Population-based Case-cohort Study Research Articles

Prediction of suicide attempts among persons with depression: a population-based case cohort study.

Studies have highlighted the potential importance of modeling interactions for suicide attempt prediction. This case-cohort study identified risk factors for suicide attempts among persons with depression in Denmark using statistical approaches that do (random forests) or do not (least absolute shrinkage and selection operator regression [LASSO]) model interactions. Cases made a nonfatal suicide attempt (n= 6032) between 1995 and 2015. The comparison subcohort was a 5% random sample of all persons in Denmark on January 1, 1995 (n= 11 963). We used random forests and LASSO for sex-stratified prediction of suicide attempts from demographic variables, psychiatric and somatic diagnoses, and treatments. Poisonings, psychiatric disorders, and medications were important predictors for both sexes. Area under the receiver-operating characteristic curve (AUC) values were higher in LASSO models (in men, 0.85, 95% CI, 0.84-0.86; in women, 0.89, 95% C, 0.88-0.90) than random forests (in men, 0.76, 95% CI, 0.74-0.78; in women, 0.79, 95% CI= 0.78-0.81). Automatic detection of interactions via random forests did not result in better model performance than LASSO models that did not model interactions. Due to the complex nature of psychiatric comorbidity and suicide, modeling interactions may not always be the optimal statistical approach to enhancing suicide attempt prediction in high-risk samples. This article is part of a Special Collection on Mental Health.

Influenza Vaccination Decreases The Risk Of Cardiovascular Disease In End Stage Renal Disease Patients.

Madam, Influenza is a viral respiratory tract infection that causes symptoms such as fever, sore throat, cough and runny nose with a mostly self-limiting prognosis. However, it can cause an increased risk of hospitalization and mortality in high-risk groups such as those suffering from end-stage renal disease (ESRD) [1]. CVD is present in >50% of cases of ESRD and is associated with a 20 times greater relative risk of death than in the general population, particularly with patients infected with influenza [2] [3]. This is due to the dysfunctional immunity in those affected by chronic kidney disease. The pathophysiology behind the influenza infection leading to CVD in ESRD patients is due to the rise of acute phase reactants in response to viral infection markers triggering a systemic inflammatory reaction. This reaction comprises damage to the endothelial cell lining of vessels, impaired vasodilation, dysfunctional platelet activation, and elevated pro-coagulation. In addition, the increased metabolic demand and altered coronary vascular tone can bring about disruption and instability of atherosclerotic plaques in coronary arteries, thus inducing an acute coronary syndrome. [1] Using influenza vaccine can significantly lower the risk of CVD in ESRD patients. Currently, available influenza vaccines include inactivated, recombinant, and live-attenuated (LAIVs).[4] Inactivated vaccines contain either surface glycoproteins such as hemagglutinin (HA) and neuraminidase (NA) or whole viral protein without the lipid envelope or chemically inactivated virus, whereas recombinant vaccines are composed of genetically synthesized HA subunits and LAIVs have the whole virus with weakened pathogenicity. These vaccines are produced as either trivalent (with both, influenza A subtypes H1N1 andH3N2 and dominant influenza B of either Yamagata or Victoria lineage) or quadrivalent (having both influenza B lineages) vaccines.[4] According to a population-based case-cohort study, annual influenza vaccinations have been seen to greatly reduce the hospitalisation rates for CVD in elderly patients with chronic kidney disease regardless of gender and influenza seasonality [5]. Moreover, it reduces the risk of CVD in patients with a hazard ratio of 0.74 for hospitalisation due to CVD among the vaccinated group compared to the non-vaccinated group, indicating a 26% lower risk and 35% reduction in overall mortality. [3] Therefore, the protective mechanism of influenza vaccination may be beneficial in reducing the risk of hospitalisations and morbidity in ESRD patients by reducing the likelihood of cardiovascular-associated complications. Thus, it should be incorporated as an integral part of the management of ESRD.

The genetic background of hydrocephalus in a population-based cohort: implication of ciliary involvement.

