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Background: The EU LifeCycle Project was launched in 2017 to combine, harmonize, and analyze data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview of the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project. Methods: Data on cognitive, behavioral, and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures. Results: The mental health data in LifeCycle contain longitudinal and cross-sectional data from birth throughout the life course, covering domains across a wide range of behavioral and psychopathology indicators and outcomes, including executive function, depression, ADHD, and cognition. These data span a unique combination of qualitative data collected through behavioral/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of imaging (MRI, fetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts. Conclusion: Mental health data harmonized through the LifeCycle project can be used to study life-course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

Background There is now good evidence that events during gestation significantly influence the developmental well-being of an individual in later life. This study aimed to investigate the relationships between intrauterine growth trajectories determined by serial ultrasound and subsequent markers of adiposity and inflammation in the 27-year-old adult offspring from the Raine Study, an Australian longitudinal pregnancy cohort. Methods Ultrasound fetal biometric measurements including abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs (Gen1–Gen2) in the Raine Study were used to develop fetal growth trajectories using group-based trajectory modeling. Linear mixed modeling investigated the relationship between adult body mass index (BMI), waist circumference (WC), and high-sensitivity C-reactive protein (hs-CRP) of Gen2 at 20 (n = 485), 22 (n = 421) and 27 (n = 437) years and the fetal growth trajectory groups, adjusting for age, sex, adult lifestyle factors, and maternal factors during pregnancy. Results Seven AC, five FL and five HC growth trajectory groups were identified. Compared to the average-stable (reference) group, a lower adult BMI was observed in two falling AC trajectories: (β = −1.45 kg/m2, 95% CI: −2.43 to −0.46, P = 0.004) and (β = −1.01 kg/m2, 95% CI: −1.96 to −0.05, P = 0.038). Conversely, higher adult BMI (2.58 kg/m2, 95% CI: 0.98 to 4.18, P = 0.002) and hs-CRP (37%, 95% CI: 9–73%, P = 0.008) were observed in a rising FL trajectory compared to the reference group. A high-stable HC trajectory associated with 20% lower adult hs-CRP (95% CI: 5–33%, P = 0.011). Conclusion This study highlights the importance of understanding causes of the unique patterns of intrauterine growth. Different fetal growth trajectories from early pregnancy associate with subsequent adult adiposity and inflammation, which predispose to the risk of diabetes and cardiometabolic disease.

Background: studies examining associations of early-life cat and dog ownership with childhood asthma have reported inconsistent results. Several factors could explain these inconsistencies, including type of pet, timing, and degree of exposure.Objective: our aim was to study associations of early-life cat and dog ownership with asthma in school-aged children, including the role of type (cat vs dog), timing (never, prenatal, or early childhood), and degree of ownership (number of pets owned), and the role of allergic sensitization.Methods: we used harmonized data from 77,434 mother-child dyads from 9 birth cohorts in the European Union Child Cohort Network when the child was 5 to 11 years old. Associations were examined through the DataSHIELD platform by using adjusted logistic regression models, which were fitted separately for each cohort and combined by using random effects meta-analysis.Results: the prevalence of early-life cat and dog ownership ranged from 12% to 45% and 7% to 47%, respectively, and the prevalence of asthma ranged from 2% to 20%. There was no overall association between either cat or dog ownership and asthma (odds ratio [OR] = 0.97 [95% CI = 0.87-1.09] and 0.92 [95% CI = 0.85-1.01], respectively). Timing and degree of ownership did not strongly influence associations. Cat and dog ownership were also not associated with cat- and dog-specific allergic sensitization (OR = 0.92 [95% CI = 0.75-1.13] and 0.93 [95% CI = 0.57-1.54], respectively). However, cat- and dog-specific allergic sensitization was strongly associated with school-age asthma (OR = 6.69 [95% CI = 4.91-9.10] and 5.98 [95% CI = 3.14-11.36], respectively). There was also some indication of an interaction between ownership and sensitization, suggesting that ownership may exacerbate the risks associated with pet-specific sensitization but offer some protection against asthma in the absence of sensitization.Conclusion: our findings do not support early-life cat and dog ownership in themselves increasing the risk of school-age asthma, but they do suggest that ownership may potentially exacerbate the risks associated with cat- and dog-specific allergic sensitization.

Context Events during gestation significantly influence the risk of cardiometabolic diseases including diabetes in the offspring during later life. Objective The study aimed to investigate relationships between serial ultrasound derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort. Research Design and Methods Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL) and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385) and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socio-economic status, adult lifestyle factors and maternal factors during pregnancy. Results The study identified seven AC, five FL and five HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%, P = 0.005) and two low HC growth trajectories (20%, P = 0.006 and 8%, P = 0.021) associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC associated with 12% (P = 0.002) and 9% (P = 0.021) lower adult HOMA-IR respectively, compared to the reference group. Conclusions Restricted fetal head and abdominal circumference from early pregnancy associate with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders.

