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. ASD birth prevalence data were obtained from the International Collaboration for Autism Registry Epidemiology database, including children born in Denmark, Finland, Norway, Sweden, and Western Australia. Empirical mode decomposition and cosinor modeling were used to assess seasonality. We show seasonal variation in ASD births for the countries of Finland and Sweden. There was a modest increase in risk for children born in the fall and a modest decrease in risk for children born in the spring. Solar radiation levels around conception and the postnatal period were inversely correlated with seasonal trends in ASD risk. In the first multinational study of birth seasonality of ASD, there was evidence supporting the presence of seasonal trends in Finland and Sweden. The observations that risk was highest for fall births (i.e., conceived in the winter) and lowest for spring births (i.e., conceived in the summer), and sunlight levels during critical neurodevelopmental periods explained much of the seasonal trends, are consistent with the hypothesis that a seasonally fluctuating risk factor may influence risk of ASD.

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. Index persons were nonadopted singleton births born between 1984 and 2009 who were at least 2 years of age at the end of follow-up on December 31, 2011, had resided in Stockholm County for at least 2 years since birth, and could be linked to both biological parents. Data analysis was conducted from May 2017 to December 2018. Exposure: Mental and neurological diagnoses of relatives of the index persons. Main Outcomes and Measures: Diagnosis of ASD, with or without co-occurring ID, in the index persons. Results: The cohort included 567 436 index persons (291 191 [51.3%] male; mean [SD] age at the end of follow-up, 14.3 [7.5] years). The prevalence of ASD with and without ID was 0.4% and 1.5%, respectively. Positive family history of mental and neurological disorders was associated with higher odds of ASD in index persons; 6895 (63.1%) of index persons with ASD had a parent with history of mental and/or neurological disorders, compared with 252 454 (45.4%) of index persons without ASD. Family history of multiple disorders was associated with higher odds of ASD in index persons, including history of ASD (odds ratio among first-degree relatives for ASD with and without ID: 14.2, 9.0), intellectual disability (7.6, 2.3), attention-deficit/hyperactivity disorder (3.3, 4.7), obsessive compulsive disorder (1.9, 2.1), schizophrenia and other nonaffective psychotic disorders (2.1, 1.8), depression (1.4, 2.0), bipolar disorder (1.4, 2.2), personality disorder (2.1, 2.6), cerebral palsy (2.2, 1.5), and epilepsy (2.0, 1.3). The more closely related the affected family member was, the higher the odds was of ASD for the index person. ASD without intellectual disability was associated with more disorders compared to ASD with intellectual disability. ASD with intellectual disability exhibited a weaker familial association with other mental disorder diagnoses but a stronger familial association with some neurological diagnoses as compared to ASD without intellectual disability. Conclusions and Relevance: This study suggests that family history of mental and neurological disorders is associated with increased risk of ASD. The familial component of ASD etiology may differ by presence or absence of co-occurring ID.

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. Cases of ASD, ADHD, OCD, and TD/CT were identified in the Danish Psychiatric Central Register and the National Patient Register. Associations with parental age were modeled using a stratified Cox regression, allowing for changes in baseline diagnostic rates across time. RESULTS: Younger parental age was significantly associated with increased estimates of risk for ADHD and TD/CT, whereas older parental age was associated with ASD and OCD. Except for OCD, no evidence for differential effects of parental ages on male versus female offspring was observed. CONCLUSION: This study provides novel evidence for the association between age at parenthood and TD/CT and OCD and for the first time shows in a population-based sample that parental age confers differential risk rates for pediatric-onset psychiatric disorders. These results are consistent with a model of shared and unshared risk architecture for pediatric-onset neuropsychiatric conditions, highlighting unique contributions of maternal and paternal ages.

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. Subjects were monitored for an ASD diagnosis in their older siblings or cousins (exposure) and for their ASD diagnosis (outcome). The relative recurrence risk was estimated for different sibling and cousin pairs, for each site separately and combined, and by sex. RESULTS: During follow-up, 29,998 cases of ASD were observed among the 2,551,918 births used to estimate recurrence in ASD and 33,769 cases of childhood autism (CA) were observed among the 6,110,942 births used to estimate CA recurrence. Compared with the risk in unaffected families, there was an 8.4-fold increase in the risk of ASD following an older sibling with ASD and a 17.4-fold increase in the risk of CA following an older sibling with CA. A 2-fold increase in the risk for cousin recurrence was observed for the 2 disorders. There also was a significant difference in sibling ASD recurrence risk by sex. CONCLUSION: The present estimates of relative recurrence risks for ASD and CA will assist clinicians and families in understanding autism risk in the context of other families in their population. The observed variation by sex underlines the need to deepen the understanding of factors influencing ASD familial risk.

