A comparison of neighbourhood level variation and risk factors for affective versus non-affective psychosis.

BACKGROUND: Studies typically highlight area level variation in the incidence of non-affective but not affective psychoses. We compared neighbourhood-level variation for both types of disorder, and the specific effects of neighbourhood urbanicity and ethnic density, using Danish national registry data. METHODS: Population based cohort (2,224,464 people) followed from 1980 to 2013 with neighbourhood exposure measured at age 15 and incidence modelled using multilevel Poisson regression. RESULTS: Neighbourhood variation was similar for both disorders with an adjusted median risk ratio of 1.37 (95% CI 1.34-1.39) for non-affective psychosis and 1.43 (1.38-1.49) for affective psychosis. Associations with neighbourhood urbanicity differed: living in the most compared to the least urban quintile at age 15 was associated with a minimal increase in subsequent affective psychosis, IRR 1.13 (1.01-1.27) but a substantial increase in rates of non-affective psychosis, IRR 1.66 (1.57-1.75). Mixed results were found for neighbourhood ethnic density: for Middle Eastern migrants there was an increased average incidence of both affective, IRR 1.54 (1.19-1.99), and non-affective psychoses, 1.13 (1.04-1.23) associated with each decrease in ethnic density quintile, with a similar pattern for African migrants, but for European migrants ethnic density appeared to be associated with non-affective psychosis only. CONCLUSIONS: While overall variation and the effect of neighbourhood ethnic density were similar for both types of disorder, associations with urbanicity were largely confined to non-affective psychosis. This may reflect differences in aetiological pathways although the mechanism behind these differences remains unknown.

Temporal changes in sex- and age-specific incidence profiles of mental disorders-A nationwide study from 1970 to 2016.

OBJECTIVE: Information on mental disorders over time is critical for documenting changes in population burden, and aiding understanding of potential causal and non-causal factors. The aim of this study was to provide temporal changes in the sex- and age-specific incidence rates (IR) of mental disorders diagnosed in Danish hospitals during five decades and investigate whether such changes may be attributable to changes in administrative reporting practice. METHODS: This population-based cohort study included all people living in Denmark between 1970 and 2016. Mental disorders diagnoses were obtained from the Danish Psychiatric Central Research Register. We estimated the IR of each mental disorder (all persons, and sex- and age-specific IRs) and examined the impact of two administrative changes. RESULTS: Our study included 9 107 157 people, followed for 233.0 million person-years. During follow-up, 9.5% were diagnosed with at least one mental disorder. The IR for any mental disorder was 39.0 per 10,000 person-years. Despite fluctuations, this increased between 1970-84 and 2005-2016, from 28.9 to 63.0 per 10,000 person-years. Increases were most pronounced for younger age groups. Administrative changes did appear to influence incidence rates. CONCLUSION: Mental disorder IRs have increased in Denmark since 1970, with age of diagnosis shifting downwards. Both trends were likely impacted by administrative changes, while the latter is likely to be (partly) attributable to earlier detection and increased reporting of child-onset conditions. Our findings may provide valuable context of the epidemiology of mental disorders across age groups for comparison with other studies and populations.

Trace elements in drinking water and the incidence of attention-deficit hyperactivity disorder.

BACKGROUND: Trace elements have been suggested to have neurotoxic effects and increase the risk of neurodevelopmental disorders, but studies of a potential role of trace elements in relation to Attention-Deficit/Hyperactivity Disorder (ADHD) are very limited. The objective of this study was to conduct an exploratory analysis investigating the associations between 17 geogenic trace elements (Ba, Co, Eu, I, Li, Mo, Rb, Re, Rh, Sb, Sc, Se, Si, Sr, Ti, U and Y) found in Danish drinking water and the risk of developing ADHD. METHODS: In this cohort study, 284,309 individuals, born 1994-2007, were followed for incidence of ADHD from the age of five until the end of study, December 31, 2016. We conducted survival analyses, using Poisson regression to estimate incidence rate ratios (IRRs) with 95 % confidence intervals (CI) in three different confounder adjustment scenarios. RESULTS: In a model including adjustments for age, sex, calendar year, parental socio-economic status, neighborhood level socio-economic status and parental psychiatric illness, we found that six of the 17 trace elements (Sr, Rb, Rh, Ti, Sb and Re) were associated with an increased risk of ADHD, whereas two (Ba and I) were inversely associated with ADHD. However, when including region as a covariate in the model, most trace elements were no longer associated with ADHD or the association changed direction. Four trace elements (I, Li, Rb, and Y) remained significantly associated with ADHD but in an inverse direction and for three of these (I, Li and Y), we found significant interactions with region in their association with ADHD. CONCLUSION: The trace elements under investigation, at levels found in Danish drinking water, do not seem to contribute to the development of ADHD and our findings highlight the importance of examining consistency of associations across geographic areas.