ObjectiveResearch on adults has identified an immigrant health advantage, known as the ‘immigrant health paradox’, by which migrants exhibit better health outcomes than natives. Is this health advantage transferred from parents to children in the form of higher birth weight relative to children of natives?SettingWestern Europe and Australia.ParticipantsWe use data from nine birth cohorts participating in the LifeCycle Project, including five studies with large samples of immigrants’ children: Etude Longitudinale Française depuis l’Enfance—France (N=12 494), the Raine Study—Australia (N=2283), Born in Bradford—UK (N=4132), Amsterdam Born Children and their Development study—Netherlands (N=4030) and the Generation R study—Netherlands (N=4877). We include male and female babies born to immigrant and native parents.Primary and secondary outcome measuresThe primary outcome is birth weight measured in grams. Different specifications were tested: birth weight as a continuous variable including all births (DV1), the same variable but excluding babies born with over 4500 g (DV2), low birth weight as a 0–1 binary variable (1=birth weight below 2500 g) (DV3). Results using these three measures were similar, only results using DV1 are presented. Parental migration status is measured in four categories: both parents natives, both born abroad, only mother born abroad and only father born abroad.ResultsTwo patterns in children’s birth weight by parental migration status emerged: higher birth weight among children of immigrants in France (+12 g, pConclusionThe immigrant health advantage is not universally transferred to children in the form of higher birth weight in all host countries. Further research should investigate whether this cross-national variation is due to differences in immigrant communities, social and healthcare contexts across host countries.

Phthalate metabolites are detectable within the majority of the population. Evidence suggests that a prenatal exposure to phthalates may be associated with the subsequent risks of obesity and elevated blood pressure. We hypothesised that a prenatal exposure to phthalates would lead to an increase in adverse cardiometabolic parameters through childhood and adulthood. The maternal serum phthalate measurements from the stored samples taken from Gen1 mothers at 18 and 34 weeks gestation were examined in relation to the cardiometabolic measures in 387 male offspring from the Raine Study. Data from the Gen2 follow-ups between 3 and 27 years were used. The primary outcomes were analysed longitudinally using linear mixed models for the repeated measures. Non-alcoholic fatty liver disease (NAFLD) was assessed at 17 years using logistic regression. A consistent positive relationship was observed between a prenatal exposure to mono-carboxy-iso-octyl phthalate (MCiOP) through adolescence into adulthood with systolic blood pressure. There were no other consistent cardiovascular associations. Mid-levels of prenatal exposures to Mono-n-butyl phthalate (MnBP) were associated with a greater incidence of NAFLD. Detectable Mono-3-carboxypropyl phthalate (MCPP) was associated with a lower serum HDL-C through late childhood into adulthood, while a higher prenatal exposure to mono-iso-butyl phthalate (MiBP), was associated with a higher LDL-C at 22 years of age. A mid-level prenatal exposure to mono-2-ethylhexyl phthalate (MEHP) metabolites was associated with higher insulin in adulthood, while a higher prenatal exposure to the sum of the Di-(2-ethyl-hexyl) phthalate (DEHP) and Di-iso-nonyl phthalate (DiNP) metabolites was associated with higher fasting serum glucose in adulthood. In conclusion, our study demonstrated that higher prenatal phthalate exposures to some phthalate metabolites was associated with some adverse metabolic profiles through adolescence into adulthood, although the consistent themes were limited to a few metabolites and the outcomes of systolic blood pressure, fasting insulin and glucose.

Understanding the biological mechanisms behind multimorbidity patterns in adolescence is important as they may act as intermediary risk factor for long-term health. We aimed to explore relationship between prenatal exposures and adolescent’s psycho-cardiometabolic intermediary traits mediated through epigenetic biomarkers, using structural equation modelling (SEM). We used data from mother-child dyads from pregnancy and adolescents at 16–17 years from two prospective cohorts: Northern Finland Birth Cohort 1986 (NFBC1986) and Raine Study from Australia. Factor analysis was applied to generate two different latent factor structures: a) prenatal exposures and b) adolescence psycho-cardiometabolic intermediary traits. Furthermore, three types of epigenetic biomarkers were included: 1) DNA methylation score for maternal smoking during pregnancy (DNAmMSS), 2) DNAm age estimate PhenoAge and 3) DNAm estimate for telomere length (DNAmTL). We observed similar factor structure was observed between both cohorts yielding three prenatal factors BMI (Body Mass Index), SOP (Socio-Obstetric-Profile) and Lifestyle, and four adolescent factors: Anthropometric, Insulin-Triglycerides, Blood Pressure and Mental health. In the SEM pathways, stronger direct effects of F1prenatal-BMI (NFBC1986 = ß: 0.27; Raine = ß: 0.39) and F2prenatal-SOP (ß: -0.11) factors were observed on adolescent psycho-cardiometabolic multimorbidity. The indirect effect of the prenatal latent factors through epigenetic markers was mediated from DNAmTL and DNAmMSS going through PhenoAge (NFBC1986 = ß: 0.04; Raine = ß: 0.14), consistently in both cohorts (P

BACKGROUND AND AIMS: Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. APPROACH & RESULTS: We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially-methylated CpG sites (dmCpGs) for which ≥2 probes per gene remained significant across four statistical models with a nominal p-value ANK1, MIR10a, PTPRN2) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced (ANK1 n=6, MIR10a n=7, PTPRN2 n=3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p-3). CONCLUSIONS: We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.

