Bias amplification of unobserved confounding in pharmacoepidemiological studies using indication-based sampling.

PURPOSE: Estimating causal effects in observational pharmacoepidemiology is a challenging task, as it is often plagued by confounding by indication. Restricting the sample to those with an indication for drug use is a commonly performed procedure; indication-based sampling ensures that the exposed and unexposed are exchangeable on the indication-limiting the potential for confounding by indication. However, indication-based sampling has received little scrutiny, despite the hazards of exposure-related covariate control. METHODS: Using simulations of varying levels of confounding and applied examples we describe bias amplification under indication-based sampling. RESULTS: We demonstrate that indication-based sampling in the presence of unobserved confounding can give rise to bias amplification, a self-inflicted phenomenon where one inflates pre-existing bias through inappropriate covariate control. Additionally, we show that indication-based sampling generally leads to a greater net bias than alternative approaches, such as regression adjustment. Finally, we expand on how bias amplification should be reasoned about when distinct clinically relevant effects on the outcome among those with an indication exist (effect-heterogeneity). CONCLUSION: We conclude that studies using indication-based sampling should have robust justification - and that it should by no means be considered unbiased to adopt such approaches. As such, we suggest that future observational studies stay wary of bias amplification when considering drug indications.

Autism and self-harm: A population-based and discordant sibling study of young individuals.

OBJECTIVE: Self-harm among young autistic individuals is a clinical challenge, and the risk of premature death by suicide is strongly increased in this group. Using the advantage of total-population and family-based data, we investigated whether autism per se is a risk factor for self-harm independently of psychiatric comorbidities and how it differs from self-harm in non-autistic individuals. METHODS: We used The Stockholm Youth Cohort, a total-population register study, including all residents in Stockholm County aged 0-17 years between 2001 and 2011.Study participants were followed from age 10 to 27 for hospital admissions because of self-harm. We used modified Poisson regression to calculate relative risks (RR) using robust standard error to derive 95% confidence intervals (CI). RESULTS: In all, 410,732 individuals were included in the cohort (9,070 with a diagnosis of autism). Autistic individuals had a fivefold increased adjusted relative risk of self-harm (RR 5.0 [95% CI 4.4-5.6]). The risk increase was more pronounced for autism without intellectual disability and particularly high for self-cutting 10.2 [7.1-14.7] and more violent methods 8.9 [5.2-15.4]. The association between autism and self-harm was independent of, but clearly exacerbated by comorbid psychiatric conditions. It was of similar magnitude as risks linked to these conditions per se, and not explained by shared familial factors. CONCLUSION: Self-harm severe enough to present to medical services is as common in autistic youth as in those with depression or ADHD. Potentially more lethal methods are more likely to be used of autistic self-harmers.

HMG-CoA reductase inhibitors and COVID-19 mortality in Stockholm, Sweden: A registry-based cohort study.

BACKGROUND: The relationship between statin treatment and Coronavirus Disease 2019 (COVID-19) mortality has been discussed due to the pleiotropic effects of statins on coagulation and immune mechanisms. However, available observational studies are hampered by study design flaws, resulting in substantial heterogeneity and ambiguities. Here, we aim to determine the relationship between statin treatment and COVID-19 mortality. METHODS AND FINDINGS: This cohort study included all Stockholm residents aged 45 or older (N = 963,876), followed up from 1 March 2020 until 11 November 2020. The exposure was statin treatment initiated before the COVID-19-pandemic, defined as recorded statin dispensation in the Swedish Prescribed Drug Register between 1 March 2019 and 29 February 2020. COVID-19-specific mortality was ascertained from the Swedish Cause of Death Registry. Hazard ratios (HRs) were calculated using multivariable Cox regression models. We further performed a target trial emulation restricted to initiators of statins. In the cohort (51.6% female), 169,642 individuals (17.6%) were statin users. Statin users were older (71.0 versus 58.0 years), more likely to be male (53.3% versus 46.7%), more often diagnosed with comorbidities (for example, ischemic heart disease 23.3% versus 1.6%), more frequently on anticoagulant and antihypertensive treatments, less likely to have a university-level education (34.5% versus 45.4%), and more likely to have a low disposable income (20.6% versus 25.2%), but less likely to reside in crowded housing (6.1% versus 10.3%). A total of 2,545 individuals died from COVID-19 during follow-up, including 765 (0.5%) of the statin users and 1,780 (0.2%) of the nonusers. Statin treatment was associated with a lowered COVID-19 mortality (adjusted HR, 0.88; 95% CI, 0.79 to 0.97, P = 0.01), and this association did not vary appreciably across age groups, sexes, or COVID-19 risk groups. The confounder adjusted HR for statin treatment initiators was 0.78 (95% CI, 0.59 to 1.05, P = 0.10) in the emulated target trial. Limitations of this study include the observational design, reliance on dispensation data, and the inability to study specific drug regimens. CONCLUSIONS: Statin treatment had a modest negative association with COVID-19 mortality. While this finding needs confirmation from randomized clinical trials, it supports the continued use of statin treatment for medical prevention according to current recommendations also during the COVID-19 pandemic.

