Absolute and relative risk of violent victimisation and perpetration following onset of mental illness: a Danish register-based study.

Background: Previous research has suggested that people with severe mental illness are at elevated risk of both violence perpetration and violent victimisation, with risk of the latter being perhaps greater than the former. However, few studies have examined risk across both outcomes. Methods: Using a total population approach, the absolute and relative risks of victimisation and perpetration were estimated for young men and women across the full psychiatric diagnostic spectrum. Information on mental disorder status was extracted from national registers and information on violent victimisation and perpetration outcomes from police records. The follow-up was from age 15 to a maximum of 31 years, with most of the person-time at risk pertaining to cohort members aged in their early twenties. Both absolute risk (at 1 and 5 years from onset of illness) and relative risk were estimated. Findings: Both types of violent outcome occurred more frequently amongst those with mental illness than the general population. However, whether risk of one was greater than the other depended on a range of factors, including sex and diagnosis. Men with a mental disorder had higher absolute risks of both outcomes than women [victimisation: Cin (5 year) = 7.15 (6.88-7.42) versus Cin (5 year) = 4.79 (4.61-4.99); perpetration: Cin (5 year) = 8.17 (7.90-8.46) versus Cin (5 year) = 1.86 (1.75-1.98)], as was the case with persons in the general population without a recorded mental illness diagnosis. Women with mental illness had higher absolute risk of victimisation than perpetration, which was also true for men and women without mental illness. However, the opposite was true for men with mental illness. Men and women with diagnoses of personality disorders, substance use disorders, and schizophrenia-spectrum disorders were at highest risk of victimisation and perpetration. Interpretation: Strategies developed to prevent violent victimisation and violence perpetration may need to be tailored for young adults with mental disorders. There may also be a benefit in taking a sex-specific approach to prevention in this group. Funding: This study was supported by an Australian National Health and Medical Research Council Investigator Grant awarded to the first author.

Exposure to air pollution and risk of respiratory tract infections in the adult Danish population-a nationwide study.

OBJECTIVES: The association between air pollution and risk of respiratory tract infection (RTI) in adults needs to be clarified in settings with low to moderate levels of air pollution. We investigated this in the Danish population between 2004 and 2016. METHODS: We included 3 653 490 persons aged 18-64 years in a nested case-control study. Exposure was defined as the average daily concentration at the individual's residential address of CO, NOX, NO2, O3, SO2, NH3, PPM2.5, black carbon, organic carbon, mineral dust, sea salt, secondary inorganic aerosols, SO42-, NO3-, NH4+, secondary organic aerosols, PM2.5, and PM10 during a 3-month exposure window. RTIs were defined by hospitalization for RTIs. Incidence rate ratios (IRRs) and 95% CIs were estimated comparing highest with lowest decile of exposure using conditional logistic regression models. RESULTS: In total, 188 439 incident cases of RTI were identified. Exposure to most air pollutants was positively associated with risk of RTI. For example, NO2 showed an IRR of 1.52 (CI: 1.48-1.55), and PM2.5 showed an IRR of 1.45 (CI: 1.40-1.50). In contrast, exposure to sea salt, PM10, NH3, and O3 was negatively associated with a risk of RTIs. DISCUSSION: In this nationwide study comprising adults, exposure to air pollution was associated with risk of RTIs and subgroups hereof. Sea salt, PM10, NH3, and O3 may be proxies for rural areas, as the levels of these species in Denmark are higher near the western coastlines and/or in rural areas with fewer combustion sources.

Perspectives on environment and health research in Denmark.

AIMS: We provide an overview of nationwide environmental data available for Denmark and its linkage potentials to individual-level records with the aim of promoting research on the potential impact of the local surrounding environment on human health. BACKGROUND: Researchers in Denmark have unique opportunities for conducting large population-based studies treating the entire Danish population as one big, open and dynamic cohort based on nationally complete population and health registries. So far, most research in this area has utilised individual- and family-level information to study the clustering of disease in families, comorbidities, risk of, and prognosis after, disease onset, and social gradients in disease risk. Linking environmental data in time and space to individuals enables novel possibilities for studying the health effects of the social, built and physical environment. METHODS: We describe the possible linkage between individuals and their local surrounding environment to establish the exposome - that is, the total environmental exposure of an individual over their life course. CONCLUSIONS: The currently available nationwide longitudinal environmental data in Denmark constitutes a valuable and globally rare asset that can help explore the impact of the exposome on human health.

