Prediction of gestational age based on genome-wide differentially methylated regions

BACKGROUND: We explored the association between gestational age and cord blood DNA methylation at birth and whether DNA methylation could be effective in predicting gestational age due to limitations with the presently used methods. We used data from the Norwegian Mother and Child Birth Cohort study (MoBa) with Illumina HumanMethylation450 data measured for 1753 newborns in two batches: MoBa 1, n = 1068; and MoBa 2, n = 685. Gestational age was computed using both ultrasound and the last menstrual period. We evaluated associations between DNA methylation and gestational age and developed a statistical model for predicting gestational age using MoBa 1 for training and MoBa 2 for predictions. The prediction model was additionally used to compare ultrasound and last menstrual period-based gestational age predictions. Furthermore, both CpGs and associated genes detected in the training models were compared to those detected in a published prediction model for chronological age. RESULTS: There were 5474 CpGs associated with ultrasound gestational age after adjustment for a set of covariates, including estimated cell type proportions, and Bonferroni-correction for multiple testing. Our model predicted ultrasound gestational age more accurately than it predicted last menstrual period gestational age. CONCLUSIONS: DNA methylation at birth appears to be a good predictor of gestational age. Ultrasound gestational age is more strongly associated with methylation than last menstrual period gestational age. The CpGs linked with our gestational age prediction model, and their associated genes, differed substantially from the corresponding CpGs and genes associated with a chronological age prediction model. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13059-016-1063-4) contains supplementary material, which is available to authorized users

Risk of miscarriage in women with psychiatric disorders

Background Some psychiatric disorders have been associated with increased risk of miscarriage. However, there is a lack of studies considering a broader spectrum of psychiatric disorders to clarify the role of common as opposed to independent mechanisms. Aims To examine the risk of miscarriage among women diagnosed with psychiatric conditions. Method We studied registered pregnancies in Norway between 2010 and 2016 (n = 593 009). The birth registry captures pregnancies ending in gestational week 12 or later, and the patient and general practitioner databases were used to identify miscarriages and induced abortions before 12 gestational weeks. Odds ratios of miscarriage according to 12 psychiatric diagnoses were calculated by logistic regression. Miscarriage risk was increased among women with bipolar disorders (adjusted odds ratio 1.35, 95% CI 1.26–1.44), personality disorders (adjusted odds ratio 1.32, 95% CI 1.12–1.55), attention-deficit hyperactivity disorder (adjusted odds ratio 1.27, 95% CI 1.21–1.33), conduct disorders (1.21, 95% CI 1.01, 1.46), anxiety disorders (adjusted odds ratio 1.25, 95% CI 1.23–1.28), depressive disorders (adjusted odds ratio 1.25, 95% CI 1.23–1.27), somatoform disorders (adjusted odds ratio 1.18, 95% CI 1.07–1.31) and eating disorders (adjusted odds ratio 1.14, 95% CI 1.08–1.22). The miscarriage risk was further increased among women with more than one psychiatric diagnosis. Our findings were robust to adjustment for other psychiatric diagnoses, chronic somatic disorders and substance use disorders. After mutual adjustment for co-occurring psychiatric disorders, we also observed a modest increased risk among women with schizophrenia spectrum disorders (adjusted odds ratio 1.22, 95% CI 1.03–1.44). Conclusions A wide range of psychiatric disorders were associated with increased risk of miscarriage. The heightened risk of miscarriage among women diagnosed with psychiatric disorders highlights the need for awareness and surveillance of this risk group in antenatal care.acceptedVersio

Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

Objective To investigate the association between smoking and infertility. Design Prospective study. Setting Nationwide cohort. Patients 28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study. Intervention Self-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization. Main outcome measure Infertility (time-to-pregnancy ≥12 months). Results Having ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11–1.28; ORadjusted 1.12; 95% CI, 1.03–1.21), also after adjusting for the partner’s tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88–0.99; ORadjusted 0.89; 95% CI, 0.84–0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75–0.91; ORadjusted, 0.83; 95% CI, 0.75–0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization. Conclusions We did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.publishedVersio

Early life growth and associations with lung function and bronchial hyperresponsiveness at 11-years of age