Hydrocephalus is one of the most common congenital disorders of the central nervous system and often displays psychiatric co-morbidities, in particular autism spectrum disorder. The disease mechanisms behind hydrocephalus are complex and not well understood, but some association with dysfunctional cilia in the brain ventricles and subarachnoid space has been indicated. A better understanding of the genetic aetiology of hydrocephalus, including the role of ciliopathies, may bring insights into a potentially shared genetic aetiology. In this population-based case-cohort study, we, for the first time, investigated variants of postulated hydrocephalus candidate genes. Using these data, we aimed to investigate potential involvement of the ciliome in hydrocephalus and describe genotype-phenotype associations with an autism spectrum disorder. One-hundred and twenty-one hydrocephalus candidate genes were screened in a whole-exome-sequenced sub-cohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research study, comprising 72 hydrocephalus patients and 4181 background population controls. Candidate genes containing high-impact variants of interest were systematically evaluated for their involvement in ciliary function and an autism spectrum disorder. The median age at diagnosis for the hydrocephalus patients was 0 years (range 0-27 years), the median age at analysis was 22 years (11-35 years), and 70.5% were males. The median age for controls was 18 years (range 11-26 years) and 53.3% were males. Fifty-two putative hydrocephalus-associated variants in 34 genes were identified in 42 patients (58.3%). In hydrocephalus cases, we found increased, but not significant, enrichment of high-impact protein altering variants (odds ratio 1.51, 95% confidence interval 0.92-2.51, P = 0.096), which was driven by a significant enrichment of rare protein truncating variants (odds ratio 2.71, 95% confidence interval 1.17-5.58, P = 0.011). Fourteen of the genes with high-impact variants are part of the ciliome, whereas another six genes affect cilia-dependent processes during neurogenesis. Furthermore, 15 of the 34 genes with high-impact variants and three of eight genes with protein truncating variants were associated with an autism spectrum disorder. Because symptoms of other diseases may be neglected or masked by the hydrocephalus-associated symptoms, we suggest that patients with congenital hydrocephalus undergo clinical genetic assessment with respect to ciliopathies and an autism spectrum disorder. Our results point to the significance of hydrocephalus as a ciliary disease in some cases. Future studies in brain ciliopathies may not only reveal new insights into hydrocephalus but also, brain disease in the broadest sense, given the essential role of cilia in neurodevelopment.

Development and validation of genome-wide polygenic risk scores for predicting breast cancer incidence in Japanese females: a population-based case-cohort study.

This study aimed to develop an ancestry-specific polygenic risk scores (PRSs) for the prediction of breast cancer events in Japanese females and validate it in a longitudinal cohort study. Using publicly available summary statistics of female breast cancer genome-wide association study (GWAS) of Japanese and European ancestries, we, respectively, developed 31 candidate genome-wide PRSs using pruning and thresholding (P + T) and LDpred methods with varying parameters. Among the candidate PRS models, the best model was selected using a case-cohort dataset (63 breast cancer cases and 2213 sub-cohorts of Japanese females during a median follow-up of 11.9years) according to the maximal predictive ability by Harrell's C-statistics. The best-performing PRS for each derivation GWAS was evaluated in another independent case-cohort dataset (260 breast cancer cases and 7845 sub-cohorts of Japanese females during a median follow-up of 16.9years). For the best PRS model involving 46,861 single nucleotide polymorphisms (SNPs; P + T method with PT = 0.05 and R2 = 0.2) derived from Japanese-ancestry GWAS, the Harrell's C-statistic was 0.598 ± 0.018 in the evaluation dataset. The age-adjusted hazard ratio for breast cancer in females with the highest PRS quintile compared with those in the lowest PRS quintile was 2.47 (95% confidence intervals, 1.64-3.70). The PRS constructed using Japanese-ancestry GWAS demonstrated better predictive performance for breast cancer in Japanese females than that using European-ancestry GWAS (Harrell's C-statistics 0.598 versus 0.586). This study developed a breast cancer PRS for Japanese females and demonstrated the usefulness of the PRS for breast cancer risk stratification.

