Large Population-based Cohort Research Articles

Trends in COPD severe exacerbations, and all-cause and respiratory mortality, before and after implementation of newer long-acting bronchodilators in a large population-based cohort

BackgroundLittle is known about the trends in morbidity and mortality at the population level that followed the introduction of newer once-daily long-acting bronchodilators for COPD. The purpose of the study was to evaluate whether the availability of new bronchodilators was associated with changes in the temporal trends in severe COPD exacerbations and mortality between 2007 and 2018 in the older population with COPD; and whether this association was homogeneous across sex and socioeconomic status classes.MethodsWe used an interrupted time-series and three segments multivariate autoregressive models to evaluate the adjusted changes in slopes (i.e., trend effect) in monthly severe exacerbation and mortality rates after 03/2013 and 02/2015 compared to the tiotropium period (04/2007 to 02/2013). Cohorts of individuals > 65 years with COPD were created from the nationally representative database of the Quebec Integrated Chronic Disease Surveillance System in the province of Quebec, Canada. Whether these trends were similar for men and women and across different socioeconomic status classes was also assessed.ResultsThere were 130,750 hospitalizations for severe exacerbation and 104,460 deaths, including 24,457 (23.4%) respiratory-related deaths, over the study period (928,934 person-years). Significant changes in trends were seen after 03/2013 for all-cause mortality (-1.14%/month;95%CI -1.90% to -0.38%), which further decreased after 02/2015 (-1.78%/month;95%CI -2.70% to -0.38%). Decreases in respiratory-related mortality (-2.45%/month;95%CI -4.38% to -0.47%) and severe exacerbation (-1,90%/month;95%CI -3.04% to -0.75%) rates were only observed after 02/2015. These observations tended to be more pronounced in women than in men and in higher socioeconomic status groups (less deprived) than in lower socioeconomic status groups (more deprived).ConclusionsThe arrival of newer bronchodilators was chronologically associated with reduced trends in severe exacerbation, all-cause and respiratory-related mortality rates among people with COPD > 65 years. Our findings document population benefits on key patient-relevant outcomes in the years following the introduction of newer once-daily long-acting bronchodilators and their combinations, which were likely multifactorial. Public health efforts should focus on closing the gap between lower and higher socioeconomic status groups.

Traumatic Brain Injury and Risk of Incident Dementia: Forensic Applications of Current Research

Abstract Objective Traumatic Brain Injury (TBI) has been purported to increase risk for later developing neurodegenerative disorders (ND). Forensic neuropsychologists are frequently asked to opine on risk for ND after an alleged TBI. We provide an evidence-based foundation to aid forensic practice by summarizing the: role of the neuropsychologist in TBI-related litigation, complexities associated with identifying TBIs in forensic cases, science of TBI in relation to incident dementia, and current scientific evidence for chronic traumatic encephalopathy. Data Selection The most applicable studies to forensic settings are large prospective cohort and population-based cohort studies given their wider generalizability and long periods of follow-up/tracking for outcomes. Data Synthesis Developing ND after TBI is the exception rather than the rule. Only a small subset (< 5%) of individuals with moderate-to-severe TBI, and even fewer (< 1%) with mild TBI, appear to develop ND, and the characteristics that place some at risk remain unclear. Positive evidence for risk of ND after mild TBI is weak and mostly consists of observational studies characterized by methodological limitations. Conclusions Forensic methods used to establish the likely occurrence of TBI are typically more extensive than those used in clinical evaluations, while TBI definitions used in current research are even more rudimentary and inconsistent. Applying clinical research findings regarding TBI and dementia outcomes to forensic cases at an individual level carries significant limitations. Estimating the contribution of remote TBI/concussion in a causal manner to ND risk is a challenge forensic experts sometimes face, yet at present, the task is impossible beyond correlations and speculation.

High lipoprotein(a) is a risk factor for peripheral artery disease, abdominal aortic aneurysms, and major adverse limb events.