BackgroundInternational sharing of cohort data for research is important and challenging. The LifeCycle project aimed to harmonise data across birth cohorts and develop methods for efficient federated analyses of early life stressors on offspring outcomes.AimTo explore feasibility of federated analyses of associations between four different types of pregnancy exposures (maternal education, area deprivation, proximity to green space and gestational diabetes) with offspring BMI from infancy to 17 years.MethodsWe used harmonised exposure and outcome data from 17 cohorts (n=200,650 mother-child pairs) from the EU Child Cohort Network. For each child, we derived BMI at five age periods: (i) 0-1 years, (ii) 2-3, (iii) 4-7, (iv) 8-13 and (v) 14-17 years. Associations were estimated using linear regression via one-stage individual participant data meta-analysis using the federated analysis platform DataSHIELD.ResultsAssociations between lower maternal education and higher child BMI emerged from age 4 years and increased with age (difference in BMI z-score comparing low with high education age 0-1 years = 0.02 [95% CI 0.00, 0.03], 2-3 years = 0.01 [CI -0.02, 0.04], 4-7 years = 0.14 [CI 0.13, 0.16], 8-13 years = 0.22 [CI 0.20, 0.24], 14-17 years = 0.20 [CI 0.16, 0.23]). A similar pattern was found for area deprivation. Gestational diabetes was positively associated with BMI from 8 years (8-13 years = 0.17 [CI 0.10, 0.24], 14-17 years = 0.012 [CI -0.13, 0.38]) but not at younger ages. The normalised difference vegetation index measure of maternal proximity to green space was weakly associated with higher BMI in the first year of life but not at older ages.ConclusionsAssociations between maternal education, area-based socioeconomic position and GDM with BMI increased with age. Maternal proximity to green space was not associated with offspring BMI, other than a weak association in infancy. Opportunities and challenges of cross-cohort federated analyses are discussed.

The Horizon2020 LifeCycle Project is a cross-cohort collaboration which brings together data from multiple birth cohorts from across Europe and Australia to facilitate studies on the influence of early-life exposures on later health outcomes. A major product of this collaboration has been the establishment of a FAIR (findable, accessible, interoperable and reusable) data resource known as the EU Child Cohort Network. Here we focus on the EU Child Cohort Network's core variables. These are a set of basic variables, derivable by the majority of participating cohorts and frequently used as covariates or exposures in lifecourse research. First, we describe the process by which the list of core variables was established. Second, we explain the protocol according to which these variables were harmonised in order to make them interoperable. Third, we describe the catalogue developed to ensure that the network's data are findable and reusable. Finally, we describe the core data, including the proportion of variables harmonised by each cohort and the number of children for whom harmonised core data are available. EU Child Cohort Network data will be analysed using a federated analysis platform, removing the need to physically transfer data and thus making the data more accessible to researchers. The network will add value to participating cohorts by increasing statistical power and exposure heterogeneity, as well as facilitating cross-cohort comparisons, cross-validation and replication. Our aim is to motivate other cohorts to join the network and encourage the use of the EU Child Cohort Network by the wider research community. The LifeCycle project received funding from the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 733206 LifeCycle). All study specific acknowledgements and funding are presented in the supplementary material. This manuscript reflects only the author’s view and the Commission is not responsible for any use that may be made of the information it contains.

Epigenetics links perinatal influences with later obesity. We identifed differentially methylated CpG (dmCpG) loci measured at 17 years associated with concurrent adiposity measures and examined whether these were associated with hsCRP, adipokines, and early life environmental factors. Genome-wide DNA methylation from 1192 Raine Study participants at 17 years, identified 29 dmCpGs (Bonferroni corrected p < 1.06E-07) associated with body mass index (BMI), 10 with waist circumference (WC) and 9 with subcutaneous fat thickness. DmCpGs within Ras Association (RalGDS/AF-6), Pleckstrin Homology Domains 1 (RAPH1), Musashi RNA-Binding Protein 2 (MSI2), and solute carrier family 25 member 10 (SLC25A10) are associated with both BMI and WC. Validation by pyrosequencing confirmed these associations and showed that MSI2 , SLC25A10 , and RAPH1 methylation was positively associated with serum leptin. These were also associated with the early environment; MSI2 methylation (β = 0.81, p = 0.0004) was associated with pregnancy maternal smoking, SLC25A10 (CpG2 β = 0.12, p = 0.002) with pre- and early pregnancy BMI, and RAPH1 (β = −1.49, p = 0.036) with gestational weight gain. Adjusting for perinatal factors, methylation of the dmCpGs within MSI2, RAPH1, and SLC25A10 independently predicted BMI, accounting for 24% of variance. MSI2 methylation was additionally associated with BMI over time (17 years old β = 0.026, p = 0.0025; 20 years old β = 0.027, p = 0.0029) and between generations (mother β = 0.044, p = 7.5e-04). Overall findings suggest that DNA methylation in MSI2, RAPH1, and SLC25A10 in blood may be robust markers, mediating through early life factors.