Risk factors for stroke recurrence in patients with hemorrhagic stroke

The risk factors for recurrence of hemorrhagic or ischemic stroke in patients with intracranial hemorrhage (ICH) are inconclusive. This study was designed to investigate the risk factors for stroke recurrence and the impact of antiplatelet on stroke recurrence in patients with ICH. This population-based case-cohort study analyzed the data obtained from a randomized sample of 2 million subjects in the Taiwan National Health Insurance Research Database. The survival of patients with hemorrhagic stroke from January 1, 2000, to December 31, 2013, was included in the study. During the 5-year follow-up period, the recurrence rate of stroke was 13.1% (7.01% hemorrhagic stroke, and 6.12% ischemic stroke). The recurrence rate of stroke was 13.3% in the without antiplatelet group and 12.6% in the antiplatelet group. The risk factor for hemorrhagic stroke was hypertension (OR 1.87). The risk factors for ischemic stroke were age (OR 2.99), diabetes mellitus (OR 1.28), hypertension (OR 2.68), atrial fibrillation (OR 1.97), cardiovascular disease (OR 1.42), and ischemic stroke history (OR 1.68). Antiplatelet may decrease risk of hemorrhagic stroke (OR 0.53). The risk of stroke recurrence is high in patients with ICH. Hypertension is a risk factor for ischemic and hemorrhagic stroke recurrence. Antiplatelet therapy does not decrease risk of ischemic stroke recurrence but may reduce recurrence of hemorrhagic stroke.

Comparative effectiveness and stage-shift effect of endoscopic exam among newly diagnosed oral cancer patients with different stages in Taiwan.

Patients with oral cancer are at higher risk of developing second primary esophageal cancer (SPEC) and the consensus for screening strategies remains unclear. This study aimed to examine comparative effectiveness and the stage-shift effect of endoscopic exam among patients with oral cancer. A population-based longitudinal retrospective observational matched case and control cohort study with at least 5 years follow-up was conducted. We identified 45 457 newly diagnosed patients with oral cancer, 2004-2013, and the eligible patient with oral cancer was 39 401. Propensity score matching was used to match comparable groups, and the two groups (screening vs. nonscreening) was 5941, individually. The study primary endpoints were to compare detection of incident SPEC and the stage-shift effect of endoscopic screening between screened and nonscreened incident oral cancer patients. Cox proportional hazard and competing risk models were analyzed. Statistical analyses were conducted in 2020-2021. Detection of incident SPEC in the screened group was significantly higher than in the nonscreened group (hazard ratio: 2.92, 95% confidence interval [CI]: 2.29-3.72). The stage-shift effect from endoscopic screening was found overall in patients with oral cancer (odds ratio [OR]: 0.39, 95%CI: 0.21-0.70), in particular in advanced-stage patients (OR: 0.25, 95%CI: 0.11-0.61), but not in early-stage patients (OR: 0.60, 95%CI: 0.26-1.40). This study confirmed that endoscopic screening achieved early detection of SPEC among patients with oral cancer. To improve the screening stage-shift effect, patients with oral cancer are encouraged to undergo routine endoscopic screening.

Vitamin D Concentrations at Birth and the Risk of Rheumatoid Arthritis in Early Adulthood: A Danish Population-Based Case-Cohort Study.

Background: Low vitamin D in pregnancy may impair the development of the fetal immune system and influence the risk of later development of rheumatoid arthritis (RA) in the offspring. The aim was to examine whether lower 25-hydroxyvitamin D3 (25(OH)D) concentrations at birth were associated with the risk of developing RA in early adulthood. Methods: This case-cohort study obtained data from Danish registers and biobanks. Cases included all individuals born during 1981–1996 and recorded in the Danish National Patient Register with a diagnosis of RA with age >18 years at first admission. The random comparison consisted of a subset of Danish children. Vitamin D concentrations were measured in newborn dried blood. In total, 805 RA cases and 2416 individuals from the subcohort were included in the final analysis. Weighted Cox regression was used to calculate hazard ratio (HR). Results: The median (interquartile rage (IQR)) 25(OH)D concentrations among cases were 24.9 nmol/L (IQR:15.4;36.9) and 23.9 nmol/L (IQR:13.6;36.4) among the subcohort. There was no indication of a lower risk of RA among individuals in the highest vitamin D quintile compared with the lowest (HRadj.:1.21 (0.90;1.63)). Conclusion: The risk of RA in early adulthood was not associated with vitamin D concentrations at birth.