Schizophrenia spectrum disorders in Denmark between 2000 and 2018: Incidence and early diagnostic transition.

BACKGROUND: Schizophrenia spectrum disorders (SSD) comprise a group of related mental disorders, which share clinical features and common genetic disposition, but it is unknown if there is a diagnostic transition between these disorders over time. We aimed to study the incidence at the first SSD diagnosis between 2000 and 2018, defined as schizophrenia, schizotypal or schizoaffective disorder, and the early diagnostic transition between these disorders. METHODS: Using Danish nationwide healthcare registers, we identified all individuals aged 15-64 years during the period from 2000 to 2018 in Denmark and calculated the yearly incidence rates for the specific SSDs. We studied the diagnostic pathways from the first ever diagnosis of an SSD across the subsequent two treatment courses with an SSD diagnosis to evaluate early diagnostic stability, and explore potential changes over time. RESULTS: Among 21,538 patients, yearly incidence rates per 10,000 individuals were similar during the observation period for schizophrenia (2000: 1.8; 2018: 1.6), lower for schizoaffective disorder (2000: 0.3; 2018: 0.1) and increasing for schizotypal disorder (2000: 0.7; 2018: 1.3). Among the subgroup of 13,417 individuals with three separate treatment courses, early diagnostic stability was present among 89.9% which differed between the disorders (schizophrenia: 95.4%; schizotypal disorder: 78.0%; schizoaffective disorder: 80.5%). Among 1352 (10.1%) experiencing an early diagnostic transition, 398 (3.0%) were diagnosed with schizotypal disorder after a schizophrenia or schizoaffective disorder diagnosis. CONCLUSION: This study provides comprehensive incidence rates for SSDs. The majority of patients experienced early diagnostic stability, but sizable proportions of people with initial schizophrenia or schizoaffective disorder are subsequently diagnosed with schizotypal disorder.

Prenatal exposure to tap water containing nitrate and the risk of small-for-gestational-age: A nationwide register-based study of Danish births, 1991-2015.

BACKGROUND: Prenatal nitrate exposure from household tap water has been associated with increased risk of fetal growth restriction, preterm birth, birth defects, and childhood cancer. We aim to examine the association between maternal consumption of drinking-water nitrate during pregnancy and small-for-gestational-age (SGA) in a nationwide study of Danish-born children, as only one prior study has examined this association. METHODS: We linked individual-level household estimates of nitrate in tap water and birth registry data to all live singleton Danish births during 1991-2015 from Danish-born parents where the mother resided in Denmark throughout the pregnancy. Exposure was both binned into four categories and modeled as an ln-transformed continuous variable. SGA was defined as the bottom 10% of births by birth weight per sex and gestational week. Multiple logistic regression models with generalized estimating equations were used to account for siblings born to the same mother while controlling for relevant confounders. RESULTS: In the cohort of 1,078,892 births, the median pregnancy nitrate exposure was 1.9 mg/L nitrate. Compared to the reference group (≤2 mg/L), we found an increased risk of SGA in the second category (>2-5 mg/L) (OR = 1.04, 95% CI: 1.03-1.06) and third category (>5-25 mg/L) (OR = 1.02, 95% CI: 1.00-1.04) but not in the highest (>25 mg/L). There was strong (p = 0.002) evidence of an increase in SGA with nitrate in the model with continuous exposure (OR = 1.02, 95% CI: 1.01-1.04 per 10-fold increase in nitrate). Results were robust when restricting to households with nitrate levels at or below the current Danish and European Union regulatory drinking water standard (50 mg/L nitrate). CONCLUSIONS: Our findings suggest that exposure from nitrate in household tap water, even below current regulatory standards, may increase risk of SGA, raising concerns of whether current allowable nitrate levels in drinking water protect children from SGA.

Smoking is associated with infection risk in healthy blood donors.