Altered maternal haemoglobin levels during pregnancy are associated with pre-clinical and clinical conditions affecting the fetus. Evidence from animal models suggests that these associations may be partially explained by differential DNA methylation in the newborn with possible long-term consequences. To test this in humans, we meta-analyzed the epigenome-wide associations of maternal haemoglobin levels during pregnancy with offspring DNA methylation in 3,967 newborn cord blood and 1,534 children and 1,962 adolescent whole-blood samples derived from 10 cohorts. DNA methylation was measured using Illumina Infinium Methylation 450K or MethylationEPIC arrays covering 450,000 and 850,000 methylation sites, respectively. There was no statistical support for the association of maternal haemoglobin levels with offspring DNA methylation either at individual methylation sites or clustered in regions. For most participants, maternal haemoglobin levels were within the normal range in the current study, whereas adverse perinatal outcomes often arise at the extremes. Thus, this study does not rule out the possibility that associations with offspring DNA methylation might be seen in studies with more extreme maternal haemoglobin levels. Study-specific funding information can be found in the Supplementary Methods. JR, AH, EL, and SS were supported by the European Union’s Horizon 2020 research and innovation program [grant numbers 633595 (DynaHEALTH) and 733206 (LifeCycle)], Academy of Finland [grant number 285547 (EGEA)] and the Biocenter Oulu. ACJ was funded by the National Institute of Environmental Health Sciences [grant number R00ES023450]. AK was supported by the National Institute of Environmental Health Sciences [grant number R01ES021357]. DCa was funded by the UK Medical Research Council [grant number MC_UU_00011/7]. EKa received funding from the Horizon2020 grant for RECAP Research on Children and Adults Born Preterm [grant number 733280], Academy of Finland [grant number 315690], Foundation for Pediatric Research, Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation and Sigrid Jusélius Foundation. EKe received funding from the Finnish Medical Association. MG was supported by Miguel Servet fellowship from the Institute of Health Carlos III [grant numbers MS13/00054, CP18/00018]. MVä received funding from the Research Funds of Oulu University Hospital, Juho Vainio Foundation and Signe and Ane Gyllenberg Foundation. RCH was supported by the National Health and Medical Research Council Fellowship Grants [grant number 1053384]. SJL was supported by the intramural research program of the National Institutes of Health, National Institute of Environmental Health Sciences. SM received funding from the University of Oulu Graduate School. SR was supported by National Health and Medical Research Council EU [grant number 1142858] and the Department of Health, Western Australia FutureHealth fund in connection with the European Union’s Horizon 2020 [grant number 733206].

Background and aims Cardiovascular disease (CVD) begins in youth, and is exacerbated by obesity and metabolic syndrome. Apolipoprotein (Apo)B-remnant cholesterol is considered a primary contributor to CVD risk. Fasting plasma apoB48 can be used as a biomarker of intestinal remnant cholesterol as well as postprandial dyslipidemia. In adults, elevated fasting plasma apoB48 strongly associates with cardiometabolic risk factors and obesity, whereas in adolescents there is limited data. The aim of this study was to measure fasting plasma apoB48 and determine the relationship with cardiometabolic risk factors in adolescents. Methods This is a cross-sectional study of fasting plasma apoB48 from the Western Australian Pregnancy Cohort (Raine) Study. Subjects were adolescent males and females aged 17 years with complete fasting plasma apoB48, biochemical, and anthropometry data (n = 1045). The relationship between fasting plasma apoB48 and other cardiometabolic risk factors was determined. The high-risk metabolic cluster variable was defined using elevated BMI, HOMA-IR, fasting plasma triglycerides, and systolic blood pressure. Results Fasting plasma apoB48 was significantly higher in male (15.28 ± 2.95 μg/mL) compared to female (12.45 ± 2.43 μg/mL) adolescents (p = 0.0003), and was increased by 21% (3.60 μg/mL; p = 0.0000) in the high-risk metabolic cluster group and more pronounced in males (31%, 6.15 μg/mL; p = 0.0000). Fasting plasma apoB48 was positively associated with fasting plasma triglycerides, total-cholesterol (but not LDL-C), insulin, leptin, HOMA-IR, and the anthropometric parameters, waist-circumference and skinfold-thickness. Fasting plasma apoB48 was inversely associated with fasting plasma HDL-C, and adiponectin. Conclusions Plasma apoB48 remnant lipoproteins associate with cardiometabolic risk factors in adolescents and provide support for the screening of remnant cholesterol in youth.

Background Previous studies have reported an association between low birthweight and elevated blood pressure (BP) in adulthood, but few have examined the relationship between foetal growth and adult BP. Method The study examined the association between intrauterine growth trajectories determined by serial ultrasound and BP of the adult offspring in the Raine Study. Foetal growth trajectories for abdominal circumference, femur length and head circumference z-scores were developed using group-based trajectory modelling from 1440 women with serial ultrasounds from 15-weeks pregnancy to birth. Seven abdominal circumference, five femur length and five head circumference trajectory groups were identified. Longitudinal linear mixed modelling examined the association between trajectory groups and offspring BP at 20 (n = 487), 22 (n = 419) and 27 (n = 436) years. Results Higher SBP in adulthood significantly associated with two abdominal circumference trajectories, one with the most restricted foetal growth [3.52 mmHg, 95% confidence interval (95% CI) = 1.20-5.83] and the other with sustained low-growth (1.92 mmHg, 95% CI = 0.11-3.73) compared with an average growth trajectory, after adjusting for sex, age, alcohol consumption and BMI. Foetal head circumference trajectories with sustained low-growth or average-to-falling growth significantly associated with higher adult systolic (3.45 mmHg, 95% CI = 1.77-5.14 and 1.54 mmHg, 95% CI = 0.30-2.78, respectively) and diastolic (2.28 mmHg, 95% CI = 0.77-3.78 and 1.47 mmHg, 95% CI = 0.54-2.39, respectively) BP compared with average growth. Low femur length growth associated with higher adult DBP after adjusting for sex, but not after accounting for adult BMI. Conclusion Our results show that restricted foetal head and abdominal circumference associated with higher adult SBP over two decades later, reinforcing the importance of the early intrauterine environment and its influence on adult BP.