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. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population-based case-control and case-sibling pair studies. Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 × 10- 7. Seven CpGs showed differences at p < 1 × 10- 5 and 48 at 1 × 10- 4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD.

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. METHODS: We conducted a population-based case-control study in the Danish population using register linkage. Our study population consisted of 11,869 ASD cases and 48,046 controls born from 1993 through 2007. Cases were identified by ICD-10 codes in the Danish Psychiatric Central Register. ASD cases and controls were linked to parental Danish International Standard Classification of Occupations (DISCO-88) job codes. Parental occupational asthmagen exposure was estimated by linking DISCO-88 codes to an asthma-specific job-exposure matrix. RESULTS: Our maternal analyses included 6706 case mothers and 29,359 control mothers employed during the pregnancy period. We found a weak inverse association between ASD and any maternal occupational asthmagen exposure, adjusting for sociodemographic covariates (adjusted OR: 0.92, 95% CI: 0.86-0.99). In adjusted analyses, including 7647 cases and 31,947 controls with employed fathers, paternal occupational asthmagen exposure was not associated with ASD (adjusted OR: 0.98, 95% CI: 0.92-1.05). CONCLUSIONS: We found a weak inverse association between maternal occupational asthmagen exposure and ASD, and a null association between paternal occupational exposure and ASD. We suggest that unmeasured confounding negatively biased the estimate, but that this unmeasured confounding is likely not strong enough to bring the effect above the null. Overall, our results were consistent with no positive association between parental asthmagen exposure and ASD in the children.

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

Objective To determine whether reduced growth velocity (GV) in extremely low birth weight infants is preceded by elevated inflammatory cytokines. Study Design 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. Results Serum interleukin-6 (IL-6) was increased at days 14 and 21 in LOS infants. LOS was associated with reduced energy intake and GV for weight (weight-GV) at 36 weeks' PMA. Linear regression analysis controlling for LOS and energy intake showed significant relationships between increased IL-6 at days 14 and 21 with reduced weight-GV at 36 weeks' PMA (p < 0.0001). The relationship between day 21 IL-6 and weight-GV was not associated with LOS (p = 0.12) when controlling for BW and energy intake. Both BW (p = 0.02) and energy intake (p = 0.003) influenced the relationship between day 14 IL-6 and weight-GV. Conclusion IL-6 elevation during the first month of life is associated with lower weight-GV at 36 weeks' PMA and may have a direct effect upon energy balance and postnatal growth.

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. Asthmagen exposure was estimated from a published job-exposure matrix. The adjusted odds ratio for ASD comparing asthmagen-exposed to unexposed was 1.39 (95 % CI 0.96-2.02). Maternal workplace asthmagen exposure was not associated with ASD risk in this study, but this result does not exclude some involvement of maternal exposure to asthma-causing agents in ASD.

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]). Additional analyses examined the effect of maternal smoking on risk for TS/CT with other comorbid psychiatric conditions. RESULTS: In final adjusted analyses, heavy smoking was associated with a 66% increased risk for TS/CT (adjusted hazard ratio = 1.66, 95% CI = 1.17-2.35). In addition, heavy smoking was associated with a 2-fold increased risk for TS/CT with comorbid attention-deficit/hyperactivity disorder (ADHD), and both light and heavy smoking were associated with a more than 2-fold increased risk for TS/CT with any non-ADHD psychiatric comorbidity. Our parallel analyses of pediatric-onset OCD were likely underpowered but showed similar relationships. CONCLUSION: Prenatal maternal smoking was associated with increased risk for TS/CT as well as TS/CT with comorbid psychiatric conditions, even after adjustment for several important variables, including maternal psychiatric history, socioeconomic status, and partner smoking. Our findings point to a pathway linking prenatal tobacco exposure and altered brain development to TS/CT.