OBJECTIVES: There is a gap in knowledge about the effects of smoking on overall infection risk in otherwise healthy populations, possibly leading to underestimation of the dangers of smoking. The present study aimed to examine the association of smoking with the risk of infections in a large cohort of healthy blood donors. METHODS: This cohort study used questionnaire and health register data from 127 831 Danish blood donors. Multivariable Cox proportional hazards analysis was applied to estimate the association of current smoking with the risk of all-cause infection defined as hospital-based treatment for infection or filled prescriptions of antimicrobials stratified for age and adjusted for relevant confounders. RESULTS: Among 18 272 current smokers, 12 272 filled an antimicrobial prescription and 2035 received hospital-based treatment for infections. Among 101 974 non-smokers, 65 117 filled a prescription and 8501 received hospital-based treatment for infections. Smokers had a higher risk of all-cause infection than non-smokers (hazard ratio estimates were 1.27 in males and 1.33 in females for hospital-based treatment and 1.11 in males and up to 1.20 in females for filled prescriptions). Smoking was most strongly associated with an increased incidence of respiratory tract infection, abscesses, skin infection, and prescriptions for these ailments (hazard ratio up to 2.29). Furthermore, smokers' risk of filled prescriptions of broad-spectrum penicillin was increased (hazard ratio up to 1.96). CONCLUSIONS: Current smoking was strongly associated with the risk of hospital-based treatment of infection and filled prescriptions of antimicrobials in a large cohort of healthy individuals. These findings warrant an increased focus on infectious disease risk among smokers.

PM2.5 air pollution components and mortality in Denmark.

BACKGROUND: Ambient fine particulate matter (PM2.5) causes millions of deaths every year worldwide. Identification of the most harmful types of PM2.5 would facilitate efficient prevention strategies. OBJECTIVES: The aim of this study was to investigate associations between components of PM2.5 and mortality in a nation-wide Danish population. METHODS: Our study base was Danes born 1921-1985 and aged 30-85 years, who were followed up for mortality from 1991 to 2015. We included 678,465 natural cause mortality cases and selected five age, sex and calendar time matched controls to each case from the study base. We retrieved the address history of the study population from Danish registries and assessed five-year average concentrations of eight PM2.5 components using deterministic Chemistry-Transport Models air pollution models. We estimated mortality rate ratios (MRRs) by conditional logistic regression and adjusted for socio-demographical factors at individual and neighborhood level. RESULTS: Single pollutant models showed the strongest associations between natural cause mortality and an interquartile increase in sulfate particles (SO4--) (MRR: 1.123; 95 % CI: 1.100-1.147 per 1.5 µg/m3) and secondary organic aerosol (SOA) (MRR: 1.054; 95 % CI: 1.048-1.061 per 0.050 µg/m3). Two-pollutant models showed robust associations between SO4-- and SOA and natural cause mortality. Elemental carbon and mineral dust showed robust associations with higher respiratory and lung cancer mortality. CONCLUSION: This nation-wide study found robust associations between natural cause mortality and SO4-- particles and SOA, which is in line with the results of previous studies. Elemental carbon and mineral dust showed robust associations with higher respiratory and lung cancer mortality.

Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

BACKGROUND: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark. METHODS: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions. RESULTS: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (ß = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15. CONCLUSIONS: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.

Lack of fit with the neighbourhood social environment as a risk factor for psychosis - a national cohort study.

BACKGROUND: Many studies report an ethnic density effect whereby psychosis incidence among ethnic minority groups is higher in low co-ethnic density areas. It is unclear whether an equivalent density effect applies with other types of socioeconomic disadvantages. METHODS: We followed a population cohort of 2 million native Danes comprising all those born on 1st January 1965, or later, living in Denmark on their 15th birthday. Socioeconomic disadvantage, based on parents' circumstances at age 15 (low income, manual occupation, single parent and unemployed), was measured alongside neighbourhood prevalence of these indices. RESULTS: Each indicator was associated with a higher incidence of non-affective psychosis which remained the same, or was slightly reduced, if neighbourhood levels of disadvantage were lower. For example, for individuals from a low-income background there was no difference in incidence for those living in areas where a low-income was least common [incidence rate ratio (IRR) 1.01; 95% confidence interval (CI) 0.93-1.10 v. those in the quintile where a low income was most common. Typically, differences associated with area-level disadvantage were the same whether or not cohort members had a disadvantaged background; for instance, for those from a manual occupation background, incidence was lower in the quintile where this was least v. most common (IRR 0.83; 95% CI 0.71-0.97), as it was for those from a non-manual background (IRR 0.77; 95% CI 0.67-0.87). CONCLUSION: We found little evidence for group density effects in contrast to previous ethnic density studies. Further research is needed with equivalent investigations in other countries to see if similar patterns are observed.