Plasma Angiopoietin-Like Protein 2 Levels and Mortality Risk Among Younger-Old Japanese People: A Population-Based Case-Cohort Study.

Aging is an important medical and social problem. Excessive angiopoietin-like protein (ANGPTL)-2 signaling causes chronic tissue inflammation, promoting development and progression of aging-related diseases. Moreover, circulating ANGPTL2 levels reportedly predict the risk of some aging-related diseases and subsequent death. However, there are, as yet, no reports of whether circulating ANGPTL2 levels predict vital prognosis in younger-old, community-dwelling populations. This study investigated associations between plasma ANGPTL2 levels and all-cause and specific-cause mortality in this population. The case-cohort study was abstracted from an ongoing, age-specific prospective cohort study: the New Integrated Suburban Seniority Investigation Project. This project enrolled 3 073 participants aged 64 years at the beginning of the investigation from 1996 through 2005. A subcohort of 714 randomly sampled participants plus 387 cases representing deceased participants followed through 2015 underwent survival analysis. Plasma ANGPTL2 concentrations were positively associated with >80% and 100% higher risk of all-cause mortality and cancer mortality, respectively, after adjustment for gender, smoking, alcohol consumption, walking time, sleep duration, caloric intake, medical status, disease history, BMI, and triglyceride, creatinine, uric acid, and high sensitivity C-reactive protein levels. A more robust association between ANGPTL2 levels and all-cause and cancer mortality was seen in participants with either frailties or with lifestyles of heavier drinking or current smoking. Elevated plasma ANGPTL2 levels are associated with high all-cause and cancer mortality in a community-dwelling sample of younger-old adults. These findings expand our knowledge of human aging and associated diseases.

The Joint Effects of Depression and Comorbid Psychiatric Disorders on Suicide Deaths: Competing Antagonism as an Explanation for Subadditivity.

Previous studies of the effect of interaction between psychiatric disorders on suicide have reported mixed results. We investigated the joint effect of depression and various comorbid psychiatric disorders on suicide. We conducted a population-based case-cohort study with all suicide deaths occurring between 1 January 1995 and 31 December 2015 in Denmark (n = 14,103) and a comparison subcohort comprised of a 5% random sample of the source population at baseline (n = 265,183). We quantified the joint effect of pairwise combinations of depression and major psychiatric disorders (e.g., organic disorders, substance use disorders, schizophrenia, bipolar disorder, neurotic disorders, eating disorders, personality disorders, intellectual disabilities, developmental disorders, and behavioral disorders) on suicide using marginal structural models and calculated the relative excess risk due to interaction. We assessed for the presence of competing antagonism for negative relative excess risk due to interactions. All combinations of depression and comorbid psychiatric disorders were associated with increased suicide risk. For example, the rate of suicide among men with depression and neurotic disorders was 20 times (95% CI = 15, 26) the rate in men with neither disorder. Most disorder combinations were associated with subadditive suicide risk, and there was evidence of competing antagonism in most of these cases. Subadditivity may be explained by competing antagonism. When both depression and a comorbid psychiatric disorder are present, they may compete to cause the outcome such that having 2 disorders may be no worse than having a single disorder with respect to suicide risk.