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. Study group classification was based on sampling source, prior diagnoses, and study screening tests and developmental evaluations. The child's primary caregiver provided demographic characteristics through a telephone (or occasionally face-to-face) interview. Groups were compared using ANOVA, chi-squared test, or multinomial logistic regression as appropriate. RESULTS: Of 2768 study children, sizeable proportions were born to mothers of non-White race (31.7%), Hispanic ethnicity (11.4%), and foreign birth (17.6%); 33.0% of households had incomes below the US median. The autism spectrum disorder and population control groups differed significantly on nearly all sociodemographic parameters. In contrast, the autism spectrum disorder and developmental delay or disorder groups had generally similar sociodemographic characteristics. CONCLUSIONS: SEED enrolled a sociodemographically diverse sample, which will allow further, in-depth exploration of sociodemographic differences between study groups and provide novel opportunities to explore sociodemographic influences on etiologic risk factor associations with autism spectrum disorder and phenotypic subtypes.

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. The data were collected from Danish longitudinal registers. A total of 3 million people born between 1955 and 2006 were followed up from January 1, 2002, through December 31, 2011. During this period, 27,236 people died. The data were analyzed primarily in June 2015. MAIN OUTCOMES AND MEASURES: We estimated mortality rate ratios (MRRs), adjusted for calendar year, age, sex, maternal and paternal age, place of residence at birth, and somatic comorbidities, to compare persons with OCT with persons without OCD. RESULTS: Of 10,155 persons with OCD (5935 women and 4220 men with a mean [SD] age of 29.1 [11.3] years who contributed a total of 54,937 person-years of observation), 110 (1.1%) died during the average follow-up of 9.7 years. The risk of death by natural or unnatural causes was significantly higher among persons with OCD (MRR, 1.68 [95% CI, 1.31-2.12] for natural causes; MRR, 2.61 [95% CI, 1.91-3.47] for unnatural causes) than among the general population. After the exclusion of persons with comorbid anxiety disorders, depression, or substance use disorders, OCD was still associated with increased mortality risk (MRR, 1.88 [95% CI, 1.27-2.67]). CONCLUSIONS AND RELEVANCE: The presence of OCD was associated with a significantly increased mortality risk. Comorbid anxiety disorders, depression, or substance use disorders further increased the risk. However, after adjusting for these and somatic comorbidities, we found that the mortality risk remained significantly increased among persons with OCD.

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. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal cohort study of children born in Denmark during the period from 1980 to 2010 who were alive at 1.5 years of age and followed up through 2013. This population-based sample of children (N = 1,912,904) was identified via linkage between the Danish Civil Registration Service and the Danish Medical Birth Register using a unique 10-digit identifier assigned to all live births and new residents in Denmark. Children were followed up for diagnoses of ASD (International Classification of Diseases, Eighth Revision [ICD-8] codes 299.00, 299.01, 299.02, and 299.03 and ICD-10 codes F84.0, F84.1, F84.5, F84.8, and F84.9) and other mental/behavioral disorders (ICD-8 codes 290-315 and ICD-10 codes F00-F99) in the Danish Psychiatric Central Research Register and for diagnoses of neurologic disorders (ICD-8 codes 320-359 and ICD-10 codes G00-G99) in the Danish National Patient Register. Data analysis was performed in December 2014. MAIN OUTCOMES AND MEASURES: Deaths and causes of death among cohort members were identified via the Danish Civil Registration Service and the Danish Cause of Death Register, respectively. Regressions analyses were performed using Cox regression. RESULTS: Of the 1,912,904 persons included in our study, 20,492 (1.1%) had ASD (15,901 [77.6%] were male). Of the 20,492 persons with ASD, 68 died (0.3%) (57 of 68 [83.8%] had comorbid mental/behavioral or neurologic disorders). The adjusted hazard ratio (aHR) for overall mortality was 2.0 (95% CI, 1.5-2.8) for ASD. The aHRs for ASD-associated mortality among cohort members who did not have neurologic (2.0 [95% CI, 1.4-3.0]) or other mental/behavioral disorders (1.7 [95% CI, 1.0-3.1]) were similar. The co-occurrence of ASD added no additional mortality risk for persons with neurologic (aHR, 0.7 [95% CI, 0.4-1.3]) or mental/behavioral disorders (aHR, 0.8 [95% CI, 0.5-1.2]) compared with persons with these disorders and no ASD. CONCLUSIONS AND RELEVANCE: The mortality risk was 2-fold higher through young adulthood for persons with ASD than for persons without ASD, although mortality affected only 0.3% of persons with ASD. The mechanisms underlying ASD-associated mortality may be mediated through or shared with neurologic or mental/behavioral disorders, thereby providing insights into their potential neurobiological links. Health care professionals and family members should recognize the importance of these disorders with regard to the mortality risk for 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. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3-5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure.