Genome-wide by Environment Interaction Study of Stressful Life Events and Hospital-Treated Depression in the iPSYCH2012 Sample.

Background: Researchers have long investigated a hypothesized interaction between genetic risk and stressful life events in the etiology of depression, but studies on the topic have yielded inconsistent results. Methods: We conducted a genome-wide by environment interaction study (GWEIS) in 18,532 patients with depression from hospital-based settings and 20,184 population controls. All individuals were drawn from the iPSYCH2012 case-cohort study, a nationally representative sample identified from Danish national registers. Information on stressful life events including family disruption, serious medical illness, death of a first-degree relative, parental disability, and child maltreatment was identified from the registers and operationalized as a time-varying count variable. Hazard ratios for main and interaction effects were estimated using Cox regressions weighted to accommodate the case-cohort design. Our replication sample included 22,880 depression cases and 50,378 controls from the UK Biobank. Results: The GWEIS in the iPSYCH2012 sample yielded three novel, genome-wide-significant (p < 5 × 10-8) loci located in the ABCC1 gene (rs56076205, p = 3.7 × 10-10), the AKAP6 gene (rs3784187, p = 1.2 × 10-8), and near the MFSD1 gene (rs340315, p = 4.5 × 10-8). No hits replicated in the UK Biobank (rs56076205: p = .87; rs3784187: p = .93; rs340315: p = .71). Conclusions: In this large, population-based GWEIS, we did not find any replicable hits for interaction. Future gene-by-stress research in depression should focus on establishing even larger collaborative GWEISs to attain sufficient power.

Postpartum depression: a developed and validated model predicting individual risk in new mothers.

Postpartum depression (PPD) is a serious condition associated with potentially tragic outcomes, and in an ideal world PPDs should be prevented. Risk prediction models have been developed in psychiatry estimating an individual's probability of developing a specific condition, and recently a few models have also emerged within the field of PPD research, although none are implemented in clinical care. For the present study we aimed to develop and validate a prediction model to assess individualized risk of PPD and provide a tentative template for individualized risk calculation offering opportunities for additional external validation of this tool. Danish population registers served as our data sources and PPD was defined as recorded contact to a psychiatric treatment facility (ICD-10 code DF32-33) or redeemed antidepressant prescriptions (ATC code N06A), resulting in a sample of 6,402 PPD cases (development sample) and 2,379 (validation sample). Candidate predictors covered background information including cohabitating status, age, education, and previous psychiatric episodes in index mother (Core model), additional variables related to pregnancy and childbirth (Extended model), and further health information about the mother and her family (Extended+ model). Results indicated our recalibrated Extended model with 14 variables achieved highest performance with satisfying calibration and discrimination. Previous psychiatric history, maternal age, low education, and hyperemesis gravidarum were the most important predictors. Moving forward, external validation of the model represents the next step, while considering who will benefit from preventive PPD interventions, as well as considering potential consequences from false positive and negative test results, defined through different threshold values.

Analysis of mortality metrics associated with a comprehensive range of disorders in Denmark, 2000 to 2018: A population-based cohort study.