To summarize evidence from recent studies of high lipoprotein(a) as a risk factor for peripheral artery disease (PAD), abdominal aortic aneurysms (AAA), and major adverse limb events (MALE). Additionally, provide clinicians with 10-year absolute risk charts enabling risk prediction of PAD and AAA by lipoprotein(a) levels and conventional risk factors. Numerous studies support high lipoprotein(a) as an independent risk factor for PAD, AAA, and MALE. The strongest evidence is from the Copenhagen General Population Study (CGPS) and the UK Biobank, two large general population-based cohorts. In the CGPS, a 50 mg/dl higher genetically determined lipoprotein(a) associated with hazard ratios of 1.39 (1.24-1.56) for PAD and 1.21 (1.01-1.44) for AAA. Corresponding hazard ratio in the UK Biobank were 1.38 (1.30-1.46) and 1.42 (1.28-1.59). In CGPS participants with levels at least 99th (≥143 mg/dl) vs, less than 50th percentile (≤9 mg/dl), hazard ratios were 2.99 (2.09-4.30) for PAD and 2.22 (1.21-4.07) for AAA, with a corresponding incidence rate ratio for MALE of 3.04 (1.55-5.98) in participants with PAD. Evidence from both observational and genetic studies support high lipoprotein(a) as a causal risk factor for PAD, AAA, and MALE, and highlight the potential of future lipoprotein(a)-lowering therapy to reduce the substantial morbidity and mortality associated with these diseases.

Identifying a Birth Cohort of Twins from Linked Data – Challenges and Opportunities

ObjectiveIn the absence of accurate perinatal records, identifying and differentiating twins in administrative records is difficult because of their similarity; they share surnames, dates of birth, and residences. In administrative databases, events within twin pairs are often incorrectly identified as being from one individual, representing a threat to data accuracy. An inability to identify twins in administrative data precludes applying powerful twin-based causal inference methods to understand health and social well-being. ApproachWe developed an algorithm using linked administrative birth, perinatal, emergency department, and hospital records in Victoria, Australia from 1 January 1993 to 31 December 2023. We probabilistically linked a sample of 1,434 ‘known’ twin pairs from the Australian Twin Registry to validate the sensitivity of our algorithm. We calculated specificity using a sample of non-twins derived from linked data. ResultsOur algorithm identified 37,900 twin pairs, 75,800 twin individuals, in the Victorian linked dataset. The accuracy of our ascertainment of twins by key characteristics will be presented and discussed. ConclusionsThe birth cohort we have generated is one of the largest twin cohorts in the world with unprecedented granularity in longitudinal health and social data. ImplicationsOur algorithm improves the accuracy of administrative data repositories and linkage, providing novel information on where errors in previous linkages have occurred due to limited familial or intergenerational information. Our large population-based birth cohort of twins can be used to investigate the familial and non-familial determinants of health using advanced causal inference which leverages the natural similarity between twins.

Sleep patterns, genetic susceptibility, and digestive diseases: a large-scale longitudinal cohort study.

Sleep problems are prevalent. However, the impact of sleep patterns on digestive diseases remains uncertain. Moreover, the interaction between sleep patterns and genetic predisposition with digestive diseases has not been comprehensively explored. Four hundred ten thousand five hundred eighty-six participants from UK Biobank with complete sleep information were included in the analysis. Sleep patterns were measured by sleep scores as the primary exposure, based on five healthy sleep behaviors. Individual sleep behaviors were secondary exposures. Genetic risk of the digestive diseases was characterized by polygenic risk score. Primary outcome was incidence of 16 digestive diseases. Healthy sleep scores showed dose-response associations with reduced risks of digestive diseases. Compared to participants scoring 0-1, those scoring 5 showed a 28% reduced risk of any digestive disease, including a 50% decrease in irritable bowel syndrome, 37% in non-alcoholic fatty liver disease, 35% in peptic ulcer, 34% in dyspepsia, 32% in gastroesophageal reflux disease, 28% in constipation, 25% in diverticulosis, 24% in severe liver disease, and 18% in gallbladder disease, whereas no correlation was observed with inflammatory bowel disease and pancreatic disease. Participants with poor sleep and high genetic risk exhibited approximately a 60% increase in the risk of digestive diseases. A healthy sleep pattern is linked to lower digestive disease risk in participants of all genetic risk levels. In this large population-based cohort, a healthy sleep pattern was associated with a reduced risk of digestive diseases, regardless of genetic susceptibility. The authors' findings underscore the potential impact of healthy sleep traits in mitigating the risk of digestive diseases.