Study question Is the cardiometabolic health of adolescents conceived through ART worse than that of their spontaneously-conceived counterparts? Summary answer The majority of cardiometabolic and vascular health parameters of ART-conceived adolescents are more favourable than those of their spontaneously-conceived counterparts of similar age. What is known already It has been proposed that ART induces epigenetic alterations during embryonic development which could lead to cardiometabolic disease later in life. However, individuals requiring ART may themselves be metabolically less healthy than the general population, which could lead to a genetically increased risk of cardiometabolic disorders in the offspring, rather than the ART procedure. The literature pertaining to cardiometabolic health of ART-conceived offspring is contradictory, but generally suggests unfavourable cardiometabolic health parameters. With over 8 million children and adults born through ART worldwide, it is imperative to investigate whether early signs of adverse cardiometabolic differences persist into adolescence and beyond. Study design, size, duration The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 ART-conceived adolescents, born 1991-2001 in Western Australia. Their health parameters, including cardiometabolic factors, were assessed and compared with spontaneously conceived counterparts of similar socioeconomic background and age from the Raine Study Generation 2 (Gen2). The 2868 Gen2 participants were born 1989-1992 and are representative of the Western Australian adolescent population. At age 16-17 (2013-2017), GUHS participants replicated assessments previously completed by Gen2. Participants/materials, setting, methods Cardiometabolic parameters were compared between 165 GUHS (male = 50.9%) and 1690 Gen2 (male = 49.8%) adolescents. Assessments consisted of a detailed questionnaire; health and demographic parameters, anthropometric assessments; height, weight, body-mass index (BMI), waist circumference and skinfold thickness, fasting serum biochemistry, arterial stiffness and blood pressure assessment using applanation tonometry, assessment of non-alcoholic fatty liver (NAFLD) and thickness of abdominal fat compartments using ultrasonography. Chi2, Fisher’s Exact and Mann-Whitney U tests, performed in SPSS V25, examined cohort differences. Main results and the role of chance GUHS adolescents appeared to be healthier from a cardiometabolic perspective than their Gen2 counterparts. They were leaner, with lower BMI (median: 21.23 vs. 22.06, P = 0.004), lower waist circumference (median: 74.10 vs. 76.75 cm, P = 0.031), and thinner skinfolds (triceps median: 12.1 vs. 14.0 mm, P = 0.019, subscapular median: 10.6 vs. 11.9 mm, P < .001, mid-abdominal median: 16.0 vs. 19.9 mm, P Limitations, reasons for caution Despite the substantial study size and the unique study design, we were unable to differentiate between different types of ART (e.g. IVF vs. ICSI), draw definite conclusions or relate outcomes to cause of infertility. Given the observational character of this study, causation cannot be proven. Wider implications of the findings In this study we did not detect any adverse effect of ART on cardiometabolic health at adolescence, in contrast to some studies. Given the lack of consensus, future well-designed and appropriately-powered studies are necessary to investigate cardiometabolic health in ART adults. Trial registration number not applicable

Background:Childhood obesity is a global issue. Excessive weight gain in early pregnancy is independently associated with obesity in the next generation. Given the uptake of e-health, our primary aim was to pilot the feasibility of an e-health intervention, starting in the first trimester, to promote healthy lifestyle and prevent excess weight gain in early pregnancy. Methods: Women were recruited between 8 and 11 weeks gestation and randomised to the intervention or routine antenatal care. The intervention involved an e-health program providing diet, physical activity and well-being advice over 12 weeks.Results:Women (n = 57, 43.9% overweight/obese) were recruited at 9.38 ± 1.12 (control) and 9.06 ± 1.29 (intervention) weeks’ gestation, mainly from obstetric private practices (81.2%). Retention was 73.7% for the 12-week intervention, 64.9% at birth and 55.8% at 3 months after birth.No difference in gestational weight gain or birth size was detected. Overall treatment effect showed a mean increase in score ranking the perceived confidence of dietary change (1.2 ± 0.46, p = 0.009) and score ranking readiness to exercise (1.21 ± 0.51, p = 0.016) over the intervention. At 3 months, infants weighed less in the intervention group (5405 versus 6193 g, p = 0.008) and had a lower ponderal index (25.5 ± 3.0 versus 28.8 ± 4.0 kg/m3) compared with the control group.Conclusion and Discussion:A lifestyle intervention starting in the first-trimester pregnancy utilising e-health mode of delivery is feasible. Future studies need strategies to target recruitment of participants of lower socio-economic status and ensure maximal blinding. Larger trials (using technology and focused on early pregnancy) are needed to confirm if decreased infant adiposity is maintained.

Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood?Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder.Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function.The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample.Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectrometry.At 17 years of age, a liver ultrasound examination was performed to determine the presence of non-alcoholic fatty liver disease (NAFLD), and serum analysed for the cytokines interleukin-18 and soluble tumour necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2).At 17 and 20 years of age, fasting blood samples were analysed for serum liver enzymes, insulin, glucose, triglycerides (TG), total cholesterol, high density lipoprotein and low density lipoprotein cholesterol, high sensitivity C-reactive protein and uric acid. The homoeostatic model assessment (HOMA) was calculated and approximated IR was defined by a HOMA4. Anthropometric data was collected and dual energy X-ray absorptiometry measurement performed for lean and total fat mass. As at this young age the prevalence of metabolic syndrome was expected to be low, a two-step cluster analysis was used using waist circumference, TGs, insulin, and systolic blood pressure to derive a distinct high-risk group with features consistent with the metabolic syndrome and increased cardiometabolic risk.Men at age 17 years with increased cardiometabolic risk had lower concentrations of serum testosterone (medians: 4.0 versus 4.9 ng/mL) and inhB (193.2 versus 221.9 pg/mL) (P0.001 for both) compared to those within the low risk metabolic cluster. Men with ultrasound evidence of NAFLD (n = 45, 9.8%) had reduced total sperm output (medians: 68.0 versus 126.00 million, P = 0.044), testosterone (4.0 versus 4.7 ng/mL, P = 0.005) and inhB (209.1 versus 218.4 pg/mL, P = 0.032) compared to men without NAFLD.Men with higher concentrations of sTNFR1 at 17 years of age had a lower sperm output and serum concentration of inhB, with an increase in LH and FSH (all P0.05 after adjustment for age, BMI, abstinence and a history of cryptorchidism, varicocele, cigarette smoking, alcohol and drug use), compared to those without an elevated sTNFR1. Multivariable regression analysis, adjusting for confounders, demonstrated that men in the high-risk metabolic cluster at 20 years had a lower serum testosterone and inhB (P = 0.003 and P = 0.001, respectively). A HOMA-IR4 was associated with a lower serum testosterone (P =0.001) and inhB (P = 0.010) and an increase in serum FSH (P = 0.015).This study is limited by the sample size and multiple comparisons, and causality cannot be proven from an observational study. Due to a 3-year interval between some metabolic assessments and assessment of testicular function, we cannot exclude the introduction of a bias into the study, as some of the participants and their testicular function will not have been fully mature at the 17-year assessment.Irrespective of a proven causation, our study findings are important in that a significant minority of the men, prior to seeking parenthood, presented co-existent features of metabolic disorder and signs of testicular impairment. Of particular note is that the presence of NAFLD at 17 years of age, although only present in a minority of men, was associated with an almost 50% reduction in sperm output at 20 years of age, and that the presence of IR at 20 years was associated with a 20% reduction in testicular volume.This study was supported by Australian NHMRC (Grant Numbers 634457, 35351417 and 403981) and received support from the Raine Medical Research Foundation, The Telethon Kids Institute, University of Western Australia, Women and Infants Research Foundation, Curtin University and Edith Cowan University. D.A.D., J.E.D., N.M., L.A.A., R.-C.H., T.A.M., J.K.O., L.J.B. have nothing to declare. R.J.H. is Medical Director of Fertility Specialists of Western Australia, has equity interests in Western IVF, and has received grant support from MSD, Merck-Serono and Ferring Pharmaceuticals. RMcL has equity interests in the Monash IVF Group. R.J.N. has equity interests in FertilitySA, and has received grant support from Merck Serono and Ferring Pharmaceuticals. D.J.H. has received institutional grant funding (but no personal income) for investigator-initiated testosterone pharmacology studies from Lawley and Besins Healthcare and has provided expert testimony to anti-doping tribunals and for testosterone litigation.This abstract was awarded the Fertility Society of Australia clinical exchange award for the oral presentation at ESHRE, Barcelona, in 2018.

Background and Aims Current strategies to reduce cardiovascular disease (CVD) risk in young adults are largely limited to those at extremes of risk. In cohort studies we have shown cluster analysis identified a large sub-group of adolescents with multiple risk factors. This study examined if individuals classified at ‘high-risk’ by cluster analysis could also be identified by their Framingham risk scores. Methods and Results Raine Study data at 17- (n=1048) and 20-years (n=1120) identified high- and low-risk groups by cluster analysis using continuous measures of systolic BP, BMI, triglycerides and insulin resistance. We assessed:- CVD risk at 20-years using the Framingham 30yr-risk-score in the high- and low-risk clusters, and cluster stability from adolescence to adulthood. Cluster analysis at 17- and 20-years identified a high-risk group comprising, 17.9% and 21.3%, respectively of the cohort. In contrast, only 1.2% and 3.4%, respectively, met the metabolic syndrome criteria, all of whom were within the high-risk cluster. Compared with the low-risk cluster, Framingham scores of the high-risk cluster were elevated in males (9.4%; 99%CI 8.3, 10.6 vs 6.0%; 99%CI 5.7, 6.2) and females (4.9%; 99%CI 4.4, 5.4 vs 3.2%; 99%CI 3.0, 3.3) (both P 8 for males and >4 for females identified those at high CVD risk with 99% confidence. Conclusion Cluster analysis using multiple risk factors identified ∼20% of young adults at high CVD risk. Application of our Framingham 30yr-risk cut-offs to individuals allows identification of more young people with multiple risk factors for CVD than conventional metabolic syndrome criteria.

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P −7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10−4; adolescence Penrichment = 2.10 × 10−7). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.