Comparing Copy Number Variations in a Danish Case Cohort of Individuals With Psychiatric Disorders

Although the association between several recurrent genomic copy number variants (CNVs) and mental disorders has been studied for more than a decade, unbiased, population-based estimates of the prevalence, disease risks and trajectories, fertility, and mortality to contrast chromosomal abnormalities and advance precision health care are lacking. To generate unbiased, population-based estimates of prevalence, disease risks and trajectories, fertility, and mortality of CNVs implicated in neuropsychiatric disorders. In a population-based case-cohort study, using the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) 2012 database, individuals born between May 1, 1981, and December 31, 2005, and followed up until December 31, 2012, were analyzed. All individuals (n = 57 377) with attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia (SCZ), autism spectrum disorder (ASD), or bipolar disorder (BPD) were included, as well as 30 000 individuals randomly drawn from the database. Data analysis was conducted from July 1, 2017, to September 7, 2021. Copy number variants at 6 genomic loci (1q21.1, 15q11.2, 15q13.3, 16p11.2, 17p12, and 17q12). Population-unbiased hazard ratio (HR) and survival estimates of CNV associations with the 5 ascertained psychiatric disorders, epilepsy, intellectual disability, selected somatic disorders, fertility, and mortality. Participants' age ranged from 1 to 32 years (mean, 12.0 [IQR, 6.9] years) during follow-up, and 38 662 were male (52.3%). Copy number variants broadly associated with an increased risk of autism spectrum disorder and ADHD, whereas risk estimates of SCZ for most CNVs were lower than previously reported. Comparison with previous studies suggests that the lower risk estimates are associated with a higher CNV prevalence in the general population than in control samples of most case-control studies. Significant risk of major depressive disorder (HR, 5.8; 95% CI, 1.5-22.2) and sex-specific risk of bipolar disorder (HR, 17; 95% CI, 1.5-189.3, in men only) were noted for the 1q21.1 deletion. Although CNVs at 1q21.1 and 15q13.3 were associated with increased risk across most diagnoses, the 17p12 deletion consistently conferred less risk of psychiatric disorders (HR 0.4-0.8), although none of the estimates differed significantly from the general population. Trajectory analyses noted that, although diagnostic risk profiles differed across loci, they were similar for deletions and duplications within each locus. Sex-stratified analyses suggest that pathogenicity of many CNVs may be modulated by sex. The findings of this study suggest that the iPSYCH population case cohort reveals broad disease risk for some of the studied CNVs and narrower risk for others, in addition to sex differential liability. This finding on genomic risk variants at the level of a population may be important for health care planning and clinical decision making, and thus the advancement of precision health care.

A Panel of 6 Biomarkers Significantly Improves the Prediction of Type 2 Diabetes in the MONICA/KORA Study Population.

ContextImproved strategies to identify persons at high risk of type 2 diabetes are important to target costly preventive efforts to those who will benefit most.ObjectiveThis work aimed to assess whether novel biomarkers improve the prediction of type 2 diabetes beyond noninvasive standard clinical risk factors alone or in combination with glycated hemoglobin A1c (HbA1c).MethodsWe used a population-based case-cohort study for discovery (689 incident cases and 1850 noncases) and an independent cohort study (262 incident cases, 2549 noncases) for validation. An L1-penalized (lasso) Cox model was used to select the most predictive set among 47 serum biomarkers from multiple etiological pathways. All variables available from the noninvasive German Diabetes Risk Score (GDRSadapted) were forced into the models. The C index and the category-free net reclassification index (cfNRI) were used to evaluate the predictive performance of the selected biomarkers beyond the GDRSadapted model (plus HbA1c).ResultsInterleukin-1 receptor antagonist, insulin-like growth factor binding protein 2, soluble E-selectin, decorin, adiponectin, and high-density lipoprotein cholesterol were selected as the most relevant biomarkers. The simultaneous addition of these 6 biomarkers significantly improved the predictive performance both in the discovery (C index [95% CI], 0.053 [0.039-0.066]; cfNRI [95% CI], 67.4% [57.3%-79.5%]) and the validation study (0.034 [0.019-0.053]; 48.4% [35.6%-60.8%]). Significant improvements by these biomarkers were also seen on top of the GDRSadapted model plus HbA1c in both studies.ConclusionThe addition of 6 biomarkers significantly improved the prediction of type 2 diabetes when added to a noninvasive clinical model or to a clinical model plus HbA1c.