Association between incretin-based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: A large population-based matched cohort study

AimTo examine the association between the use of incretin-based drugs [glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4Is)] and the risk of cholangiocarcinoma (CCA) in the United States. MethodsThis large population-based, retrospective cohort study using the TriNetX datasets included adult patients with type 2 diabetes mellitus (T2DM) who were new users of GLP-1RAs, DPP-4Is, or other second- or third-line antidiabetic drugs between 2010 and 2021. The primary outcome was the incidence of CCA. ResultsA total of 3,816,071 patients were included (mean age, 61.4 years, female, 49.3 %). A 51 % and 23 % risk reduction in CCA after 1 year of exposure to GLP-1RAs (hazard ratio 0.49; 95 % CI 0.40–0.60) and DPP4Is (0.77, 95 % CI 0.67–0.90), respectively compared to new second-or third-line users. Results were consistent at 3, 5, and 7 years of follow-up (0.66, 0.71, and 0.72 for GLP-1RAs and 0.84, 0.87, and 0.85 for DPP-4Is, respectively). Compared to new metformin users, GLP-1RA users were associated with a 42 % lower risk of developing CCA, whereas DPP-4I group was not associated with an increased risk. ConclusionsGLP-1RAs and DPP-4Is were not associated with a significantly increased risk of CCA. GLP-1RAs even showed a reduced risk of CCA development. They can be considered as safe and effective treatment options for patients with T2DM at risk of CCA.

Association of ventricular-arterial coupling with biomarkers involved in heart failure pathophysiology-the STANISLAS cohort.

Impaired left ventricular-arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population-based cohort of middle-aged individuals. In the forth visit of the STANISLAS family cohort, involving 1309 participants (mean age 48 ± 14 years; 48% male) from parent and children generations, we analysed the association of 32 HF-related proteins with non-invasively assessed VAC using pulse wave velocity (PWV)/global longitudinal strain (GLS) and arterial elastance (Ea)/ventricular end-systolic elastance (Ees). Among the 32 tested proteins, fatty acid-binding protein adipocyte 4, interleukin-6, growth differentiation factor 15, matrix metalloproteinase (MMP)-1, and MMP-9 and adrenomedullin were positively associated with PWV/GLS whereas transforming growth factor beta receptor type 3, MMP-2 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were negatively associated. In multivariable models, only MMP-2 and NT-proBNP were significantly and inversely associated with PWV/GLS in the whole population and in the parent generation. Higher levels of NT-proBNP were also negatively associated with Ea/Ees in the whole cohort but this association did not persist in the parent subgroup. Elevated MMP-2 and NT-proBNP levels correlate with better VAC (lower PWV/GLS), possibly indicating a compensatory cardiovascular response to regulate left ventricular pressure amidst cardiac remodelling and overload.

Testing for a causal role of thyroid hormone measurements within the normal range on human metabolism and diseases: a systematic Mendelian randomization

Variation in thyroid function parameters within the normal range has been observationally associated with adverse health outcomes. Whether those associations reflect causal effects is largely unknown. We systematically tested associations between genetic differences in thyrotropin (TSH) and free thyroxine (FT4) within the normal range and more than 1100 diseases and more than 6000 molecular traits (metabolites and proteins) in three large population-based cohorts. This was performed by combining individual and summary level genetic data and using polygenic scores and Mendelian randomization (MR) methods. We performed a phenome-wide MR study in the OpenGWAS database covering thousands of complex phenotypes and diseases. Genetically predicted TSH or FT4 levels within the normal range were predominately associated with thyroid-related outcomes, like goitre. The few extra-thyroidal outcomes that were found to be associated with genetic liability towards high but normal TSH levels included atrial fibrillation (odds ratio=0.92, p-value=2.13×10-3), thyroid cancer (odds ratio=0.57, p-value=2.97×10-4), and specific biomarkers, such as sex hormone binding globulin (β=-0.046, p-value=1.33×10-6) and total cholesterol (β=0.027, p-value=5.80×10-3). In contrast to previous studies that have described the association with thyroid hormone levels and disease outcomes, our genetic approach finds little evidence of an association between genetic differences in thyroid function within the normal range and non-thyroidal phenotypes. The association described in previous studies may be explained by reverse causation and confounding. This research was funded by the Swiss National Science Foundation (P1BEP3_200041). The Fenland study (DOI 10.22025/2017.10.101.00001) is funded by the Medical Research Council (MC_UU_12015/1, MC_PC_13046 and MC_UU_00006/1). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1, MC_PC_13048 and MC_UU_00006/1).