Migration and risk of intellectual disability with and without autism: A population-based cohort study.

OBJECTIVE: To investigate whether parental migration, parental region of origin, timing of child's birth in relation to maternal migration and parental reason for migration are associated with intellectual disability (ID) with and without autism. METHODS: We used a register-based cohort of all individuals aged 0-17 years in Stockholm County during 2001-2011. General estimating equation logistic model and additionally sibling comparison were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The models were adjusted for child's sex and birth year and parental age at child's birth, and additionally for migrant-specific variables in the analyses including only children with migrant parent(s). RESULTS: Within the eligible sample of 670,098 individuals, 3781 (0.6%) had ID with autism, and 5076 (0.8%) had ID without autism. Compared with children with Swedish-born parents, children with both parents born abroad had an increased risk of ID with autism (OR = 1.6, CI 1.5-1.8) and ID without autism (OR = 1.9, CI 1.7-2.0). Among these children with both parents born abroad, it was protective of ID with autism when the child's birth occurred before and later than four years after maternal migration, which was replicated in the sibling comparison. The associations with both conditions were more pronounced with parental origin in regions comprising low- and middle-income countries and with reasons other than work or study. CONCLUSIONS: Parental migration is associated with ID regardless of co-occurrence of autism. Our results indicate an association between environmental factors during pregnancy related to migration and offspring ID with autism, although further confirmative studies are needed.

No association between moist oral snuff (snus) use and oral cancer: pooled analysis of nine prospective observational studies.

Aims: Worldwide, smokeless-tobacco use is a major risk factor for oral cancer. Evidence regarding the particular association between Swedish snus use and oral cancer is, however, less clear. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between snus use and oral cancer. Methods: A total of 418,369 male participants from nine cohort studies were followed up for oral cancer incidence through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. Results: During 9,201,647 person-years of observation, 628 men developed oral cancer. Compared to never-snus use, ever-snus use was not associated with oral cancer (adjusted HR 0.90, 95% CI: 0.74, 1.09). There were no clear trends in risk with duration or intensity of snus use, although lower intensity use (⩽ 4 cans/week) was associated with a reduced risk (HR 0.65, 95% CI: 0.45, 0.94). Snus use was not associated with oral cancer among never smokers (HR 0.87, 95% CI: 0.57, 1.32). Conclusions: Swedish snus use does not appear to be implicated in the development of oral cancer in men.

Use of moist oral snuff (snus) and pancreatic cancer: Pooled analysis of nine prospective observational studies.