STUDY QUESTION Do the epigenome-wide DNA methylation profiles of adolescents born from ART differ from the epigenome of naturally conceived counterparts? SUMMARY ANSWER No significant differences in the DNA methylation profiles of adolescents born from ART [IVF or ICSI] were observed when compared to their naturally conceived, similar aged counterparts. WHAT IS KNOWN ALREADY Short-term and longer-term studies have investigated the general health outcomes of children born from IVF treatment, albeit without common agreement as to the cause and underlying mechanisms of these adverse health findings. Growing evidence suggests that the reported adverse health outcomes in IVF-born offspring might have underlying epigenetic mechanisms. STUDY DESIGN, SIZE, DURATION The Growing Up Healthy Study (GUHS) is a prospective study that recruited 303 adolescents and young adults, conceived through ART, to compare various long-term health outcomes and DNA methylation profiles with similar aged counterparts from Generation 2 from the Raine Study. GUHS assessments were conducted between 2013 and 2017. The effect of ART on DNA methylation levels of 231 adolescents mean age 15.96 ± 1.59 years (52.8% male) was compared to 1188 naturally conceived counterparts, 17.25 ± 0.58 years (50.9% male) from the Raine Study. PARTICIPANTS/MATERIALS, SETTING, METHODS DNA methylation profiles from a subset of 231 adolescents (13–19.9 years) from the GUHS, generated using the Infinium Methylation Epic Bead Chip (EPIC) array were compared to 1188 profiles from the Raine Study previously measured using the Illumina 450K array. We conducted epigenome-wide association approach (EWAS) and tested for an association between the cohorts applying Firth’s bias reduced logistic regression against the outcome of ART versus naturally conceived offspring. Additionally, within the GUHS cohort, we investigated differences in methylation status in fresh versus frozen embryo transfers, cause of infertility as well as IVF versus ICSI conceived offspring. Following the EWAS analysis we investigated nominally significant probes using Gene Set Enrichment Analysis (GSEA) to identify enriched biological pathways. Finally, within GUHS we compared four estimates (Horvath, Hanuum, PhenoAge [Levine], and skin Horvath) of epigenetic age and their correlation with chronological age. MAIN RESULTS AND THE ROLE OF CHANCE Between the two cohorts, we did not identify any DNA methylation probes that reached a Bonferroni corrected P-value < 1.24E−0.7. When comparing IVF versus ICSI conceived adolescents within the GUHS cohort, after adjustment for participant age, sex, maternal smoking, multiple births, and batch effect, three methylation probes (cg15016734, cg26744878 and cg20233073) reached a Bonferroni correction of 6.31E−08. After correcting for cell count heterogeneity, two of the aforementioned probes remained significant and an additional two probes (cg 0331628 and cg 20235051) were identified. A general trend towards hypomethylation in the ICSI offspring was observed. All four measures of epigenetic age were highly correlated with chronological age and showed no evidence of accelerated epigenetic aging within their whole blood. LIMITATIONS, REASONS FOR CAUTION The small sample size coupled with the use of whole blood, where epigenetic differences may occur in other tissue. This was corrected by the utilized statistical method that accounts for imbalanced sample size between groups and adjusting for cell count heterogeneity. Only a small portion of the methylome was analysed and rare individual differences may be missed. WIDER IMPLICATIONS OF THE FINDINGS Our findings provide further reassurance that the effects of the ART manipulations occurring during early embryogenesis, existing in the neonatal period are indeed of a transient nature and do not persist into adolescence. However, we have not excluded that alternative epigenetic mechanisms may be at play. STUDY FUNDING/COMPETING INTEREST(S) This project was supported by NHMRC project Grant no. 1042269 and R.J.H. received funding support from Ferring Pharmaceuticals Pty Ltd. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from Merck Sharp & Dohme Corp.- Australia, Merck-Serono Australia Pty Ltd and Ferring Pharmaceuticals Pty Ltd. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. The remaining authors have no conflicts of interest.

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs. Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.

Background: Fetal exposure to maternal smoking during pregnancy is associated with the development of noncommunicable diseases in the offspring. Maternal smoking may induce such long-term effects through persistent changes in the DNA methylome, which therefore hold the potential to be used as a biomarker of this early life exposure. With declining costs for measuring DNA methylation, we aimed to develop a DNA methylation score that can be used on adolescent DNA methylation data and thereby generate a score for in utero cigarette smoke exposure. Methods: We used machine learning methods to create a score reflecting exposure to maternal smoking during pregnancy. This score is based on peripheral blood measurements of DNA methylation (Illumina’s Infinium HumanMethylation450K BeadChip). The score was developed and tested in the Raine Study with data from 995 white 17-y-old participants using 10-fold cross-validation. The score was further tested and validated in independent data from the Northern Finland Birth Cohort 1986 (NFBC1986) (16-y-olds) and 1966 (NFBC1966) (31-y-olds). Further, three previously proposed DNA methylation scores were applied for comparison. The final score was developed with 204 CpGs using elastic net regression. Results: Sensitivity and specificity values for the best performing previously developed classifier (“Reese Score”) were 88% and 72% for Raine, 87% and 61% for NFBC1986 and 72% and 70% for NFBC1966, respectively; corresponding figures using the elastic net regression approach were 91% and 76% (Raine), 87% and 75% (NFBC1986), and 72% and 78% for NFBC1966. Conclusion: We have developed a DNA methylation score for exposure to maternal smoking during pregnancy, outperforming the three previously developed scores. One possible application of the current score could be for model adjustment purposes or to assess its association with distal health outcomes where part of the effect can be attributed to maternal smoking. Further, it may provide a biomarker for fetal exposure to maternal smoking. https://doi.org/10.1289/EHP6076