Efficacy of aspirin, clopidogrel, and ticlopidine in stroke prevention: A population-based case-cohort study in Taiwan.

In real-world practice settings, there is insufficient evidence on the efficacy of antiplatelet drugs, including clopidogrel, aspirin, and ticlopidine, in stroke prevention. To compare the efficacies between aspirin and clopidogrel and aspirin and ticlopidine in stroke prevention. This population-based case-cohort study utilized the data obtained from a randomized sample of one million subjects in the Taiwan National Health Insurance Research Database. Patients who were hospitalized owing to the primary diagnosis of ischemic stroke from January 1, 2000 to December 31, 2010 and treated with aspirin, ticlopidine, or clopidogrel were included in the study. Propensity score matching with a 1:4 ratio was performed to compare aspirin with ticlopidine and clopidogrel. The criteria for inclusion were the use of one of the three antiplatelet drugs for more than 14 days within the first month after the stroke and then continued use of the antiplatelet drugs until the study endpoint of recurrent stroke. During the 3-year follow-up period, the recurrent stroke rates were 1.62% (42/2585), 1.48% (3/203), and 2.55% (8/314) in the aspirin, ticlopidine, and clopidogrel groups, respectively. Compared with the patients treated with aspirin, those treated with clopidogrel and ticlopidine showed competing risk-adjusted hazard ratios of recurrent stroke of 2.27 (1.02-5.07) and 0.62 (0.08-4.86), respectively. Compared with the patients treated with aspirin, those treated with clopidogrel were at a higher risk of recurrent stroke. For stroke prevention, aspirin was superior to clopidogrel whereas ticlopidine was not inferior to aspirin.

Adolescent residential mobility, genetic liability and risk of schizophrenia, bipolar disorder and major depression.

Residential mobility during upbringing, and especially adolescence, is associated with multiple negative mental health outcomes. However, whether associations are confounded by unmeasured familial factors, including genetic liability, is unclear. We used a population-based case-cohort study to assess whether polygenic risk scores (PRSs) for schizophrenia, bipolar disorder and major depression were associated with mobility from ages 10-14 years, and whether PRS and parental history of mental disorder together explained associations between mobility and each disorder. Information on cases (n = 4207 schizophrenia, n = 1402 bipolar disorder, n = 18 215 major depression) and a random population sample (n = 17 582), born 1981-1997, was linked between Danish civil and psychiatric registries. Genome-wide data were obtained from the Danish Neonatal Screening Biobank and PRSs were calculated based on results of separate, large meta-analyses. PRSs for schizophrenia and major depression were weakly associated with moving once (odds ratio 1.07, 95% CI 1.00-1.16; and odds ratio 1.10, 95% CI 1.04-1.17, respectively), but not twice or three or more times. Mobility was positively associated with each disorder, with more moves associated with greater risk. Adjustment for PRS produced slight reductions in the magnitude of associations. Adjustment for PRS and parental history of mental disorder together reduced estimates by 5-11%. In fully adjusted models mobility was associated with all three disorders; hazard ratios ranged from 1.33 (95% CI 1.08-1.62; one move and bipolar disorder) to 3.05 (95% CI 1.92-4.86; three or more moves and bipolar disorder). Associations of mobility with schizophrenia, bipolar disorder and depression do not appear to be attributable to genetic liability as measured here. Potential familial confounding of mobility associations may be predominantly environmental in nature.

Psychiatric morbidity and cervical cancer screening: a retrospective population-based case-cohort study.