BACKGROUND: The provision of different types of mortality metrics (e.g., mortality rate ratios [MRRs] and life expectancy) allows the research community to access a more informative set of health metrics. The aim of this study was to provide a panel of mortality metrics associated with a comprehensive range of disorders and to design a web page to visualize all results. METHODS AND FINDINGS: In a population-based cohort of all 7,378,598 persons living in Denmark at some point between 2000 and 2018, we identified individuals diagnosed at hospitals with 1,803 specific categories of disorders through the International Classification of Diseases-10th Revision (ICD-10) in the National Patient Register. Information on date and cause of death was obtained from the Registry of Causes of Death. For each of the disorders, a panel of epidemiological and mortality metrics was estimated, including incidence rates, age-of-onset distributions, MRRs, and differences in life expectancy (estimated as life years lost [LYLs]). Additionally, we examined models that adjusted for measures of air pollution to explore potential associations with MRRs. We focus on 39 general medical conditions to simplify the presentation of results, which cover 10 broad categories: circulatory, endocrine, pulmonary, gastrointestinal, urogenital, musculoskeletal, hematologic, mental, and neurologic conditions and cancer. A total of 3,676,694 males and 3,701,904 females were followed up for 101.7 million person-years. During the 19-year follow-up period, 1,034,273 persons (14.0%) died. For 37 of the 39 selected medical conditions, mortality rates were larger and life expectancy shorter compared to the Danish general population. For these 37 disorders, MRRs ranged from 1.09 (95% confidence interval [CI]: 1.09 to 1.10) for vision problems to 7.85 (7.77 to 7.93) for chronic liver disease, while LYLs ranged from 0.31 (0.14 to 0.47) years (approximately 16 weeks) for allergy to 17.05 (16.95 to 17.15) years for chronic liver disease. Adjustment for air pollution had very little impact on the estimates; however, a limitation of the study is the possibility that the association between the different disorders and mortality could be explained by other underlying factors associated with both the disorder and mortality. CONCLUSIONS: In this study, we show estimates of incidence, age of onset, age of death, and mortality metrics (both MRRs and LYLs) for a comprehensive range of disorders. The interactive data visualization site (https://nbepi.com/atlas) allows more fine-grained analysis of the link between a range of disorders and key mortality estimates.

Mortality Associated With Mental Disorders and Comorbid General Medical Conditions.

Importance: Premature mortality has been observed among people with mental disorders. Comorbid general medical conditions contribute substantially to this reduction in life expectancy. Objective: To provide an analysis of mortality associated with comorbidity between a broad range of mental disorders and general medical conditions. Design, Setting, and Participants: Population-based cohort study of 5 946 800 individuals born in Denmark from 1900 to 2015 and residing in the country at the start of follow-up (January 1, 2000, or their date of birth, whichever occurred later). Exposures: Danish health registers were used to identify people with mental disorders and general medical conditions. Main Outcomes and Measures: Considering pairs of mental disorders and general medical conditions, we calculated mortality rate ratios (MRRs) and differences in life expectancy (ie, life-years lost) to assess the association of mortality with both disorders of interest compared with the mental disorder of interest, the general medical condition of interest, and neither disorder of interest. Results: The study population comprised 2 961 397 males and 2 985 403 females, with a median (IQR) age of 32.0 years (7.3-52.9) at start of follow-up and 48.9 years (42.5-68.8) at the end. Based on all pairs of comorbid mental disorders and general medical conditions, the mean MRR compared with people without these conditions was 5.90 (median, 4.94; IQR, 3.80-7.30), and the mean reduction of life expectancy compared with the general population was 11.35 years (median, 11.08; range, 5.27-23.53; IQR, 8.22-13.72). The association with general medical condition comorbidity in those with mental disorders varied by general medical condition; for example, the addition of a neurological condition for each of the mental disorders was associated with a mean MRR of 1.22, whereas for cancer, the mean MRR for all mental disorders was 4.07. Conclusions and Relevance: In this study, shorter life expectancy was associated with comorbid mental disorders and general medical conditions compared with the entire population and also when compared with patients who had either mental disorders only or general medical conditions only. Prevention and early detection of comorbidities could reduce premature mortality in patients with mental disorders.

Nitrate in drinking water and risk of birth defects: Findings from a cohort study of over one million births in Denmark.