Residential ambient air pollution exposure and the development of white matter microstructure throughout adolescence

BackgroundRecent evidence suggests an association of air pollution exposure with brain development, but evidence on white matter microstructure in children is scarce. We investigated how air pollution exposure during pregnancy and childhood impacts longitudinal development of white matter microstructure throughout adolescence. MethodsOur study population consisted of 4108 participants of Generation R, a large population-based birth cohort from Rotterdam, the Netherlands. Residential air pollution exposure to 14 air pollutants during pregnancy and childhood was estimated with land-use regression models. Diffusion tensor images were obtained around age 10 and 14, resulting in a total of 5422 useable scans (n = 3082 for wave 1 and n = 2340 for wave 2; n = 1314 for participants with data on both waves). We calculated whole-brain fractional anisotropy (FA) and mean diffusivity (MD) and performed single- and multi-pollutant analyses using mixed effects models adjusted for life-style and socioeconomic status variables. ResultsHigher exposure to PM2.5 during pregnancy, and PM10, PM2.5, PM2.5-10, and NOX during childhood was associated with a consistently lower whole-brain FA throughout adolescence (e.g. – 0.07 × 10−2 FA [95%CI -0.12; −0.02] per 1 standard deviation higher PM2.5 exposure during pregnancy). Higher exposure to silicon (Si) in PM2.5 and oxidative potential of PM2.5 during pregnancy, and PM2.5 during childhood was associated with an initial higher MD followed by a faster decrease in MD throughout adolescence (e.g. – 0.02 × 10−5 mm2/s MD [95%CI -0.03; −0.00] per year of age per 1 standard deviation higher Si exposure during pregnancy). Results were comparable when performing the analysis in children with complete data on the outcome for both neuroimaging assessments. ConclusionsExposure to several pollutants was associated with a consistently lower whole-brain FA throughout adolescence. The association of few pollutants with whole-brain MD at baseline attenuated throughout adolescence. These findings suggest both persistent and age-limited associations of air pollution exposure with white matter microstructure.

A Large Cohort Study of Height and Mammographic Density in Relation to Breast Cancer Risk among Korean Women.

Height and mammographic breast density are well-known risk factors for breast cancer. This study aims to investigate the association between height and mammographic density with breast cancer risk in a large population-based cohort of Korean women. This retrospective cohort study included 4,851,115 women aged 40 and older who underwent screening mammography through the Korean National Cancer Screening Program (KNCSP) between 2009 and 2014 and were followed up until 2016. Multivariable Cox proportional hazard models were employed to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between height, mammographic density, and breast cancer risk. A taller stature was associated with an increased risk of breast cancer, with women in the highest quintile of height (Q5) having a 1.54-fold [95% CI: 1.49, 1.59] greater risk compared to those in the lowest quintile (Q1). When analyzing breast cancer risk based on height and mammographic density, women in the highest quintile for height (Q5) with extremely dense breasts had a 4.51-fold [95% CI: 4.24, 4.79] greater risk compared to those in the lowest quintile (Q1) with almost entirely fatty breasts (p trend < 0.001). This first study to simultaneously examine these two variables found that height and mammographic density were independently associated with breast cancer risk in this large cohort of Korean women. Height and mammographic density can help stratify risk in screening populations for breast cancer. Careful consideration of screening strategies may be beneficial for taller women with dense breasts.

Is seborrhoeic dermatitis of infancy and childhood related to maternal history of seborrhoeic dermatitis? A large population-based cohort study from the UK.