While smoking is a well-established risk factor for pancreatic cancer, the effect of smokeless tobacco is less well understood. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess the association between Swedish snus use and the risk of pancreatic cancer. A total of 424,152 male participants from nine cohort studies were followed up for risk of pancreatic cancer through linkage to health registers. We used shared frailty models with random effects at the study level, to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for confounding factors. During 9,276,054 person-years of observation, 1,447 men developed pancreatic cancer. Compared to never-snus use, current snus use was not associated with risk of pancreatic cancer (HR 0.96, 95% CI 0.83-1.11) after adjustment for smoking. Swedish snus use does not appear to be implicated in the development of pancreatic cancer in men. Tobacco smoke constituents other than nicotine or its metabolites may account for the relationship between smoking and pancreatic cancer.

Smokeless tobacco (snus) use and colorectal cancer incidence and survival: Results from nine pooled cohorts.

AIMS: Although smoking is considered to be an established risk factor for colorectal cancer, the current evidence on the association between smokeless tobacco and colorectal cancer is scant and inconclusive. We used pooled individual data from the Swedish Collaboration on Health Effects of Snus Use to assess this association. METHODS: A total of 417,872 male participants from nine cohort studies across Sweden were followed up for incidence of colorectal cancer and death. Outcomes were ascertained through linkage to health registers. We used shared frailty models with random effects at the study level to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During 7,135,504 person-years of observation, 4170 men developed colorectal cancer. There was no clear association between snus use and colorectal cancer overall. Exclusive current snus users, however, had an increased risk of rectal cancer (HR 1.40: 95% CI 1.09, 1.79). There were no statistically significant associations between snus use and either all-cause or colorectal cancer-specific mortality after colorectal cancer diagnosis. CONCLUSIONS: Our findings, from a large sample, do not support any strong relationships between snus use and colorectal cancer risk and survival among men. However, the observed increased risk of rectal cancer is noteworthy, and in merit of further attention.

Do overeducated individuals have increased risks of ill health?: a Swedish population-based cohort study.

Previous studies indicate that the increasing educational level in many post-industrial nations may imply that subgroups of the population work in occupations for which they are overeducated. We aimed to investigate whether overeducation is associated with future self-rated health and psychological distress. The analytical sample consisted of 21,159 participants from the Stockholm Public Health Cohort. Individuals with upper secondary or university education, who in 2006 or 2007 had occupations requiring less education, were considered overeducated. The outcomes were self-rated health (SRH) and psychological distress in 2010. Overeducated women had an increased risk of less than good SRH, compared to university-educated women in matching occupations (adjusted odds ratios (OR): 2.44 confidence intervals (CI): 1.32-4.51 for overeducated women with secondary school education), but not compared to less educated women in the same occupational class (adjusted OR: 0.87 CI:0.32-2.38 for overeducated women with secondary school education). We found no increased risk of less than good SRH for overeducated men, and no association between overeducation and psychological distress for either sex. The results indicate that overeducation is not per se associated with onset of less than good SRH or psychological distress in a short-term perspective, and the findings support education expansion as a means of improving public health.

Completion of Upper Secondary Mainstream School in Autistic Students in Sweden.

Higher education is an increasingly necessary achievement to attain employment. However, even in cases where a student has the academic skills to succeed, educational environments may not support students across all other domains necessary for education success, including social and communication needs. This is especially true for students with disabilities and autistic students, where the rate of completion of non-compulsory education is unknown. We used the Stockholm Youth Cohort (children aged 0-17 years from 2001 to 2011), a total population cohort (N = 736,180) including 3,918 autistic individuals, to investigate the association between autism without intellectual disability and completion of upper secondary education. We assessed the impact of sex and co-occurring Attention-Deficit/Hyperactivity Disorder (ADHD) on this association. By age 20 years (the expected age of completion), 68% of autistic students and 91% of non-autistic students admitted to upper secondary education had completed. In logistic regression models adjusted for student demographics, autistic students had almost five-fold higher odds of not completing secondary school (OR 4.90, 95% CI 4.56 5.26) compared to their non-autistic peers. Autistic students with ADHD had particularly high odds of non-completion of upper secondary school. Autistic students without intellectual disability attending mainstream education are substantially less likely to complete upper secondary education as compared to their peers. These findings have implications for the appraisal of how inclusive school policies serve autistic students' academic and social needs, ultimately addressing population health and independent living.