Context Circulating concentrations of free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) are partly heritable traits. Recent studies have advanced knowledge of their genetic architecture. Epigenetic modifications, such as DNA methylation (DNAm), may be important in pituitary-thyroid axis regulation and action, but data are limited. Objective To identify novel associations between fT3, fT4, and TSH and differentially methylated positions (DMPs) in the genome in subjects from 2 Australian cohorts. Method We performed an epigenome-wide association study (EWAS) of thyroid function parameters and DNAm using participants from: Brisbane Systems Genetics Study (median age 14.2 years, n = 563) and the Raine Study (median age 17.0 years, n = 863). Plasma fT3, fT4, and TSH were measured by immunoassay. DNAm levels in blood were assessed using Illumina HumanMethylation450 BeadChip arrays. Analyses employed generalized linear mixed models to test association between DNAm and thyroid function parameters. Data from the 2 cohorts were meta-analyzed. Results We identified 2 DMPs with epigenome-wide significant (P Conclusions This study has demonstrated associations between blood-based DNAm and both fT3 and TSH. This may provide insight into mechanisms underlying thyroid hormone action and/or pituitary-thyroid axis function.

Background Early excess and inadequate gestational weight gain (GWG) have been associated with negative outcomes for mother and child. The use of digital media to deliver pregnancy lifestyle interventions is increasing, but there is little data on participant engagement. The Pregnancy Lifestyle Activity and Nutrition (PLAN) intervention pilot study was an electronic health and dietetic-delivered intervention program promoting healthy GWG in early pregnancy. Objective This study aims to explore the interactions of participants with the program and to assess its acceptability. Methods This study uses both quantitative and qualitative methods using data from parent randomized controlled trial (ACTRN12617000725369). Quantitative data from 22 participants in the intervention arm who completed the study provided measures of the interactions participants had with the digital components of the program and with dietetic consultations. A descriptive qualitative analysis employed semistructured interviews with 9 participants to elicit views on the acceptability of the intervention and its components. Results The electronic delivery of information and recording of weight from 8 to 20 weeks of gestation were universally accepted. Component (face-to-face dietitian, weight tracker, website information delivery, and SMS goal prompting) acceptability and engagement differed between individuals. A total of 4 key themes emerged from the qualitative analysis: supporting lifestyle change, component acceptability and value, delivery platforms, and engagement barriers. Conclusions The PLAN intervention and its delivery via a blend of personal dietetic consultations and digital program delivery was found to be acceptable and valuable to pregnant women. Individuals responded differently to various components, emphasizing the importance of including women in the development of lifestyle interventions and allowing participants to choose and tailor programs. Larger randomized controlled trials using these insights in a broader section of the community are needed to inform the iterative development of practical, time-efficient, and cost-effective ways of supporting optimal GWG with the potential to optimize outcomes for pregnant women and their child.

Context Adolescents with polycystic ovary syndrome (PCOS) have increased incidence of cardiometabolic risk factors including dyslipidemia. Atherogenic apolipoprotein (apo) B-lipoprotein remnants are associated with increased cardiovascular disease (CVD) risk. Objective The aim of this study was to determine the concentrations of fasting plasma apoB-lipoprotein remnants, apoB48 and apoB100, and their association with cardiometabolic risk factors and androgen indices in adolescent girls with and without PCOS. Design, setting and participants Participants (n = 184) aged 17 years were recruited in the Menstruation in Teenagers Study from the Western Australian Pregnancy Cohort (Raine) Study. The main outcome measures Fasting plasma apo-B48 and -B100 lipoprotein remnant concentrations in adolescent girls with and without PCOS. Results Fasting plasma apoB48-lipoprotein remnants but not apoB100-lipoprotein remnants were elevated in adolescent girls with increased cardiometabolic risk compared with those with lower cardiometabolic risk (13.91 ± 5.06 vs 12.09 ± 4.47 µg/mL, P < .01). ApoB48-lipoprotein remnants were positively correlated with fasting plasma triglycerides (b = .43, P < .0001). The prevalence of increased cardiometabolic risk factors was 2-fold higher in those diagnosed with PCOS (35.3%) than in those without PCOS (16.3%).Conclusion: Adolescents with PCOS have a 2-fold higher incidence of cardiometabolic risk factors than those without PCOS. Fasting apoB48-lipoprotein remnants are elevated in adolescent girls with a high prevalence of cardiometabolic risk factors.

Background Machine learning is a sub-field of artificial intelligence, which utilises large data sets to make predictions for future events. Although most algorithms used in machine learning were developed as far back as the 1950s, the advent of big data in combination with dramatically increased computing power has spurred renewed interest in this technology over the last two decades. Main body Within the medical field, machine learning is promising in the development of assistive clinical tools for detection of e.g. cancers and prediction of disease. Recent advances in deep learning technologies, a sub-discipline of machine learning that requires less user input but more data and processing power, has provided even greater promise in assisting physicians to achieve accurate diagnoses. Within the fields of genetics and its sub-field epigenetics, both prime examples of complex data, machine learning methods are on the rise, as the field of personalised medicine is aiming for treatment of the individual based on their genetic and epigenetic profiles. Conclusion We now have an ever-growing number of reported epigenetic alterations in disease, and this offers a chance to increase sensitivity and specificity of future diagnostics and therapies. Currently, there are limited studies using machine learning applied to epigenetics. They pertain to a wide variety of disease states and have used mostly supervised machine learning methods.

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P − 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.