The pathophysiology of seborrhoeic dermatitis (SebD) is complex and is likely to be related to an interplay of the microbial colonization of the skin and local immunity. There are also genetic components to the illness. At least two forms of SebD exist, infantile (ISebD), which has onset early in life, and SebD with later onset. We aimed to improve our understanding of SebD by evaluating whether maternal history of SebD is associated with increased risk of ISebD or childhood-onset SebD (CSebD, with onset after 5 years of life). We performed a prospective cohort study of mother-child pairs using data from a large UK primary care electronic medical records database. We analysed 1 023 140 children with linked maternal data. The mean (SD) time of follow-up for the children was 10.2 (7.9) years for a total follow-up of more than 10 million person-years. Proportional hazards models [HRs (95% confidence intervals)] were used to examine the association between presence of SebD in mothers and SebD in the child. Maternal history of SebD was associated with development of SebD [1.99 (1.91-2.09)], ISebD [1.86 (1.74-1.99)] and CSebD [2.12 (1.97-2.29)] in their children. However, ISebD in a child was not associated with that child later developing CSebD [0.91 (0.82-1.01)]. Maternal history of SebD is a risk factor for the development of SebD in children. While we cannot fully differentiate SebD risk due to mother's genetics (inheritance) from a newborn's environment, our results lend credence to the possible role of genetics in SebD. A child with ISebD does not appear to be at risk for developing CSebD.

The role of body image dissatisfaction in the relationship between body size and disordered eating and self-harm: complimentary Mendelian randomization and mediation analyses.

Disordered eating and self-harm commonly co-occur in young people suggesting potential for shared underlying causes. Body image dissatisfaction (BID) has been recognised as a psychological correlate of body size, associated with both disordered eating and self-harm. However, the investigation into etiological pathways early in the lifecourse to provide detail on how body size and BID may foster disordered eating and self-harm remains largely unexplored. Employing data from two large population-based cohorts, the UK Biobank and the Avon Longitudinal Study of Parents And Children (ALSPAC), we conducted bidirectional Mendelian randomization (MR) to determine the causal direction of effect between genetically predicted prepubertal body size and two measures of BID indicating (i) desire to be smaller, and (ii) desire to be larger. We then used multivariable regression followed by counterfactual mediation analyses. Bidirectional MR indicated robust evidence that increased genetically predicted prepubertal body size increased desire to be smaller and decreased desire to be larger. Evidence for the reverse causal direction was negligible. These findings remained very similar across sensitivity analyses. In females and males, multivariable regression analyses demonstrated that being overweight increased the risk of disordered eating (risk ratio (RR), 95% confidence interval (CI): 1.19, 1.01 to 1.40 and 1.98, 1.28 to 3.05, respectively) and self-harm (RR, 95% CI: 1.35, 1.04 to 1.77 and 1.55, 0.86 to 2.81, respectively), while being underweight was protective against disordered eating (RR, 95% CI: 0.57, 0.40 to 0.81 and 0.81, 0.38 to 1.73, respectively). There was weak evidence of an increase in the risk of self-harm among underweight individuals. Mediation analyses indicated that the relationship between being overweight and subsequent disordered eating was largely mediated by the desire to be smaller. Our research carries important public health implications, suggesting distinct risk profiles for self-harm and disordered eating in relation to weight and body image. In addition, a better understanding of genetically predicted prepubertal BID may be valuable in the prevention and treatment of disordered eating and self-harm in adolescence.

Risk factors for raised left ventricular filling pressure by cardiovascular magnetic resonance: Prognostic insights.

Cardiovascular magnetic resonance (CMR) imaging shows promise in estimating pulmonary capillary wedge pressure (PCWP) non-invasively. At the population level, the prognostic role of CMR-modelled PCWP remains unknown. Furthermore, the relationship between CMR-modelled PCWP and established risk factors for cardiovascular disease has not been well characterized. The main aim of this study was to investigate the prognostic value of CMR-modelled PCWP at the population level. Employing data from the imaging substudy of the UK Biobank, a very large prospective population-based cohort study, CMR-modelled PCWP was calculated using a model incorporating left atrial volume, left ventricular mass and sex. Logistic regression explored the relationships between typical cardiovascular risk factors and raised CMR-modelled PCWP (≥15mmHg). Cox regression was used to examine the impact of typical risk factors and CMR-modelled PCWP on heart failure (HF) and major adverse cardiovascular events (MACE). Data from 39163 participants were included in the study. Median age of all participants was 64years (inter-quartile range: 58 to 70), and 47% were males. Clinical characteristics independently associated with raised CMR-modelled PCWP included hypertension [odds ratio (OR) 1.57, 95% confidence interval (CI) 1.44-1.70, P<0.001], body mass index (BMI) [OR 1.57, 95% CI 1.52-1.62, per standard deviation (SD) increment, P<0.001], male sex (OR 1.37, 95% CI 1.26-1.47, P<0.001), age (OR 1.33, 95% CI 1.27-1.41, per decade increment, P<0.001) and regular alcohol consumption (OR 1.10, 95% CI 1.02-1.19, P=0.012). After adjusting for potential confounders, CMR-modelled PCWP was independently associated with incident HF [hazard ratio (HR) 2.91, 95% CI 2.07-4.07, P<0.001] and MACE (HR 1.48, 95% CI 1.16-1.89, P=0.002). Raised CMR-modelled PCWP is an independent risk factor for incident HF and MACE. CMR-modelled PCWP should be incorporated into routine CMR reports to guide HF diagnosis and further management.