Migration and autism spectrum disorder: population-based study.

BACKGROUND: Migration has been implicated as a risk factor for autism, but evidence is limited and inconsistent. AIMS: To investigate the relationship between parental migration status and risk of autism spectrum disorder, taking into consideration the importance of region of origin, timing of migration and possible discrepancies in associations between autism subtypes. METHOD: Record-linkage study within the total child population of Stockholm County between 2001 and 2007. Individuals with high- and low-functioning autism were defined as having autism spectrum disorder with and without comorbid intellectual disability, and ascertained via health and habilitation service registers. RESULTS: In total, 4952 individuals with autism spectrum disorder were identified, comprising 2855 children with high-functioning autism and 2097 children with low-functioning autism. Children of migrant parents were at increased risk of low-functioning autism (odds ratio (OR) = 1.5, 95% CI 1.3-1.7); this risk was highest when parents migrated from regions with a low human development index, and peaked when migration occurred around pregnancy (OR = 2.3, 95% CI 1.7-3.0). A decreased risk of high-functioning autism was observed in children of migrant parents, regardless of area of origin or timing of migration. Parental age, income or obstetric complications did not fully explain any of these associations. CONCLUSIONS: Environmental factors associated with migration may contribute to the development of autism presenting with comorbid intellectual disability, especially when acting in utero. High- and low-functioning autism may have partly different aetiologies, and should be studied separately.

The age- and sex-specific occurrence of bothersome neck pain in the general population--results from the Stockholm public health cohort.

BACKGROUND: Neck pain is very common but the occurrence of bothersome neck pain is not well described. Therefore our objective was to report on the prevalence and incidence of, as well as the rate of recovery from, bothersome neck pain in men and women of different ages in the general population. METHODS: We used data from a recently conducted population-based cohort study, comprising 23,794 individuals in Stockholm County, Sweden. Study participants were surveyed with a self-administered questionnaire in 2002/2003 and 2007, and information on episodes of neck pain was gathered at baseline and at follow-up. We then measured bothersome neck pain in 2005 and 2006 retrospectively in 2007 using the follow-up questionnaire. RESULTS: The one-year prevalence of bothersome neck pain for at least seven consecutive days was 25% (95% confidence interval (CI): 24-25) among women and 16% (95% CI: 15-16) among men, peaking in individuals aged 30-59 years. The one-year incidence proportion of bothersome neck pain was 7% (95% CI: 6-7) among women, and 4% (95% CI: 4-5) among men. Women recovered more infrequently than men. The one-year incidence proportion of recovery (of at least one year duration) was 11% (95% CI: 10-12) among women and 14% (95% CI: 12-16) among men. CONCLUSION: Bothersome neck pain is most common in middle-aged individuals. Women are more likely than men to have and to develop bothersome neck pain, and less likely to recover from such pain. Younger men and women have a higher incidence, but recover more often from bothersome neck pain than older individuals.

Maternal smoking and smokeless tobacco use during pregnancy and offspring development: sibling analysis in an intergenerational Swedish cohort.

BACKGROUND: The association between maternal smoking in pregnancy and offspring intellectual disability (ID) is less well understood than that of smoking and fetal growth restriction. As fetal growth and cognitive development may share similar confounding structures, comparison of the two associations may improve understanding of the causal nature of the association with ID. Furthermore, comparisons of smoking with smokeless tobacco use may aid identification of mechanisms of action. METHODS: This was a cohort study of all Swedish births between 1999 and 2012 (n = 1 070 013), with prospectively recorded data. We assessed the association between maternal smoking during pregnancy and offspring outcomes ID and born small for gestational age (SGA). Analyses were repeated for snus use in pregnancy. Using a sibling design, we estimated within-family effects that control for shared sibling characteristics. RESULTS: Those exposed to maternal smoking in pregnancy had increased odds of ID [odds ratio (OR) = 1.24, 95% confidence interval (CI): 1.16-1.33] and SGA (OR = 2.19, 95% CI: 2.11-2.27) after confounder adjustment. Within-family effects were found for SGA (OR = 1.44, 95% CI: 1.27-1.63) but not ID (OR = 0.92, 95% CI: 0.74-1.14). For snus use, the results for ID were similar to smoking. We found increased odds of offspring SGA among mothers who used snus in pregnancy in sensitivity analyses but not in primary analyses. CONCLUSIONS: Our findings are consistent with a causal effect of maternal smoking in pregnancy on risk of offspring born SGA but not on risk of ID. We found no evidence for a causal effect of snus use in pregnancy on ID and inconclusive evidence for SGA.