BACKGROUND: A few studies have reported an increased risk of birth defects (BD) with maternal exposure to nitrate in drinking water. We examined this association in a large cohort study with well-characterized exposure. METHODS: Danish singletons liveborn to Danish-born parents from 1991-2013 were identified using civil and patient registries (n=1,018,914). Exposure to nitrate was estimated using a spatial model based on national data linked with individual addresses. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. FINDINGS: In total, 33,182 cases of BD were identified. Nitrate concentrations were generally well below US and EU standards. We observed an exposure-response relationship (p=0·004) between nitrate during pregnancy and eye BD, and increased risk in the highest exposure group (≥25 mg/L nitrate) (OR: 1·29; 95% CI: 1·00, 1·66). An interaction was observed between maternal age and continuous nitrate exposure for nervous system BD (p<0·001) indicating an increased risk among mothers <25 years-of-age (OR for 10 mg/L (OR10): 1·20; 95% CI: 1·06, 1·35). An interaction (p<0.01) with maternal age and continuous nitrate exposure was also observed for ear, face, and neck BD indicating an increased risk among babies born to mothers <25 years-of-age (OR10: 1·35; 95% CI: 1·11, 1·66). There was evidence of an inverse exposure-response relationship for any, digestive system, female genital, and urinary BD. INTERPRETATION: Our study is the first to report an association between nitrate and eye BD and BD of the ear, face, and neck. It also provides support to prior reports of increased risk of nervous system BD. FUNDING: This study was supported by a grant from the United States National Institute of Environmental Health Sciences (R01 ES027823-01A1).

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.

Exposure to ambient air pollution during childhood and subsequent risk of self-harm: A national cohort study.

A growing body of evidence indicates that exposure to air pollution not only impacts on physical health but is also linked with a deterioration in mental health. We conducted the first study to investigate exposure to ambient particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) and nitrogen dioxide (NO2) during childhood and subsequent self-harm risk. The study cohort included persons born in Denmark between January 1, 1979 and December 31, 2006 (N = 1,424,670), with information on daily exposures to PM2.5 and NO2 at residence from birth to 10th birthday. Follow-up began from 10th birthday until first hospital-presenting self-harm episode, death, or December 31, 2016, whichever came first. Incidence rate ratios estimated by Poisson regression models revealed a dose relationship between increasing PM2.5 exposure and rising self-harm risk. Exposure to 17-19 µg/m3 of PM2.5 on average per day from birth to 10th birthday was associated with a 1.45 fold (95% CI 1.37-1.53) subsequently elevated self-harm risk compared with a mean daily exposure of <13 µg/m3, whilst those exposed to 19 µg/m3 or above on average per day had a 1.59 times (1.45-1.75) elevated risk. Higher mean daily exposure to NO2 during childhood was also linked with increased self-harm risk, but the dose-response relationship observed was less evident than for PM2.5. Covariate adjustment attenuated the associations, but risk remained independently elevated. Although causality cannot be assumed, these novel findings indicate a potential etiological involvement of ambient air pollution in the development of mental ill health.

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.

Exposure to nitrate from drinking water and the risk of childhood cancer in Denmark.

BACKGROUND: There is limited evidence that nitrate, a common contaminant in drinking water, increases the risk of childhood cancers. Our objective was to examine this association in Denmark. METHODS: We conducted a nationwide case-control study based on all singletons liveborn to Danish-born parents from 1991 to 2015 (N = 1,219,140) that included 596 leukemias, 180 lymphomas, and 310 central nervous system cancers (CNC) who were ≤15 years of age at diagnosis and were identified from the Danish Cancer Registry. Approximately 100 controls were randomly selected and matched to each case on date of birth and sex. Nitrate measurements in public water systems were linked with an address registry to estimate individual average nitrate concentrations during preconception, prenatal, and postnatal periods. Odd ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression controlling for the matching variables, and birth order, birthweight, urbanicity, maternal education, employment, income and smoking, and parental age. RESULTS: There was no evidence of an association of nitrate with leukemia or lymphoma. An association between CNC and the highest category of nitrate exposure (>25 mg/L nitrate) was observed for preconception (OR = 1.82, 95%CI:1.09 to 3.04), prenatal (OR = 1.65, 95%CI:0.97 to 2.81), and postnatal exposure (OR = 1.48, 95%CI:0.82 to 2.68) in fully adjusted models. There was also some evidence of an exposure-response in models of continuous nitrate exposure and CNC. CONCLUSIONS: Our findings provide some evidence that exposure to nitrate from drinking water may increase the risk of childhood CNC cancer, but not leukemia or lymphoma.