Association between gastrectomy and the risk of type 2 diabetes in gastric cancer survivors: A nationwide cohort study

AimPostprandial glycemic fluctuations after gastrectomy are seen in patients with gastric cancer but, no studies have investigated the association between gastrectomy and type 2 diabetes mellitus (T2DM) in gastric cancer survivors. This study aimed to elucidate the relationship between gastrectomy (total or subtotal) and incident T2DM. In addition, we explored whether vitamin B12 supplementation modulates this risk among patients who have undergone total gastrectomy. MethodsIn this large nationwide population-based retrospective cohort study using the National Health Insurance Service database of South Korea, we identified patients aged >20 years who underwent gastrectomy from 2008 to 2015 (n = 150,074) and age- and sex-matched controls without gastrectomy (n = 301,508). A Cox proportional hazards model was used. ResultsDuring the median follow-up duration of 4.4 years after the 2-year time lag after gastrectomy, of the 78,006 subjects, 4,597 (5.9 %) developed T2DM. Compared with matched controls, the adjusted hazard ratio (AHR[95 % confidence interval]) for T2DM of patients with total gastrectomy was 1.34[1.23;1.47]. The corresponding AHR after subtotal gastrectomy was 0.81[0.76;0.86]. Among the patients with total gastrectomy, the risk of T2DM was significantly increased in those who did not receive any vitamin B12 supplementation (AHR=1.60[1.33;1.92]), whereas the risk of T2DM was lower (close to being statistically significant) in those who received continuous vitamin B12 supplementation after gastrectomy (AHR=0.70[0.49;1.01]). ConclusionThese results show a significantly reduced risk of T2DM in gastric cancer patients undergoing subtotal gastrectomy and a significantly increased risk of T2DM in gastric cancer patients undergoing total gastrectomy, which is mitigated by continuous vitamin B12 supplementation.

Cohorte Cantabria - A biomedical research tool open to the world.

The contribution of large population-based study cohorts to the knowledge of disease risk factors and causes is unquestionable. The Framingham Cohort, a paradigm for the population-based studies that changed the history of medicine, emerged after the antibiotic revolution, the decrease in infection-related mortality, and the boom in cardiovascular morbidity and mortality.

72309 - Postoperative complications after breast cancer surgery and effect on recurrence and survival – a large population-based cohort study

72309 - Postoperative complications after breast cancer surgery and effect on recurrence and survival – a large population-based cohort study

Prevalence and Temporal Trends of Epilepsy in Children: A Retrospective Birth Cohort Study.