Qualification for upper secondary education in individuals with autism without intellectual disability: Total population study, Stockholm, Sweden.

LAY ABSTRACT: Obtaining a quality education is important for any individual's chances of leading a healthy and thriving life. Currently, educational policies in many countries underscore the rights of students with autism to be educated in mainstream schools. While there is some knowledge on school outcomes among students with autism from older studies, little is known about rates of qualification for upper secondary education among children with autism in mainstream schools today. This lack of knowledge is problematic since autism is diagnosed more widely, and prior evidence may not be relevant for individuals with autism and their families today. Using Swedish registers, we therefore examined this in a study including all children and young people in Stockholm County in 2001 through 2011. We found that about two thirds of children with autism without intellectual disability qualified for upper secondary education at the expected age, in comparison with about nine in ten among typically developing peers. We also found that girls with autism had further difficulties obtaining such qualification than boys and that those who were additionally diagnosed with attention-deficit hyperactivity disorder were particularly at risk of non-qualification. Finally, students with autism without intellectual disability had a greater chance of completing compulsory education if given an extended period to graduate. These findings underline the need for supportive interventions for children with autism during compulsory school. They may also challenge the inclusive education policy adopted by majority of western countries, at least in the wake of addressing special needs in mainstream schooling.

Labour market position of young people and premature mortality in adult life: A 26-year follow-up of 569 528 Swedish 18 year-olds.

BACKGROUND: Throughout the industrialized world, demand for low skilled labour is falling. The length of schooling is increasing in response, but so is the proportion of individuals not finishing upper secondary school. The objective of this study was to evaluate the associations between labour market positions at age 18 and all-cause and suicide- and accident-specific mortality in later adulthood. METHODS: Labour market positions at age 18 were categorized for all Swedes born 1972-77 (n=630 959) into four main groups: employed, successful students, students not about to qualify (SNAQs), and individuals not in employment, education or training (NEETs). Cox proportional hazard models were fitted to assess all-cause, suicide and accident mortality up to 2016 (ages 39-44), adjusting for high school grades, parental and own prior psychiatric diagnoses, and childhood socioeconomic status. FINDINGS: SNAQs had substantially increased all-cause (men: HR=2.10; 95% CI 1.92-2.28, women: HR=1.64; 95% CI: 1.44-1.86), suicide (men: HR=2.16; CI: 1.86-2.51, women: HR=2.10; 95% CI 1.64-2.69), and accident specific (men: HR=2.08; 95% CI 1.77-2.44, women: 1.87; 95% CI 1.33;2.62) mortality risks compared to successful students. The risks were similar for NEETs. There was no increased risk among full-time employed compared to successful students. INTERPRETATION: Expanding the educational system may be a natural response to falling demand for low skilled labour but not by far one that corrects the major societal challenge of it. Unless educational systems adequately respond to this challenge, only more inequality is to be expected ahead. FUNDING: This work was supported by a grant to FR and AL from the Swedish Research Council for Health, Working Life, and Welfare with contract number (2014-2009).

Swedish snus use is associated with mortality: a pooled analysis of eight prospective studies.