Prenatal Exposure to Nitrate from Drinking Water and Markers of Fetal Growth Restriction: A Population-Based Study of Nearly One Million Danish-Born Children.

BACKGROUND: High levels of nitrate (NO3-) in drinking water cause methemoglobinemia in infants; however, few studies have examined the potential effects of low-level exposure on fetal growth, and the results have been inconsistent. OBJECTIVES: We sought to assess the association between maternal exposure to nitrate in drinking water during pregnancy and offspring size at birth in a nationwide study of full-term (≥37 wk gestation) live-born singletons. METHODS: We estimated maternal nitrate exposure for 898,206 births in Denmark during 1991-2011 by linkage of individual home address(es) with nitrate data from the national monitoring database. Maternal address during pregnancy, infant size at birth [i.e., birth weight, low birth weight (LBW), body length, and birth head circumference] and covariates were compiled from the Danish Civil Registration System, the Danish Medical Birth Register, and The Integrated Database for Longitudinal Labor Market Research. Linear and logistic models with generalized estimating equations were used to account for multiple births to an individual. Nitrate exposure was modeled using five categories and as a log-transformed continuous variable. RESULTS: There was evidence of a decreasing trend in models for term birth weight using categorical or continuous measures of exposure. Modeling exposure continuously, a difference of -9.71 g (95% confidence interval: -14.60, -4.81) was predicted at 25 mg/L (half the value of the European Union drinking water standard) compared with 0 mg/L NO3-. Body length also decreased as nitrate concentrations increased in categorical and continuous models. There was little evidence of an association between NO3- and head circumference or LBW. DISCUSSION: Although the estimated effects were small, our findings for live singleton births to Danish-born parents suggest that maternal intake of nitrate from drinking water may reduce term birth weight and length, which are markers of intrauterine growth. However, there was little evidence for an association between nitrate and head circumference or LBW. Future studies in other populations and with data on dietary sources of nitrate are encouraged to confirm or refute these findings. https://doi.org/10.1289/EHP7331.

Risk of Early-Onset Depression Associated With Polygenic Liability, Parental Psychiatric History, and Socioeconomic Status.

Importance: Combining information on polygenic risk scores (PRSs) with other known risk factors could potentially improve the identification of risk of depression in the general population. However, to our knowledge, no study has estimated the association of PRS with the absolute risk of depression, and few have examined combinations of the PRS and other important risk factors, including parental history of psychiatric disorders and socioeconomic status (SES), in the identification of depression risk. Objective: To assess the individual and joint associations of PRS, parental history, and SES with relative and absolute risk of early-onset depression. Design, Setting, and Participants: This case-cohort study included participants from the iPSYCH2012 sample, a case-cohort sample of all singletons born in Denmark between May 1, 1981, and December 31, 2005. Hazard ratios (HRs) and absolute risks were estimated using Cox proportional hazards regression for case-cohort designs. Exposures: The PRS for depression; SES measured using maternal educational level, maternal marital status, and paternal employment; and parental history of psychiatric disorders (major depression, bipolar disorder, other mood or psychotic disorders, and other psychiatric diagnoses). Main Outcomes and Measures: Hospital-based diagnosis of depression from inpatient, outpatient, or emergency settings. Results: Participants included 17 098 patients with depression (11 748 [68.7%] female) and 18 582 (9429 [50.7%] male) individuals randomly selected from the base population. The PRS, parental history, and lower SES were all significantly associated with increased risk of depression, with HRs ranging from 1.32 (95% CI, 1.29-1.35) per 1-SD increase in PRS to 2.23 (95% CI, 1.81-2.64) for maternal history of mood or psychotic disorders. Fully adjusted models had similar effect sizes, suggesting that these risk factors do not confound one another. Absolute risk of depression by the age of 30 years differed substantially, depending on an individual's combination of risk factors, ranging from 1.0% (95% CI, 0.1%-2.0%) among men with high SES in the bottom 2% of the PRS distribution to 23.7% (95% CI, 16.6%-30.2%) among women in the top 2% of PRS distribution with a parental history of psychiatric disorders. Conclusions and Relevance: This study suggests that current PRSs for depression are not more likely to be associated with major depressive disorder than are other known risk factors; however, they may be useful for the identification of risk in conjunction with other risk factors.