Arvid Sjölander

Medication for Attention Deficit–Hyperactivity Disorder and Criminality

BACKGROUND Attention deficit-hyperactivity disorder (ADHD) is a common disorder that has been associated with criminal behavior in some studies. Pharmacologic treatment is available for ADHD and may reduce the risk of criminality. METHODS Using Swedish national registers, we gathered information on 25,656 patients with a diagnosis of ADHD, their pharmacologic treatment, and subsequent criminal convictions in Sweden from 2006 through 2009. We used stratified Cox regression analyses to compare the rate of criminality while the patients were receiving ADHD medication, as compared with the rate for the same patients while not receiving medication. RESULTS As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime). CONCLUSIONS Among patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication. These findings raise the possibility that the use of medication reduces the risk of criminality among patients with ADHD. (Funded by the Swedish Research Council and others.).

Paternal age at childbearing and offspring psychiatric and academic morbidity

IMPORTANCE Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors. OBJECTIVE To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity. DESIGN, SETTING, AND PARTICIPANTS We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins. EXPOSURE Paternal age at childbearing. MAIN OUTCOMES AND MEASURES Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity. RESULTS In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings. CONCLUSIONS AND RELEVANCE Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

Serious Transport Accidents in Adults With Attention-Deficit/Hyperactivity Disorder and the Effect of Medication: A Population-Based Study

IMPORTANCE Studies have shown that attention-deficit/hyperactivity disorder (ADHD) is associated with transport accidents, but the magnitude of the association remains unclear. Most important, it is also unclear whether ADHD medication reduces this risk. OBJECTIVES To estimate the association between ADHD and the risk of serious transport accidents and to explore the extent to which ADHD medication influences this risk among patients with ADHD. DESIGN, SETTING, AND PARTICIPANTS In total, 17,408 patients with a diagnosis of ADHD were observed from January 1, 2006, through December 31, 2009, for serious transport accidents documented in Swedish national registers. The association between ADHD and accidents was estimated with Cox proportional hazards regression. To study the effect of ADHD medication, we used stratified Cox regression to compare the risk of accidents during the medication period with the risk during the nonmedication period within the same patients. MAIN OUTCOMES AND MEASURES Serious transport accident, identified as an emergency hospital visit or death due to transport accident. RESULTS Compared with individuals without ADHD, male patients with ADHD (adjusted hazard ratio, 1.47; 95% CI, 1.32-1.63) and female patients with ADHD (1.45; 1.24-1.71) had an increased risk of serious transport accidents. In male patients with ADHD, medication was associated with a 58% risk reduction (hazard ratio, 0.42; 95% CI, 0.23-0.75), but there was no statistically significant association in female patients. Estimates of the population-attributable fractions suggested that 41% to 49% of the accidents in male patients with ADHD could have been avoided if they had been receiving treatment during the entire follow-up. CONCLUSIONS AND RELEVANCE Attention-deficit/hyperactivity disorder is associated with an increased risk of serious transport accidents, and this risk seems to be possibly reduced by ADHD medication, at least among male patients. This should lead to increased awareness among clinicians and patients of the association between serious transport accidents and ADHD medication.

Ignoring the matching variables in cohort studies – when is it valid and why?

In observational studies of the effect of an exposure on an outcome, the exposure-outcome association is usually confounded by other causes of the outcome (potential confounders). One common method to increase efficiency is to match the study on potential confounders. Matched case-control studies are relatively common and well covered by the literature. Matched cohort studies are less common but do sometimes occur. It is often argued that it is valid to ignore the matching variables, in the analysis of matched cohort data. In this paper, we provide analyses delineating the scope and limits of this argument. We discuss why the argument does not carry over to effect estimation in matched case-control studies, although it does carry over to null-hypothesis testing. We also show how the argument does not extend to matched cohort studies when one adjusts for additional confounders in the analysis. Ignoring the matching variables can sometimes reduce variance, even though this is not guaranteed. We investigate the trade-off between bias and variance in deciding whether adjustment for matching factors is advisable.

Bounds on natural direct effects in the presence of confounded intermediate variables.

In epidemiological studies we often want to learn about the direct effect of an exposure on an outcome, i.e. the effect that is not relayed by a specific intermediate variable. In the literature, there are two common definitions of direct effects; controlled and natural. When the intermediate variable and the outcome have common causes, neither the controlled nor the natural direct effect is identified. Cai et al. (Biometrics 2007; 64(3):695-701) derived bounds for the controlled direct effect under a set of hierarchical assumptions. In this paper we derive bounds on the natural direct effect under the same assumptions.

Maternal pre-pregnancy body mass index and offspring attention deficit hyperactivity disorder: a population-based cohort study using a sibling-comparison design

BACKGROUND High maternal pre-pregnancy body mass index (BMI) is associated with increased risk of offspring attention deficit hyperactivity disorder (ADHD). However, the role of unmeasured familial confounding for this association remains unclear. METHODS We conducted a population-based cohort study via linkage of Swedish national and regional registers to investigate maternal pre-pregnancy BMI (underweight: BMI <18.5; overweight: 25≤ BMI <30; obesity: BMI ≥30) in relation to offspring ADHD. We followed 673 632 individuals born in Sweden between 1992 and 2000, with prospectively collected information on maternal pre-pregnancy BMI, until they received an ADHD diagnosis or ADHD medication, death, emigration or 31 December 2009. Hazard ratios (HRs) were estimated by Cox proportional hazards models. Stratified Cox proportional hazards models were applied to data on full siblings to control for unmeasured familial confounding. RESULTS At the population level, pre-pregnancy overweight/obesity was associated with increased risk of offspring ADHD (HR(overweight) = 1.23, 95% CI = 1.18-1.27, P = 0.01; HR(obesity) = 1.64, 95% CI = 1.57-1.73, P = 0.01), after adjustment for measured covariates. In full sibling comparisons, however, previously observed associations no longer remained (HR(overweight) = 0.98, 95% CI = 0.83-1.16, P = 0.82; HR(obesity) = 1.15, 95% CI = 0.85-1.56, P = 0.38). CONCLUSIONS The results suggested that the association between maternal pre-pregnancy overweight/obesity and offspring ADHD could be ascribed to unmeasured familial confounding.