BACKGROUND: The health consequences of the use of Swedish snus, including its relationship with mortality, have not been fully established. We investigated the relationship between snus use and all-cause and cause-specific mortality (death due to cardiovascular diseases, cancer diseases and all other reasons, respectively) in a nationwide collaborative pooling project. METHODS: We followed 169 103 never-smoking men from eight Swedish cohort studies, recruited in 1978-2010. Shared frailty models with random effects at the study level were used in order to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of mortality associated with snus use. RESULTS: Exclusive current snus users had an increased risk of all-cause mortality (aHR 1.28, 95% CI 1.20-1.35), cardiovascular mortality (aHR 1.27, 95% CI 1.15-1.41) and other cause mortality (aHR 1.37, 95% CI 1.24-1.52) compared with never-users of tobacco. The risk of cancer mortality was also increased (aHR 1.12, 95% CI 1.00-1.26). These mortality risks increased with duration of snus use, but not with weekly amount. CONCLUSIONS: Snus use among men is associated with increased all-cause mortality, cardiovascular mortality, with death from other causes and possibly with increased cancer mortality.

Persistent use of secondary preventive drugs declines rapidly during the first 2 years after stroke.

BACKGROUND AND PURPOSE: To prevent new cardiovascular events after stroke, prescribed preventive drugs should be used continuously. This study measures persistent use of preventive drugs after stroke and identifies factors associated with persistence. METHODS: A 1-year cohort (21,077 survivors) from Riks-Stroke, the Swedish Stroke Register, was linked to the Swedish Prescribed Drug Register. RESULTS: The proportion of patients who were persistent users of drugs prescribed at discharge from hospital declined progressively over the first 2 years to reach 74.2% for antihypertensive drugs, 56.1% for statins, 63.7% for antiplatelet drugs, and 45.0% for warfarin. For most drugs, advanced age, comorbidity, good self-perceived health, absence of low mood, acute treatment in a stroke unit, and institutional living at follow-up were independently associated with persistent medication use. CONCLUSIONS: Persistent secondary prevention treatment declines rapidly during the first 2 years after stroke, particularly for statins and warfarin. Effective interventions to improve persistent secondary prevention after stroke need to be developed.

Nationwide drug-dispensing data reveal important differences in adherence to drug label recommendations on CYP2D6-dependent drug interactions.

AIMS: The study aimed to investigate the clinical adherence to drug label recommendations on important drug-drug interactions (DDIs). Dispensing data on drug combinations involving selective serotonin reuptake inhibitor (SSRI) antidepressants could help to identify areas for intensified medical education. METHODS: This was a retrospective, cross-sectional analysis of individual dispensing data regarding all individuals > or =15 years old in Sweden. The study analysed the prescribing and dispensing of CYP2D6 drugs (metoprolol, donepezil, galantamine, codeine, tamoxifen) together with CYP2D6-blocking SSRIs (paroxetine/fluoxetine) or SSRIs without significant CYP2D6 inhibition (citalopram/escitalopram/sertraline), and the related prescribing of CYP2D6-independent comparator drugs (atenolol, rivastigmine, propoxyphene, anastrozole). Odds were calculated between each CYP2D6 drug and the corresponding comparator drug in patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline, respectively. The odds ratio (OR) was calculated by dividing the obtained odds in patients on fluoxetine/paroxetine by the corresponding odds in patients on citalopram/escitalopram/sertraline. RESULTS: Compared with patients that were dispensed citalopram/escitalopram/sertraline, patients dispensed fluoxetine/paroxetine had lower prescribing rates of metoprolol (adjusted OR 0.80; 95% confidence interval 0.76, 0.85), donepezil (0.65; 0.49, 0.86) and galantamine (0.58; 0.41, 0.81). In contrast, the use of prodrugs codeine (compared woth propoxyphene) or tamoxifen (compared with anastrozole) was similar among patients on fluoxetine/paroxetine and citalopram/escitalopram/sertraline (adjusted OR 1.03; 0.94, 1.12 and 1.29; 0.96, 1.73, respectively). CONCLUSIONS: Clinically important DDIs that are associated with impaired bioactivation of prodrugs might be more easily neglected in clinical practice compared with DDIs that cause drug accumulation and symptomatic adverse drug reactions.