The Association between Residential Green Space in Childhood and Development of Attention Deficit Hyperactivity Disorder: A Population-Based Cohort Study.

BACKGROUND: Access to green space has been hypothesized to have a beneficial impact on children's mental well-being and cognitive development. The underlying mechanisms of the mental health benefits of green space are not fully understood, but different pathways have been suggested, such as the psychologically restoring capacities of green space, the ability to facilitate physical activity and social cohesion, and the mitigation of exposure to air pollution. OBJECTIVES: In this nationwide cohort study, we investigated associations between residential green space in early childhood and a clinical diagnosis of attention deficit hyperactivity disorder (ADHD). METHODS: The cohort included individuals, who were born in Denmark between 1992 and 2007 (n=814,689) and followed for a diagnosis of ADHD from age 5, during the period 1997-2016. We used the normalized difference vegetation index (NDVI) as a measure of vegetation greenness surrounding each residential address in a quadratic area of 210m×210m in which the residence was located in the center of the quadrate. Individual exposure to green space was calculated as the average of NDVI surrounding each individual's residential address (or addresses if more than one) between birth and the fifth birthday. Multilevel modeling was used to estimate the incidence rate ratios (IRRs) with 95% confidence intervals (CI) for ADHD, according to exposure level and adjusted for calendar time, age, sex, parental socioeconomic status, neighborhood level socioeconomic status, and urbanicity. RESULTS: Individuals living in areas defined by sparse green vegetation (lowest decile of NDVI) had an increased risk of developing ADHD, compared with individuals living in areas within the highest decile of NDVI (IRR=1.55; 95% CI: 1.46, 1.65). Adjusting for the known confounders attenuated the result, but the association remained (IRR=1.20; 95% CI: 1.13, 1.28). CONCLUSION: Our findings suggest that lower levels of green space in residential surroundings, during early childhood, may be associated with a higher risk of developing ADHD. https://doi.org/10.1289/EHP6729.

Exposure to Manganese in Drinking Water during Childhood and Association with Attention-Deficit Hyperactivity Disorder: A Nationwide Cohort Study.

BACKGROUND: Manganese (Mn) in drinking water may increase the risk of several neurodevelopmental outcomes, including attention-deficit hyperactivity disorder (ADHD). Earlier epidemiological studies on associations between Mn exposure and ADHD-related outcomes had small sample sizes, lacked spatiotemporal exposure assessment, and relied on questionnaire data (not diagnoses)-shortcomings that we address here. OBJECTIVE: Our objective was to assess the association between exposure to Mn in drinking water during childhood and later development of ADHD. METHODS: In a nationwide population-based registry study in Denmark, we followed a cohort of 643,401 children born 1992-2007 for clinical diagnoses of ADHD. In subanalyses, we classified cases into ADHD-Inattentive and ADHD-Combined subtypes based on hierarchical categorization of International Classification of Diseases (ICD)-10 codes. We obtained Mn measurements from 82,574 drinking water samples to estimate longitudinal exposure during the first 5 y of life with high spatiotemporal resolution. We modeled exposure as both peak concentration and time-weighted average. We estimated sex-specific hazard ratios (HRs) in Cox proportional hazards models adjusted for age, birth year, socioeconomic status (SES), and urbanicity. RESULTS: We found that exposure to increasing levels of Mn in drinking water was associated with an increased risk of ADHD-Inattentive subtype, but not ADHD-Combined subtype. After adjusting for age, birth year, and SES, females exposed to high levels of Mn (i.e., >100µg/L) at least once during their first 5 y of life had an HR for ADHD-Inattentive subtype of 1.51 [95% confidence interval (CI): 1.18, 1.93] and males of 1.20 (95% CI: 1.01, 1.42) when compared with same-sex individuals exposed to <5µg/L. When modeling exposure as a time-weighted average, sex differences were no longer present. DISCUSSION: Mn in drinking water was associated with ADHD, specifically the ADHD-Inattentive subtype. Our results support earlier studies suggesting a need for a formal health-based drinking water guideline value for Mn. Future Mn-studies should examine ADHD subtype-specific associations and utilize direct subtype measurements rather than relying on ICD-10 codes alone. https://doi.org/10.1289/EHP6391.

Air pollution and family related determinants of asthma onset and persistent wheezing in children: nationwide case-control study.