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. Analyses were adjusted for sex, age, calendar year, parental age and place at residence at time of birth. As measures of relative risk incidence rate ratios (IRR) and accompanying 95% confidence intervals (CIs) were employed. RESULTS: The risk of a comorbid diagnosis of OCD in individuals with autism spectrum disorder and aggregation of autism spectrum disorders in offspring of parents with OCD were increased. Individuals first diagnosed with autism spectrum disorders had a 2-fold higher risk of a later diagnosis of OCD (IRR = 2.18, 95% CI = 1.91-2.48), whereas individuals diagnosed with OCD displayed a nearly 4-fold higher risk to be diagnosed with autism spectrum disorders (IRR = 3.91, 95% CI = 3.46-4.40) later in life. The observed associations were somewhat stronger for less severe types of autism spectrum disorders without a comorbid diagnosis of mental disabilities. CONCLUSIONS: The high comorbidity, sequential risk, and shared familial risks between OCD and autism spectrum disorders are suggestive of partially shared etiological mechanisms. The results have implications for current gene-searching efforts and for clinical practice.

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. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). All measurements were evaluated as gestational age and sex specific z-scores and in z-score percentile groups, adjusted for potential confounders, and stratified on gestational age groups (<32, 32-36, 37-38, 39, 40, ≥ 41 weeks). RESULTS: We identified 503,784 singleton births, of which 983 were confirmed cases of CP. Head/ abdominal circumference ratio (aHR:1.12; 95%CI:1.07-1.16) and cephalization index (aHR:1.14; 95%CI:1.11-1.16) were associated with the risk of CP irrespective of gestational age. Birth weight-placental weight ratio was also associated with CP in the entire cohort (aHR:0.90; 95%CI:0.83-0.97). Ponderal index had a u-shaped association with CP, where both children with low and high ponderal index were at higher risk of CP. CONCLUSIONS: CP is associated with disproportions between birth weight, birth length, placental weight and head circumference suggesting pre and perinatal conditions contribute to fetal growth restriction in children with CP.

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. DESIGN, SETTING, AND PARTICIPANTS: We performed a population-based study of national health registries in Denmark, including all individuals (n = 1 741 271) born in Denmark from January 1, 1980, through December 31, 2007, and followed up through December 31, 2013. We identified those with TS/CT and/or OCD. MAIN OUTCOMES AND MEASURES: The prevalence of TS/CT and OCD and relative recurrence risk (RRR) for TS/CT or OCD among individuals with an oldest sibling or a parent diagnosed as having TS/CT or OCD compared with individuals without an affected oldest sibling or an affected parent. RESULTS: In this sample, 5596 individuals were diagnosed as having TS/CT; 6191, OCD; and 412, both disorders. The overall cohort prevalence of TS/CT was 0.42% (95% CI, 0.41%-0.43%) and of OCD, 0.84% (95% CI, 0.81%-0.87%). The mean sibling recurrence risk for TS/CT across all birth years was 9.88% (95% CI, 8.02%-12.16%) and for OCD, 4.01% (95% CI, 2.78%-5.76%). The sibling RRR for TS/CT was 18.63 (95% CI, 15.34-22.63). In contrast, the sibling RRR for OCD was 4.89 (95% CI, 3.45-6.93). The parent-offspring RRR for TS/CT was 61.02 (95% CI, 44.43-83.82), whereas the parent-offspring RRR for OCD was 6.25 (95% CI, 4.82-8.11). The sibling and parent-offspring cross-disorder risks were also significant, ranging from 3.20 (95% CI, 2.22-4.62) to 10.27 (95% CI, 5.17-20.39). CONCLUSIONS AND RELEVANCE: Tourette syndrome/CT and OCD cluster in families. The familial aggregation of TS/CT is profound and substantially higher than the familial aggregation for OCD. The recurrence risk estimates provide an important clinical framework for identifying individuals at risk and provide insights into the causes of these disorders.