Epilepsy is one of the most common chronic neurologic diseases in children; however, few recent studies examine the prevalence of epilepsy and its evolution over time according to birth or maternal characteristics. The aim of the study was to examine the prevalence of epilepsy in children born between 2002 and 2020 and the temporal trends by year of birth, in Ontario, Canada, overall, and according to maternal and birth characteristics. We included all in-hospital deliveries between 2002 and 2020 (N = 2,343,482) in Ontario, Canada, using linked administrative health dataset. We estimated the overall prevalence of epilepsy diagnosed before the age of 18 years, by birth and maternal characteristics. For temporal trend analyses, we restricted our population to children born up to 2012 (N = 1,405,271) and examined the prevalence of epilepsy diagnosed by age 8 by their year of birth, using Poisson regression. The overall prevalence of epilepsy in our cohort was 8.1 per 1,000 live births (95% CI: 8.0-8.2). Prevalence was higher for boys, for children born preterm, with congenital malformations, from multiple pregnancies, from mothers born in Canada, and for children living in deprived areas. Epilepsy prevalence diagnosed by age 8 increased slightly between 2002 and 2012 cohorts (6.9 [95% CI: 6.2-7.6] to 7.3 [95% CI: 6.6-8.1] per 1,000 live births, respectively). Differences by gestational age as gradient and socioeconomic characteristics were persistent and stable over time, while those by pregnancy plurality and sex decreased. In a large population-based birth cohort in Canada, we observed a slight increase in epilepsy prevalence over time among children born in 2002 and those born in 2012 and persistent disparities by gestational age, socioeconomic position, and maternal immigration status. This study highlights the need for continued surveillance of rates to see if this increasing trend is persistent, to understand the potential causes behind it, and to understand the persistence of these disparities.

Childhood Adversity and Incident Psychotic Experiences in Early Adulthood: Cognitive and Psychopathological Mediators.

Childhood adversity is often described as a potential cause of incident psychotic experiences, but the underlying mechanisms are not well understood. We aimed to examine the mediating role of cognitive and psychopathological factors in the relation between childhood adversity and incident psychotic experiences in early adulthood. We analyzed data from the Avon Longitudinal Study of Parents and Children, a large population-based cohort study. Childhood adversity was measured prospectively from birth to age 11 years, mediators (anxiety, depression, external locus of control [LoC], negative symptoms) were assessed at approximately 16 years of age, and incident psychotic experiences were assessed at ages 18 and 24 years. Mediation was examined via the counterfactual g-computation formula. In total, 7% of participants had incident suspected or definite psychotic experiences in early adulthood. Childhood adversity was related to more incident psychotic experiences (ORadjusted = 1.34, 95% CI = 1.21; 1.49), and this association was partially mediated via all mediators examined (proportion mediated: 19.9%). In separate analyses for each mediator, anxiety, depression, external LoC, and negative symptoms were all found to mediate the link between adversity and incident psychotic experiences. Accounting for potential confounders did not modify our results. Our study shows that cognitive biases as well as mood symptomatology may be on the causal pathway between early-life adversity and the development of psychotic experiences. Future studies should determine which mediating factors are most easily modifiable and most likely to reduce the risk of developing psychotic experiences.

Unraveling the metabolomic architecture of autism in a large Danish population-based cohort

BackgroundThe prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth.MethodsWe analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features.ResultsWe detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e − 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels.ConclusionsCyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.

How many future dementia cases would be missed by a high-risk screening program? A retrospective cohort study in a population-based cohort.

Risk prediction models aim to identify those at high risk to receive targeted interventions. We aimed to identify the proportion of future dementia cases that would be missed by a high-risk screening program. We identified validated dementia risk prediction models from systematic reviews. We applied these to European Prospective Investigation of Cancer Norfolk, a large population-based cohort of 30,387 individuals with 29 years of linked healthcare data. A maximum of 16.0% (14.7,17.2) and 31.9% (30.2,33.5) of cases arose from the highest risk decile and quintiles, respectively. For every 1000 people considered to be at high risk, a maximum of 235 (215, 255) developed dementia. Seven in every 10 cases of dementia arose from people at normal risk, and eight in every 10 people at high risk did not develop dementia. Individual-level prevention approaches targeted at high-risk groups are unlikely to produce large reductions in disease incidence at the population level. Dementia, a significant public health challenge, is not an inevitability of aging; risk reduction is possible. Several dementia risk prediction models have been validated in the general population, and these aim to identify people at high risk of the disease who can then be targeted with primary prevention interventions. An alternative prevention approach is to focus on interventions that reduce risk across the population, irrespective of risk status. In our study, seven out of every ten people who developed dementia during 29 year follow-up were classed as 'normal-risk' (rather than 'high risk') at baseline. Eight out of every ten people who were at high risk at baseline did not go on to develop dementia. Even if effective, dementia risk reduction efforts based upon targeted high-risk approaches are unlikely to reduce incidence of disease at the population level.