OBJECTIVE: To identify risk factors (air pollution and family related) for the onset of asthma and persistent wheezing in children. DESIGN: Nationwide case-control study. SETTING: Denmark. PARTICIPANTS: All Danish children born from 1997 to 2014 and followed for asthma onset and persistent wheezing from age 1 year to 15 years. MAIN OUTCOME MEASURE: Onset of asthma and persistent wheezing. RESULTS: A higher incidence of asthma was found in children of parents with asthma (adjusted hazard ratio 2.29 (95% confidence interval 2.22 to 2.35) and mothers who smoked during pregnancy (1.20, 1.18 to 1.22), whereas a lower incidence was found in children of parents with high educational attainment (0.72, 0.69 to 0.75) and high incomes (0.85, 0.81 to 0.89). Exposure to particulate matter ≤2.5 µm (PM2.5) and ≤10 µm (PM10) and nitrate was associated with an increased risk of asthma and persistent wheezing, with hazard ratios per 5 µg/m3 increase in pollutant concentrations 1.05 (1.03 to 1.07) for PM2.5, 1.04 (1.02 to 1.06) for PM10, and 1.04 (1.03 to 1.04) for nitrogen dioxide. Only the positive association of PM2.5 with asthma and persistent wheezing remained robust across the different models and in sensitivity analyses. CONCLUSIONS: The findings of this study suggest that children exposed to higher levels of PM2.5 are more likely to develop asthma and persistent wheezing than children who are not exposed. Other risk factors associated with these outcomes were parental asthma, parental education, and maternal smoking during pregnancy.

Incidence Rates and Cumulative Incidences of the Full Spectrum of Diagnosed Mental Disorders in Childhood and Adolescence.

Importance: Knowledge about the epidemiology of mental disorders in children and adolescents is essential for research and planning of health services. Surveys can provide prevalence rates, whereas population-based registers are instrumental to obtain precise estimates of incidence rates and risks. Objective: To estimate age- and sex-specific incidence rates and risks of being diagnosed with any mental disorder during childhood and adolescence. Design: This cohort study included all individuals born in Denmark from January 1, 1995, through December 31, 2016 (1.3 million), and followed up from birth until December 31, 2016, or the date of death, emigration, disappearance, or diagnosis of 1 of the mental disorders examined (14.4 million person-years of follow-up). Data were analyzed from September 14, 2018, through June 11, 2019. Exposures: Age and sex. Main Outcomes and Measures: Incidence rates and cumulative incidences of all mental disorders according to the ICD-10 Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research, diagnosed before 18 years of age during the study period. Results: A total of 99 926 individuals (15.01%; 95% CI, 14.98%-15.17%), including 41 350 girls (14.63%; 95% CI, 14.48%-14.77%) and 58 576 boys (15.51%; 95% CI, 15.18%-15.84%), were diagnosed with a mental disorder before 18 years of age. Anxiety disorder was the most common diagnosis in girls (7.85%; 95% CI, 7.74%-7.97%); attention-deficit/hyperactivity disorder (ADHD) was the most common in boys (5.90%; 95% CI, 5.76%-6.03%). Girls had a higher risk than boys of schizophrenia (0.76% [95% CI, 0.72%-0.80%] vs 0.48% [95% CI, 0.39%-0.59%]), obsessive-compulsive disorder (0.96% [95% CI, 0.92%-1.00%] vs 0.63% [95% CI, 0.56%-0.72%]), and mood disorders (2.54% [95% CI, 2.47%-2.61%] vs 1.10% [95% CI, 0.84%-1.21%]). Incidence peaked earlier in boys than girls in ADHD (8 vs 17 years of age), intellectual disability (5 vs 14 years of age), and other developmental disorders (5 vs 16 years of age). The overall risk of being diagnosed with a mental disorder before 6 years of age was 2.13% (95% CI, 2.11%-2.16%) and was higher in boys (2.78% [95% CI, 2.44%-3.15%]) than in girls (1.45% [95% CI, 1.42%-1.49%]). Conclusions and Relevance: This nationwide population-based cohort study provides a first comprehensive assessment of the incidence and risks of mental disorders in childhood and adolescence. By 18 years of age, 15.01% of children and adolescents in this study were diagnosed with a mental disorder. The incidence of several neurodevelopmental disorders peaked in late adolescence in girls, suggesting possible delayed detection. The distinct signatures of the different mental disorders with respect to sex and age may have important implications for service planning and etiological research.

Exposure to air pollution in early childhood and the association with Attention-Deficit Hyperactivity Disorder.