Low birthweight and being born small-for-gestational age (SGA) are linked to asthma and impaired lung function. Particularly, poor intrauterine growth followed by rapid catch-up growth during childhood may predispose for respiratory disease. Bronchial hyperresponsiveness (BHR) is an essential feature of asthma, but how foetal and early childhood growth are associated with BHR is less studied. Our hypothesis was that children born SGA or with accelerated early life growth have increased BHR and altered lung function at 11-years of age. We studied the associations between SGA and early childhood growth with lung function and BHR at 11-years of age in a subgroup of 468 children from the Norwegian Mother, Father and Child Cohort Study (MoBa), and included data from the Medical Birth Registry of Norway (MBRN). Weight at 6 months of age was positively associated with forced vital capacity (adjusted Beta: 0.121; 95% Confidence interval: 0.023, 0.219) and negatively associated with the ratio of forced expiratory flow in first second/forced vital capacity (−0.204; −0.317, −0.091) at 11-years of age. Similar patterns were found for weight at 36 months and for change in weight from birth to 6 months of age. SGA or other various variables of early childhood growth were not associated with BHR at 11-years of age. Early life growth was associated with an obstructive lung function pattern, but not with BHR in 11-year old children. Foetal growth restriction or weight gain during early childhood do not seem to be important risk factors for subsequent BHR in children.acceptedVersio

DNA methylation in newborns conceived by assisted reproductive technology

Assisted reproductive technology (ART) may affect fetal development through epigenetic mechanisms as the timing of ART procedures coincides with the extensive epigenetic remodeling occurring between fertilization and embryo implantation. However, it is unknown to what extent ART procedures alter the fetal epigenome. Underlying parental characteristics and subfertility may also play a role. Here we identify differences in cord blood DNA methylation, measured using the Illumina EPIC platform, between 962 ART conceived and 983 naturally conceived singleton newborns. We show that ART conceived newborns display widespread differences in DNA methylation, and overall less methylation across the genome. There were 607 genome-wide differentially methylated CpGs. We find differences in 176 known genes, including genes related to growth, neurodevelopment, and other health outcomes that have been associated with ART. Both fresh and frozen embryo transfer show DNA methylation differences. Associations persist after controlling for parents’ DNA methylation, and are not explained by parental subfertility.publishedVersio

An agent model for business relationships

Relationships are fundamental to all but the most impersonal forms of interaction in business. An agent aims to secure projected needs by attempting to build a set of (business) relationships with other agents. A relationship is built by exchanging private information, and is characterised by its intimacy — degree of closeness — and balance — degree of fairness. Each argumentative interaction between two agents then has two goals: to satisfy some immediate need, and to do so in a way that develops the relationship in a desired direction. An agent’s desire to develop each relationship in a particular way then places constraints on the argumentative utterances. This paper describes argumentative interaction constrained by a desire to develop such relationships.Peer Reviewe

Growth in children conceived by ART

STUDY QUESTION Is the growth pattern of children conceived by ART different compared to naturally conceived children. SUMMARY ANSWER Both ART and underlying parental subfertility may contribute to differences in early childhood growth between children conceived with and without the use of ART. WHAT IS KNOWN ALREADY Children conceived by ART weigh less and are shorter at the time of delivery. The extent to which differences in growth according to mode of conception persist during childhood, and the role of underlying parental subfertility, remains unclear. STUDY DESIGN, SIZE, DURATION We conducted a prospective study population-based study. We studied 81 461 children participating in the Norwegian Mother, Father and Child Cohort Study (MoBa) and 544 113 adolescents screened for military conscription. PARTICIPANTS/MATERIALS, SETTING, METHODS Conception by ART as registered in the Medical Birth Registry. We compared maternally reported length/height and weight among children in MoBa from mid-pregnancy to age 7 according to mode of conception using mixed-effects linear regression. Differences in self-reported height and weight at 17 years of age at screening for military conscription were assessed with linear regression. MAIN RESULTS AND THE ROLE OF CHANCE At birth, children conceived by ART were shorter (boys −0.3 cm; 95% CI, −0.5 to −0.1), girls −0.4 cm; 95% CI, −0.5 to −0.3) and lighter (boys −113 grams; 95% CI, −201 to −25, girls −107 grams; 95% CI, −197 to −17). After birth, children conceived by ART grew more rapidly, achieving both greater height and weight at age 3. Children conceived by ART had a greater height up to age 7, but did not have a greater height or weight by age 17. Naturally conceived children of parents taking longer time to conceive had growth patterns similar to ART children. Children born after frozen embryo transfer had larger ultrasound measures and were longer and heavier the first 2 years than those born after fresh embryo transfer. LIMITATIONS, REASONS FOR CAUTIONS Selection bias could have been introduced due to the modest participation rate in the MoBa cohort. Our reliance on self-reported measures of length/height and weight could have introduced measurement error. WIDER IMPLICATIONS OF THE FINDINGS Our findings provide reassurance that offspring conceived by ART are not different in height, weight or BMI from naturally conceived once they reach adolescence.publishedVersio