Cervical cancer screening reduces disease-specific mortality. This study aimed to estimate whether bipolar disorder or schizophrenia is associated with disparities in cervical cancer screening rates. This was a retrospective population-based matched case-cohort study of community-dwelling women aged 19-69 in Ontario using linked health administrative databases. We used odds ratios (ORs), hazards ratios and rate ratios (RRs) adjusted for demographic characteristics and relevant comorbidities to compare cervical cancer screening outcomes between women with a diagnosis of bipolar disorder or schizophrenia to women without that history matched on key demographic characteristics, between 2003 and 2015. In total, 1 245 457 women were identified for inclusion in the analyses, 119 948 with a diagnosis of bipolar disorder or schizophrenia, and 1 125 509 without. Over a median follow-up duration of 12.5 years, women with the exposure were 36% less likely to be screened (OR 0.64, 95% confidence interval [CI] 0.64-0.65) than those without, and they took longer to undergo screening (median 18.98 mo v. 16.63 mo; χ2 = 3718.2, p < 0.001). They were also screened less frequently (median 6.16 yr v. 4.69 yr per screen; RR 0.85, 95% CI 0.84-0.85). These effects were consistent after we excluded the 86 475 women (6.9%) with suspected major depressive disorder, and they were larger for the 59 141 women (4.7%) not attached to a family physician. Women with bipolar disorder or schizophrenia were less likely to undergo cervical cancer screening, their screening was delayed, and they were screened at a lower rate compared to women without this psychiatric history. This practice gap suggests a need to further address barriers to screening, including access to a family physician, among women with bipolar disorder or schizophrenia.

Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics

Obesity exerts adverse effects on breast cancer survival, but the means have not been fully elucidated. We evaluated obesity as a contributor to breast cancer survival according to tumor molecular subtypes in a population-based case–cohort study using data from the Surveillance Epidemiology and End Results (SEER) program. We determined whether obese women were more likely to be diagnosed with poor prognosis tumor characteristics and quantified the contribution of obesity to survival. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated via Cox multivariate models. The effect of obesity on survival was evaluated among 859 incident breast cancers (subcohort; 15% random sample; median survival 7.8 years) and 697 deaths from breast cancer (cases; 100% sample). Obese women had a 1.7- and 1.8-fold increased risk of stage III/IV disease and grade 3/4 tumors, respectively. Obese women with Luminal A- and Luminal B-like breast cancer were 1.8 (95% CI 1.3–2.5) and 2.2 (95% CI 0.9–5.0) times more likely to die from their cancer compared to normal weight women. In mediation analyses, the proportion of excess mortality attributable to tumor characteristics was 36.1% overall and 41% and 38% for Luminal A- and Luminal B-like disease, respectively. Obesity was not associated with breast cancer-specific mortality among women who had Her2-overexpressing or triple-negative tumors. Obesity may influence hormone-positive breast cancer-specific mortality in part through fostering poor prognosis tumors. When tumor biology is considered as part of the causal pathway, the public health impact of obesity on breast cancer survival may be greater than previously estimated.

Effect of prothrombotic genotypes on the risk of venous thromboembolism in patients with and without ischemic stroke. The Tromsø Study

Essentials Prothrombotic genotypes may agument the risk of venous thromboembolism (VTE) after ischemic stroke. We studied this effect in a case-cohort study using a genetic risk score. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of VTE. The risk of VTE in stroke patients increased with an increasing number of risk alleles. SUMMARY: Background Patients with ischemic stroke have a transiently increased risk of subsequent venous thromboembolism (VTE). Prothrombotic genotypes may augment VTE risk under conditions of high thrombosis risk related to stroke. Aims To investigate the effect of prothrombotic genotypes in patients with ischemic stroke on the risk of VTE in a population-based case-cohort study. Methods Cases with incident VTE (n=664) and a randomly selected age-weighted subcohort (n=1817) were sampled from three surveys of the Tromsø Study (1994-2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914) single-nucleotide polymorphisms (SNPs). Cox regression models were used to calculate hazard ratios (HRs) for incident VTE according to individual SNPs and categories of risk alleles (5-SNP score; 0-1, 2, 3-4 and ≥5) in participants with and without ischemic stroke. Results There were 192 patients with incident stroke, of whom 43 developed VTE during a median of 15.2years of follow-up. The risk alleles of individual SNPs augmented the elevated VTE risk brought about by ischemic stroke. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of overall VTE (HR1.5, 95% confidence interval [CI]1.3-1.8) and an 80% higher relative risk of provoked VTE (HR1.8, 95%CI1.5-2.1). Stroke patients with ≥5 risk alleles had a 12-fold (HR11.7, 95%CI4.1-33.3) higher relative risk of VTE than stroke-free participantswith 0-1 risk alleles. Conclusions Prothrombotic genotypes increased the risk of VTE in stroke patients, and the risk increased with an increasing number of riskalleles.