BACKGROUND: Exposure to air pollution in early life has been linked to cognitive deficits and adverse neurodevelopmental effects. However, studies examining associations between air pollutants and Attention-Deficit/Hyperactivity Disorder (ADHD) have had conflicting findings. METHODS: Individuals born in Denmark 1992-2007 (n = 809,654) were followed for the development of ADHD from 1997 to 2013. Data on daily concentrations of nitrogen dioxide (NO2) and fine particulate matter (PM2.5) from air-modeling data at a 1 km × 1 km resolution at residences within the first five years of life, was linked with population-based data from the Danish national registers, including data on clinical diagnoses of ADHD. We estimated incidence rate ratios (IRRs) with 95% confidence intervals (CI) for ADHD, according to increases in exposures, adjusting for age, year, sex, and parental education and income. RESULTS: Exposure to NO2 and PM2.5 during early life was associated with a significantly increased risk of ADHD: IRR of 1.38 (Cl: 1.35 to 1.42) per 10 µg/m3 increase in NO2 and an IRR of 1.51 (Cl: 1.41 to 1.62) per 5 µg/m3 increase in PM2.5. In two-pollutant models, the association between NO2 and ADHD did not change (IRR 1.35; 95% CI: 1.31 to 1.39), while the association with PM2.5 was substantially attenuated (IRR 1.07; 95% CI: 0.98 to 1.16), although in stratified models an elevated association with PM2.5 was found in the lowest quintile of NO2 exposure. CONCLUSIONS: In this large nationwide prospective cohort study, residential air pollution exposure, specifically NO2, during early childhood was associated with the development of ADHD, even when adjusted for parental level of income and education.

Nitrate in drinking water and colorectal cancer risk: A nationwide population-based cohort study.

Nitrate in drinking water may increase risk of colorectal cancer due to endogenous transformation into carcinogenic N-nitroso compounds. Epidemiological studies are few and often challenged by their limited ability of estimating long-term exposure on a detailed individual level. We exploited population-based health register data, linked in time and space with longitudinal drinking water quality data, on an individual level to study the association between long-term drinking water nitrate exposure and colorectal cancer (CRC) risk. Individual nitrate exposure was calculated for 2.7 million adults based on drinking water quality analyses at public waterworks and private wells between 1978 and 2011. For the main analyses, 1.7 million individuals with highest exposure assessment quality were included. Follow-up started at age 35. We identified 5,944 incident CRC cases during 23 million person-years at risk. We used Cox proportional hazards models to estimate hazard ratios (HRs) of nitrate exposure on the risk of CRC, colon and rectal cancer. Persons exposed to the highest level of drinking water nitrate had an HR of 1.16 (95% CI: 1.08-1.25) for CRC compared with persons exposed to the lowest level. We found statistically significant increased risks at drinking water levels above 3.87 mg/L, well below the current drinking water standard of 50 mg/L. Our results add to the existing evidence suggesting increased CRC risk at drinking water nitrate concentrations below the current drinking water standard. A discussion on the adequacy of the drinking water standard in regards to chronic effects is warranted.

Neighbourhood ethnic density and psychosis - Is there a difference according to generation?

BACKGROUND: For different migrant groups living in an area with few people from the same ethnic background is associated with increased psychosis incidence (the ethnic density effect). We set out to answer the question: are there generational differences in this effect? METHODS: Analysis of a population based cohort (2.2 million) comprising all those born 1st January 1965, or later, living in Denmark on their 15th birthday. This included 90,476 migrants from Africa, Europe (excluding Scandinavia) and the Middle East, with 55% first generation and the rest second-generation migrants. Neighbourhood co-ethnic density was determined at age 15 and we adjusted for age, gender, calendar period, parental psychiatric history and parental income. RESULTS: For first-generation migrants from Africa, there was no statistically significant difference (p=0.30) in psychosis rates when comparing lowest with highest ethnic density quintiles, whereas the second generation showed a 3.87-fold (95% CI 1.77-8.48) increase. Similarly, for migrants from the Middle East, the first generation showed no evidence of an ethnic density effect (p=0.94) while the second showed a clear increase in psychosis when comparing lowest with highest quintiles, incidence rate ratio (IRR) 2.43 (95% CI, 1.18-5.00). For European migrants, there was some limited evidence of an effect in the first generation, (IRR) 1.69 (95% CI, 1.19-2.40), with this slightly raised in the second: IRR 1.80 (95% CI, 1.27-2.56). CONCLUSIONS: We found strong evidence for an ethnic density effect on psychosis incidence for second-generation migrants but this was either weak or absent for the first generation.

