Big data in autism research: Methodological challenges and solutions.

While the concept of big data has emerged over the past decade as a hot topic in nearly all areas of scientific inquiry, it has rarely been discussed in the context of autism research. In this commentary we describe aspects of big data that are relevant to autism research and methodological issues such as confounding and data error that can hamper scientific investigation. Although big data studies can have transformative impact, bigger is not always better, and big data require the same methodological considerations and interdisciplinary collaboration as "small data" to extract useful scientific insight.

Birth seasonality and risk of autism spectrum disorder.

Season of birth has been hypothesized to be a risk factor for autism spectrum disorder (ASD). However, the evidence has been mixed and limited due to methodological challenges. We examine ASD birth trends for 5,464,628 births across 5 countries.

Recurrence Risk of Autism in Siblings and Cousins: A Multinational, Population-Based Study.

Objective: Familial recurrence risk is an important population-level measure of the combined genetic and shared familial liability of autism spectrum disorder (ASD). Objectives were to estimate ASD recurrence risk among siblings and cousins by varying degree of relatedness and by sex.

Method: This is a population-based cohort study of livebirths from 1998 to 2007 in California, Denmark, Finland, Israel, Sweden and Western Australia followed through 2011 to 2015.

Parental Age and Differential Estimates of Risk for Neuropsychiatric Disorders: Findings From the Danish Birth Cohort.

Objective: Parental age at birth has been shown to affect the rates of a range of neurodevelopmental disorders, but the understanding of the mechanisms through which it mediates different outcomes is still lacking. A population-based cohort was used to assess differential effects of parental age on estimates of risk across pediatric-onset neuropsychiatric disorders: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and Tourette's disorder/chronic tic disorder (TD/CT).

Method: The study cohort included all singleton births in Denmark from 1980 through 2007 with full information on parental ages (N = 1,490,745) and was followed through December 31, 2013.

Family History of Mental and Neurological Disorders and Risk of Autism.

Importance: Familial aggregation of mental and neurological disorders is often observed in autism spectrum disorders (ASD), but reports have generally focused on single disorders and are limited to first-degree relatives.

Objectives: To examine family history of mental and neurological disorders among first- to fourth-degree relatives and risk of ASD with and without intellectual disability (ID) in index persons.

Design, Setting, And Participants: In this population-based cohort study, 567 436 index persons were identified from the Stockholm Youth Cohort, an ongoing longitudinal register-linkage cohort study of the total population aged 0 to 17 years residing in Stockholm County, Sweden.

Cumulative Incidence of Autism Into Adulthood for Birth Cohorts in Denmark, 1980-2012.

This Research Letter examines cumulative incidence on autism spectrum disorder in Denmark using nationwide registered diagnosis data from 1980 to 2012 and assesses whether prevalence was stabilized.

Case-control meta-analysis of blood DNA methylation and autism spectrum disorder.

Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes.

Prenatal antidepressant use and risk of autism.

Should be viewed through the kaleidoscope of possible causes of autism

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

Background: Environmental exposures and immune conditions during pregnancy could influence development of autism spectrum disorder (ASD) in offspring. However, few studies have examined immune-triggering exposures in relation to ASD. We evaluated the association between parental workplace exposures to risk factors for asthma ("asthmagens") and ASD.

Maternal Exposure to Occupational Asthmagens During Pregnancy and Autism Spectrum Disorder in the Study to Explore Early Development.

Maternal immune activity has been linked to children with autism spectrum disorder (ASD). We examined maternal occupational exposure to asthma-causing agents during pregnancy in relation to ASD risk. Our sample included 463 ASD cases and 710 general population controls from the Study to Explore Early Development whose mothers reported at least one job during pregnancy.

Prenatal Maternal Smoking and Increased Risk for Tourette Syndrome and Chronic Tic Disorders.

Objective: We assessed the role of prenatal maternal smoking in risk for Tourette syndrome and chronic tic disorder (TS/CT) and pediatric-onset obsessive-compulsive disorder (OCD).

Method: In an analysis of 73,073 singleton pregnancies from the Danish National Birth Cohort, we calculated incidence rates (IR) per 1,000 person-year for TS/CT and OCD. We then determined crude and adjusted hazard ratios and 95% CIs associated with prenatal maternal smoking, considering smoking as a dichotomous (yes/no) variable or a stratified variable (no smoking, light smoking, and heavy smoking [≥10 cigarettes/day]).

Early Elevation in Interleukin-6 is Associated with Reduced Growth in Extremely Low Birth Weight Infants.

 To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines.  GV was determined at 36 weeks' postmenstrual age (PMA) in 768 infants 401 to 1,000 g birth weight (BW). Association between blood cytokines measured through day of life 21 and GV was explored using linear regression models that adjusted for late-onset sepsis (LOS), BW, small for gestational age (SGA), gender, race, energy intake, and center.

Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder.

Background: The Study to Explore Early Development (SEED) is designed to enhance knowledge of autism spectrum disorder characteristics and etiologies.

Objective: This paper describes the demographic profile of enrolled families and examines sociodemographic differences between children with autism spectrum disorder and children with other developmental problems or who are typically developing.

Methods: This multi-site case-control study used health, education, and birth certificate records to identify and enroll children aged 2-5 years into one of three groups: 1) cases (children with autism spectrum disorder), 2) developmental delay or disorder controls, or 3) general population controls.

Mortality Among Persons With Obsessive-Compulsive Disorder in Denmark.

Importance: Several mental disorders have consistently been found to be associated with decreased life expectancy, but little is known about whether this is also the case for obsessive-compulsive disorder (OCD).

Objective: To determine whether persons who receive a diagnosis of OCD are at increased risk of death.

Design, Setting, And Participants: Using data from Danish registers, we conducted a nationwide prospective cohort study with 30 million person-years of follow-up.

Association of Psychiatric and Neurologic Comorbidity With Mortality Among Persons With Autism Spectrum Disorder in a Danish Population.

Importance: Increased mortality has been reported among persons with autism spectrum disorder (ASD), especially among those who also have the comorbid condition of epilepsy or intellectual disability. The effects of psychiatric and neurologic comorbidity on mortality among persons with ASD have not been rigorously examined in large, population-based studies.

Objective: To investigate the mortality patterns among persons with ASD overall and to assess the associations of comorbid mental, behavioral, and neurologic disorders with mortality among persons with ASD.

Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood.

Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified.

Obsessive-Compulsive Disorder and Autism Spectrum Disorders: Longitudinal and Offspring Risk.

Background: Despite substantial similarities and overlaps in the pathophysiology of obsessive-compulsive disorders (OCD) and autism spectrum disorders, little is known about the clinical and etiologic cohesion of these two disorders. We therefore aimed to determine the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders.

Methods: In a prospective study design we explored the effect of a prior diagnosis of OCD in patients and parents on the susceptibility to autism spectrum disorders and vice versa.

Disproportionate fetal growth and the risk for congenital cerebral palsy in singleton births.

Objective: To investigate the association between proportionality of fetal and placental growth measured at birth and the risk for congenital cerebral palsy (CP).

Study Design: We identified all live-born singletons born in Denmark between 1995 and 2003 and followed them from 1 year of age until December 31st, 2008. Information on four indices of fetal growth: ponderal index, head circumference/ abdominal circumference ratio, cephalization index and birth weight/ placenta weight ratio was collected.

Familial clustering of tic disorders and obsessive-compulsive disorder.

Importance: Tourette syndrome/chronic tic disorder (TS/CT) and obsessive-compulsive disorder (OCD) overlap in their phenomenological features and often co-occur in affected individuals and families. Understanding how these disorders cluster in families provides important clinical information and is an important step in understanding the causes of these disorders.

Objective: To determine familial recurrence for TS/CT and OCD using a national epidemiologic sample.

Explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices.

Importance: The prevalence of autism spectrum disorders (ASDs) has increased markedly in recent decades, which researchers have suggested could be caused in part by nonetiologic factors such as changes in diagnosis reporting practices. To our knowledge, no study has quantified the degree to which changes in reporting practices might explain this increase. Danish national health registries have undergone a change in diagnostic criteria in 1994 and the inclusion of outpatient contacts to health registries in 1995.

The increasing prevalence of reported diagnoses of childhood psychiatric disorders: a descriptive multinational comparison.

The objective of this study is to compare the time trend of reported diagnoses of autism spectrum disorder (ASD), hyperkinetic disorder, Tourette's syndrome, and obsessive-compulsive disorder across four countries after standardizing the study period, diagnostic codes used to define the conditions and statistical analyses across countries. We use a population-based cohort, including all live-born children in Denmark, Finland, Sweden and Western Australia, from January 1, 1990, through December 31, 2007 and followed through December 31, 2011. The main outcome measure is age-specific prevalence of diagnoses reported to population-based registry systems in each country.

Maternal infections during pregnancy and cerebral palsy: a population-based cohort study.

Background: Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child.

Methods: Liveborn singletons in Denmark between 1997 and 2003 were identified from the Danish National Birth Registry and followed from 1 year of life until 2008.

Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study.

Importance: To date, this is the first population-based study to examine the recurrence risk for autism spectrum disorders (ASDs), including time trends, and the first study to consider the ASDs recurrence risk for full- and half-siblings.

Objectives: To estimate the relative recurrence risk for ASDs in a Danish population, including recurrence in full- and half-siblings, and to examine time trends in ASDs relative to the recurrence risk.

Design, Setting, And Participants: Population-based cohort study in Denmark.