Anxiety Disorders in Adults with Autism Spectrum Disorder: A Population-Based Study.

Anxiety is common in children with ASD; however, the burden of specific anxiety disorders for adults with ASD is under-researched. Using the Stockholm Youth Cohort, we compared anxiety disorder diagnoses among autistic adults (n = 4049), with or without intellectual disability, and population controls (n = 217,645). We conducted additional sibling analyses. Anxiety disorders were diagnosed in 20.1% of adults with ASD compared with 8.7% of controls (RR = 2.62 [95% CI 2.47-2.79]), with greatest risk for autistic people without intellectual disability. Rates of almost all individual anxiety disorders were raised, notably obsessive-compulsive disorder and phobic anxiety disorders. Anxiety disorders were more common in full siblings and half-siblings of people with ASD. The implications of this are explored.

Using Logistic Regression to Predict Onset and Recovery With Tau Equivalency.

Many studies analyze the effect of a predictor X on the onset or recovery of an outcome Y, for example some kind of disorder. The findings from this simulation study indicate that such effects can be found even if there are no changes in individuals' true scores on the outcome, i.e., with tau equivalency, given some degree of positive test-retest correlation of the outcome and a correlation between the predictor and the outcome at baseline. Researchers predicting onset/recovery should be aware of this fact and in order not to draw hasty conclusions to control for what can be expected from these correlations alone.

Association Between Autism Spectrum Disorders With or Without Intellectual Disability and Depression in Young Adulthood.

Importance: Depression is a frequently occurring mental disorder and may be common in adults with autism spectrum disorders (ASD), but there is a lack of longitudinal population-based studies examining this association. Whether any increased risk of depression in ASD has a shared familial basis and whether it differs by co-occurring intellectual disability is not well known. Objectives: To examine whether individuals with ASD are more likely to be diagnosed as having depression in adulthood than the general population and their nonautistic siblings and to investigate whether these risks differ by the presence or absence of intellectual disability. Design, Setting, and Participants: Population-based cohort study with a nested sibling comparison. The Stockholm Youth Cohort is a total population record linkage study that includes all children and young people (age range, 0-17 years) who were ever resident in Stockholm County, Sweden, between January 2001 and December 2011 (n = 735 096). Data analysis was conducted between January 5 and November 30, 2017, in Stockholm County, Sweden. Main Outcomes and Measures: Clinical diagnosis of depressive disorders was identified using the Stockholm County Adult Psychiatric Outpatient Register and the Swedish National Patient Register. Results: Participants were 223 842 individuals followed up to age 27 years by 2011, of whom 4073 had diagnosed ASD (mean [SD] age, 21.5 [2.7] years; 65.9% male; 2927 without intellectual disability and 1146 with intellectual disability) and 219 769 had no ASD (mean [SD] age, 22.1 [2.8] years; 50.9% male). By age 27 years, 19.8% (n = 808) of individuals diagnosed having ASD had a diagnosis of depression compared with 6.0% (n = 13 114) of the general population (adjusted relative risk [RR], 3.64; 95% CI, 3.41-3.88). The risk of a depression diagnosis was higher in ASD without intellectual disability (adjusted RR, 4.28; 95% CI, 4.00-4.58) than in ASD with intellectual disability (adjusted RR, 1.81; 95% CI, 1.51-2.17). Nonautistic full-siblings (adjusted RR, 1.37; 95% CI, 1.23-1.53) and half-siblings (adjusted RR, 1.42; 95% CI, 1.23-1.64) of individuals with ASD also had a higher risk of depression than the general population. Compared with their nonautistic full-siblings, individuals with ASD had more than a 2-fold risk of a depression diagnosis (adjusted odds ratio, 2.50; 95% CI, 1.91-3.27) in young adulthood. Conclusions and Relevance: According to this study's results, ASD, particularly ASD without intellectual disability, is associated with depression by young adulthood compared with the general population. It appears that this association is unlikely to be explained by shared familial liability. Future research to identify modifiable pathways between ASD and depression may assist in the development of preventive interventions.