Parental exposures to occupational asthmagens and risk of autism spectrum disorder in a Danish population-based case-control study.

BACKGROUND: Environmental exposures and immune conditions during pregnancy could influence development of autism spectrum disorder (ASD) in offspring. However, few studies have examined immune-triggering exposures in relation to ASD. We evaluated the association between parental workplace exposures to risk factors for asthma ("asthmagens") and ASD. METHODS: We conducted a population-based case-control study in the Danish population using register linkage. Our study population consisted of 11,869 ASD cases and 48,046 controls born from 1993 through 2007. Cases were identified by ICD-10 codes in the Danish Psychiatric Central Register. ASD cases and controls were linked to parental Danish International Standard Classification of Occupations (DISCO-88) job codes. Parental occupational asthmagen exposure was estimated by linking DISCO-88 codes to an asthma-specific job-exposure matrix. RESULTS: Our maternal analyses included 6706 case mothers and 29,359 control mothers employed during the pregnancy period. We found a weak inverse association between ASD and any maternal occupational asthmagen exposure, adjusting for sociodemographic covariates (adjusted OR: 0.92, 95% CI: 0.86-0.99). In adjusted analyses, including 7647 cases and 31,947 controls with employed fathers, paternal occupational asthmagen exposure was not associated with ASD (adjusted OR: 0.98, 95% CI: 0.92-1.05). CONCLUSIONS: We found a weak inverse association between maternal occupational asthmagen exposure and ASD, and a null association between paternal occupational exposure and ASD. We suggest that unmeasured confounding negatively biased the estimate, but that this unmeasured confounding is likely not strong enough to bring the effect above the null. Overall, our results were consistent with no positive association between parental asthmagen exposure and ASD in the children.

Ethnic density, urbanicity and psychosis risk for migrant groups - A population cohort study.

BACKGROUND: Rates of psychotic disorder are raised for many migrant groups. Understanding the role played by the social context in which they live may help explain why. This study investigates the effect of both neighbourhood ethnic density and urbanicity on the incidence of non-affective psychosis for migrant groups. METHOD: Population based cohort of all those born 1965 or later followed from their 15th birthday (2,224,464 people) to 1st July 2013 (37,335,812 person years). Neighbourhood exposures were measured at age 15. RESULTS: For all groups incidence of non-affective psychosis was greater in lower ethnic density neighbourhoods. For migrants of African origin there was a 1.94-fold increase (95% CI, 1.17-3.23) comparing lowest and highest density quintiles; with similar effects for migrants from Europe (excluding Scandinavia): incidence rate ratio (IRR) 1.99 (95% CI, 1.56-2.54); Asia: IRR 1.63 (95% CI, 1.02-2.59); and the Middle East: IRR 1.68 (95% CI, 1.19-2.38). This initial analysis found no evidence for an urbanicity effect for migrant groups. Adjusting for ethnic density revealed a positive association between level of urbanicity and psychosis for two groups, with a statistically significant linear trend (average effect of a one quintile increase) for migrants from Europe: IRR 1.09 (95% CI, 1.02-1.16) and the Middle East: IRR 1.12 (95% CI, 1.01-1.23). CONCLUSIONS: In this first nationwide population-based study of ethnic density, urbanicity and psychosis we show that lower ethnic density is associated with increased incidence of non-affective psychosis for different migrant groups; masking urban/rural differences in psychosis for some groups.

Oxytocin-augmented labor and risk for autism in males.

The use of synthetic oxytocin (OT) to induce and/or augment labor and delivery is on the rise. Maternal exposure to OT during birth may have adverse effects on the infant's development, including increased risk for autism. Yet, studies that test this biologically plausible association and whether it is modified by sex are limited and show inconsistent findings. To this end, we conducted an epidemiological analysis, including all singleton live births in Denmark between 2000 and 2009 (N = 557,040), with a follow-up through 2012. A total of 2110 children in this cohort were subsequently diagnosed with autistic disorder according to the ICD-10-DCR. Augmentation of labor with OT was modestly associated with an increased risk for autism in males (HR 1.13; 95% CI, 1.00-1.26; P = 0.04), but not in females (0.99; 0.77-1.27; P=0.95). Among males exposed to OT augmentation, 560 were subsequently diagnosed with autistic disorder, and among those not exposed, 1177 met criteria for autism (incidence rate 103.2 and 81.4 per 100,000 person-years, respectively). Our findings suggest a modest association between OT-augmented labor and risk for autism in males. However, given the known benefits of using synthetic OT during labor and delivery caution is warranted when interpreting the findings. Future studies should also investigate dose-dependent effect of OT on infant's development.