Autism Spectrum Disorders in Catalonia, Spain: A New Population-Based Case-Cohort Study to Investigate Environmental Factors

Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by impaired social interaction, deficits in social communication and restricted, repetitive, and stereotyp...

In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring

ObjectivesIn utero exposure to antiepileptic drugs has previously been associated with adverse outcome among offspring, but evidence on longer term milestone development remains limited. We investigated the association between in...

Exposure to selective serotonin reuptake inhibitors in utero and early elementary school outcomes.

Data on special education in offspring exposed to selective serotonin reuptake inhibitors (SSRIs) in utero are lacking. We examined associations of in utero SSRI exposure with special education needs and delayed elementary school start. A population-based case-cohort study using Danish nationwide birth and prescription registry data from 2005 to 2008. Follow-up ends during 2011-2015 to capture special education needs during and delayed entry to the first elementary school year. Cases were in utero SSRI-exposed offspring. Cohort-controls were SSRI-unexposed offspring of mothers previously on SSRIs. We reported odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for relevant potential confounders. Of 117 475 first-incident non-multiple pregnancy births, 3314 were SSRI-exposed, and 3536 were unexposed. Among SSRI-exposed offspring, 3.2% (n = 98) had special school needs vs. 2.4% (n = 77) in unexposed offspring, P-value=0.048. Correspondingly, 12.3% (n = 383) among SSRI-exposed children had delayed school entry vs. 9.4% (n = 308) in unexposed offspring, P-value < 0.001. Adjusted OR for the association with special school needs was 1.12 (95% CI 0.82-1.55; P-value = 0.48) and 1.38 (95% CI 0.90-2.13; P-value = 0.14) for exposure in all three trimesters. The corresponding adjusted ORs for delayed school entry were 1.17 (95% CI 0.99-1.38; P-value = 0.073) and 1.40 (95% CI 1.11-1.76; P-value = 0.004). In utero SSRI exposure in all three trimesters was associated with delayed elementary school start but not special education needs.

Socioeconomic Status and Childhood Cancer Incidence: A Population-Based Multilevel Analysis.

The etiology of childhood cancers remains largely unknown, especially regarding environmental and behavioral risk factors. Unpacking the association between socioeconomic status (SES) and incidence may offer insight into such etiology. We tested associations between SES and childhood cancer incidence in a population-based case-cohort study (source cohort: Minnesota birth registry, 1989-2014). Cases, ages 0-14 years, were linked from the Minnesota Cancer Surveillance System to birth records through probabilistic record linkage. Controls were 4:1 frequency matched on birth year (2,947 cases and 11,907 controls). We tested associations of individual-level (maternal education) and neighborhood-level (census tract composite index) SES using logistic mixed models. In crude models, maternal education was positively associated with incidence of acute lymphoblastic leukemia (odds ratio (OR) = 1.10, 95% confidence interval (CI): 1.02, 1.19), central nervous system tumors (OR = 1.12, 95% CI: 1.04, 1.21), and neuroblastoma (OR = 1.15, 95% CI: 1.02, 1.30). Adjustment for established risk factors-including race/ethnicity, maternal age, and birth weight-substantially attenuated these positive associations. Similar patterns were observed for neighborhood-level SES. Conversely, higher maternal education was inversely associated with hepatoblastoma incidence (adjusted OR = 0.70, 95% CI: 0.51, 0.98). Overall, beyond the social patterning of established demographic and pregnancy-related exposures, SES is not strongly associated with childhood cancer incidence.