF/tE in healthy, awake 3‐month‐old infants, while a weak association was observed adjusting for fetal femur length.publishedVersio

Eczema distribution in girls and boys during infancy: A cohort study on atopic dermatitis

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Birth mode is associated with development of atopic dermatitis in infancy and early childhood

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