Drug treatment for attention-deficit/hyperactivity disorder and suicidal behaviour: register based study

Objective To investigate the association between drug treatment for attention-deficit/hyperactivity disorder (ADHD) and risk of concomitant suicidal behaviour among patients with ADHD. Design Register based longitudinal study using within patient design. Setting Linkage of multiple national registers in Sweden. Participants 37 936 patients with ADHD born between 1960 and 1996 and followed from 2006 to 2009 for treatment status by ADHD drug treatment and suicide related events (suicide attempt and completed suicide). Main outcome measure Incidence rate of suicide related events during ADHD drug treatment periods compared with that during non-treatment periods. Results Among 37 936 patients with ADHD, 7019 suicide related events occurred during 150 721 person years of follow-up. At the population level, drug treatment of ADHD was associated with an increased rate of suicide related events (hazard ratio 1.31, 95% confidence interval 1.19 to 1.44). However, the within patient comparison showed a reverse association between ADHD drug treatment and rate of suicide related events (0.89, 0.79 to 1.00). Among stimulant users, a reduced within patient rate of suicide related events was seen during treatment periods (0.81, 0.70 to 0.94). Among non-stimulant/mixed users, no significantly increased within patient rate of suicide related events during non-stimulant treatment periods was seen (0.96, 0.72 to 1.30). Conclusions This study found no evidence for a positive association between the use of drug treatments for ADHD and the risk of concomitant suicidal behaviour among patients with ADHD. If anything, the results pointed to a potential protective effect of drugs for ADHD on suicidal behaviour, particularly for stimulant drugs. The study highlights the importance of using within patient designs to control for confounding in future pharmacoepidemiological studies.

Linkage disequilibrium mapping of CHEK2: Common variation and breast cancer risk

Background Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). Methods and Findings We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population—0.7% in cases and 0.4% in controls—with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99–5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population. Conclusions Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.

Physical Activity and Survival among Men Diagnosed with Prostate Cancer

Background: Few studies have investigated the association between post-diagnosis physical activity and mortality among men diagnosed with prostate cancer. The aim of this study was to investigate the effect of physical activity after a prostate cancer diagnosis on both overall and prostate cancer–specific mortality in a large cohort. Methods: Data from 4,623 men diagnosed with localized prostate cancer 1997–2002 and followed-up until 2012 were analyzed. HRs with 95% confidence intervals (CI) were estimated using Cox proportional hazards models to examine the association between post-diagnosis recreational MET-h/d, time spent walking/bicycling, performing household work or exercising, and time to overall and prostate cancer–specific death. All models were adjusted for potential confounders. Results: During the follow-up, 561 deaths of any cause and 194 deaths from prostate cancer occurred. Statistically significantly lower overall mortality rates were found among men engaged in ≥5 recreational MET-h/d (HR, 0.63; 95% CI, 0.52–0.77), walking/bicycling ≥20 min/d (HR, 0.70; 95% CI, 0.57–0.86), performing household work ≥1 h/d (HR, 0.71; 95% CI, 0.59–0.86), or exercising ≥1 h/wk (HR, 0.74; 95% CI, 0.61–0.90), compared with less active men within each activity type. For prostate cancer–specific mortality, statistically significantly lower mortality rates were seen among men walking/bicycling ≥20 min/d (HR, 0.61; 95% CI, 0.43–0.87) or exercising ≥1 h/wk (HR, 0.68; 95% CI, 0.48–0.94). Conclusions: Higher levels of physical activity were associated with reduced rates of overall and prostate cancer–specific mortality. Impact: Our study further strengthens previous results indicating beneficial effects of physical activity on survival among men with prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 57–64. ©2014 AACR.

ESR1 and EGF genetic variation in relation to breast cancer risk and survival

IntroductionOestrogen exposure is a central factor in the development of breast cancer. Oestrogen receptor alpha (ESR1) is the main mediator of oestrogen effect in breast epithelia and has also been shown to be activated by epidermal growth factor (EGF). We sought to determine if common genetic variation in the ESR1 and EGF genes affects breast cancer risk, tumour characteristics or breast cancer survival.MethodsWe genotyped 157 single nucleotide polymorphisms (SNPs) in ESR1 and 54 SNPs in EGF in 92 Swedish controls and selected haplotype tagging SNPs (tagSNPs) that could predict both single SNP and haplotype variation in the genes with an R2 of at least 0.8. The tagSNPs were genotyped in 1,590 breast cancer cases and 1,518 controls, and their association with breast cancer risk, tumour characteristics and survival were assessed using unconditional logistic regression models, Cox proportional hazard models and haplotype analysis.ResultsThe single tagSNP analysis did not reveal association evidence for breast cancer risk, tumour characteristics, or survival. A multi-locus analysis of five adjacent tagSNPs suggested a region in ESR1 (between rs3003925 and rs2144025) for association with breast cancer risk (p = 0.001), but the result did not withstand adjustment for multiple comparisons (p = 0.086). A similar region was also implicated by haplotype analyses, but its significance needs to be verified by follow-up analysis.ConclusionOur results do not support a strong association between common variants in the ESR1 and EGF genes and breast cancer risk, tumour characteristics or survival.